Compositions and methods for treating neurodegenerative diseases

Abstract

Provided herein are methods and compositions for treating neurodegenerative diseases using an agent of urolithin A and an agent of fisetin.

Description

[0001] Claiming priority

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 443,690, filed February 6, 2023, and U.S. Provisional Patent Application Serial No. 63 / 512,012, filed July 5, 2023, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0003] Neurodegenerative diseases of the central nervous system (CNS) cause progressive loss of neuronal structure and function, and are extremely devastating for affected patients and their families. While various medications are known or have been suggested for the treatment of neurodegenerative diseases, effective therapies are few or nonexistent. Therefore, there is a need for improved approaches to the treatment of neurodegenerative diseases. Summary of the Invention

[0004] This disclosure provides certain insights and techniques for the treatment and / or prevention of neurodegenerative diseases. Among other things, this disclosure provides certain combinations of agents that have unexpected and / or synergistic effects in the treatment and / or prevention of neurodegenerative diseases. This disclosure also identifies sources of problems with certain conventional or recommended strategies for the treatment and / or prevention of neurodegenerative diseases, such as a failure to understand the importance and / or benefits of certain combination therapies.

[0005] This disclosure specifically provides combinations of urolithin A and fisetin, and demonstrates the surprising characteristics of such combination therapy with urolithin A and fisetin in the treatment and / or prevention of neurodegenerative diseases. This disclosure further describes the usefulness of such combination therapy with urolithin A and fisetin when further combined with other agents.

[0006] In one aspect, this document provides a method for treating or preventing neurodegenerative diseases in a subject in need, the method comprising administering to the subject a therapeutically effective amount of urolithin A and a therapeutically effective amount of fisetinone. In some embodiments, this disclosure provides a method for reducing pathogenic microglial pro-inflammatory activation in a subject, the method comprising administering to the subject a therapeutically effective amount of urolithin A and a therapeutically effective amount of fisetinone. In some embodiments, this disclosure provides a method for promoting microglial Aβ clearance in a subject, the method comprising administering to the subject a therapeutically effective amount of urolithin A and a therapeutically effective amount of fisetinone. In some embodiments, this disclosure provides a method for reducing pathogenic microglial pro-inflammatory activation and promoting microglial Aβ clearance in a subject, the method comprising administering to the subject a therapeutically effective amount of urolithin A and a therapeutically effective amount of fisetinone.

[0007] In some embodiments, this disclosure provides methods for treating, preventing, or reducing neuroinflammation. In some embodiments, neuroinflammation may be caused by or related to neurodegenerative conditions (e.g., those described herein), other diseases, conditions, and illnesses (such as viral infections, autoimmune diseases, psychological stress (e.g., stress caused by overwork and lack of sleep), metabolic disorders, and damage), or aging. In some embodiments, neuroinflammation is caused by or related to a viral infection. In some embodiments, the viral infection is SARS-CoV-2 infection. In some embodiments, neuroinflammation is characterized by microglial cell activation in the subject.

[0008] In some embodiments, this disclosure provides methods for treating or preventing symptoms or features associated with neurodegenerative diseases. In some embodiments, the symptoms or features of neurodegenerative diseases are memory loss, cognitive decline, brain fog, increased Aβ plaque production, and / or increased Aβ plaque levels.

[0009] In some embodiments, this disclosure provides methods for treating or preventing brain fog. In some embodiments, brain fog is not related to any specific clinical disease, symptom, or condition. In some embodiments, brain fog is associated with sleep deprivation and stress. In some implementation schemes, neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, a polyglutamine expansion disorder, a trinucleotide repeat expansion disorder, Alexander's disease, Alpe's disease, ataxia-telangiectasia, Barten's disease, Canavan's disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, ischemic stroke, Krabby's disease, Lewy body dementia, multiple system atrophy, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Refsum's disease, and Sandhoff's disease. This includes diseases such as Schilder's disease, spinal cord injury, spinal muscular atrophy, progressive supranuclear palsy (Steele Richardson-Olszewski disease), or tabes dorsalis. In some embodiments, urolithin A and phenobarbital are administered simultaneously. In some embodiments, urolithin A and phenobarbital are administered separately. In some embodiments, urolithin A and phenobarbital are administered daily. In some embodiments, urolithin A and phenobarbital are administered once daily, twice daily, or three or more times daily. In some embodiments, the urolithin A is urolithin A. In some embodiments, the method includes administering urolithin A to the subject at a dose of about 1 mg to about 2500 mg. In some embodiments, urolithin A is administered to the subject at a dose of about 1 mg to about 1000 mg daily. In some embodiments, urolithin A is administered to the subject once daily. In some embodiments, the method includes administering urolithin A to the subject twice daily at a dose of about 300 mg to about 900 mg. In some embodiments, the fisetin agent is fisetin. In some embodiments, the method includes administering fisetin to the subject at a dose of about 0.5 mg to about 2500 mg. In some embodiments, fisetin is administered to the subject at a dose of about 1 mg to about 10 mg daily. In some embodiments, fisetin is administered to the subject once daily.In some embodiments, the method includes administering fisetin to the subject twice daily at a dose of about 1 mg to about 10 mg. In some embodiments, the method includes administering fisetin twice daily at a dose of about 2 mg to about 6 mg. In some embodiments, the subject has one or more symptoms associated with neurodegenerative diseases. In some embodiments, the subject is at risk of developing neurodegenerative diseases. In some embodiments, the method further includes determining, or having determined, that the subject is at risk of developing neurodegenerative diseases prior to administration. In some embodiments, the method further includes administering to the subject nicotinamide nucleoside or a pharmaceutically acceptable salt thereof, and one or both of cat's claw extract or components thereof.

[0010] In some embodiments, the method includes administering to a subject a therapeutically effective amount of a combination of urolithin A and a fisetin. In some embodiments, the method includes administering to a subject a therapeutically effective amount of a combination of urolithin A and a fisetin, wherein the urolithin A is urolithin A and the fisetin is fisetin. In some embodiments, the method includes administering to a subject a therapeutically effective amount of a combination of urolithin A and a fisetin, wherein the urolithin A is urolithin A and the fisetin is quercetin. In some embodiments, urolithin A is administered at a dose of about 1 mg to about 2500 mg daily. In some embodiments, fisetin is administered at a dose of about 1 mg to about 1000 mg daily. In some embodiments, quercetin is administered at a dose of about 1 mg to about 1000 mg daily.

[0011] In some embodiments, the method further includes administering nicotinamide nucleoside to the subject. In some embodiments, nicotinamide nucleoside is administered in an amount from about 1 mg to about 800 mg daily. In some embodiments, the method further includes administering quercetin to the subject. In some embodiments, quercetin is administered in an amount from about 1 mg to about 1000 mg. In some embodiments, the method further includes administering cat's claw extract to the subject. In some embodiments, cat's claw extract is administered in an amount from about 1 mg to about 1200 mg. In some embodiments, nicotinamide nucleoside is administered in an amount from about 100 mg to about 800 mg daily. In some embodiments, the method further includes administering quercetin to the subject. In some embodiments, quercetin is administered in an amount from about 50 mg to about 1000 mg. In some embodiments, the method further includes administering cat's claw extract to the subject. In some embodiments, cat's claw extract is administered in an amount from about 100 mg to about 1200 mg.

[0012] In some aspects, this document provides methods for treating or preventing neurodegenerative diseases in subjects in need, methods comprising administering to the subject a therapeutically effective amount of ellagitannin or ellagic acid and a therapeutically effective amount of fisetin. In some embodiments, the subject is a urolithin A producer. In some embodiments, the method further comprises determining, or having determined, that the subject is a urolithin A producer prior to administration. In some embodiments, the method comprises detecting, or having detected, one or more bacterial species associated with urolithin A production in a biological sample of the subject. In some embodiments, the bacterial species are *Gordonibacter urolithinfaciens* or *Ellagibacter isourolithinifaciens*. In some implementations, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, polyglutamine amplification syndrome, trinucleotide repeat amplification syndrome, Alexander disease, Alpert disease, ataxia-telangiectasia, Barten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, ischemic stroke, Crabb's disease, Lewy body dementia, multiple system atrophy, Peyre's disease, Pick's disease, primary lateral sclerosis, Rifsum disease, Sandhof's disease, Sheld's disease, spinal cord injury, spinal muscular atrophy, progressive supranuclear palsy, or tabes dorsalis. In some implementations, ellagitannins or ellagic acid and phenacetin are administered concurrently. In some implementations, ellagitannins or ellagic acid and phenacetin are administered separately. In some implementations, ellagitannins or ellagic acid and phenacetin are administered daily. In some embodiments, ellagitannin or ellagic acid and the fisetin agent are administered once daily, twice daily, or three or more times daily. In some embodiments, the fisetin agent is fisetin. In some embodiments, the method includes administering fisetin to the subject at a dose of about 0.5 mg to about 2500 mg. In some embodiments, fisetin is administered to the subject at a dose of about 1 mg to about 10 mg daily. In some embodiments, fisetin is administered to the subject once daily. In some embodiments, the method includes administering fisetin to the subject twice daily at a dose of about 1 mg to about 10 mg. In some embodiments, the method includes administering fisetin twice daily at a dose of about 2 mg to about 6 mg. In some embodiments, the fisetin agent is quercetin. In some embodiments, the method includes administering quercetin to the subject at a dose of about 0.5 mg to about 2500 mg. In some embodiments, quercetin is administered to the subject at a dose of about 1 mg to about 10 mg daily. In some implementation schemes, quercetin is administered to subjects once daily.In some embodiments, the method includes administering quercetin to a subject twice daily at a dose of about 1 mg to about 10 mg. In some embodiments, the method includes administering quercetin to a subject twice daily at a dose of about 2 mg to about 6 mg. In some embodiments, the subject has one or more symptoms associated with neurodegenerative diseases. In some embodiments, the subject is at risk of developing neurodegenerative diseases. In some embodiments, the method further includes determining, or having determined, that the subject has one or more symptoms associated with neurodegenerative diseases prior to administration. In some embodiments, the method further includes determining, or having determined, that the subject is at risk of developing neurodegenerative diseases prior to administration. In some embodiments, the method further includes administering to the subject nicotinamide nucleoside or a pharmaceutically acceptable salt thereof, and one or both of cat's claw extract or components thereof.

[0013] In some embodiments, the method includes administering to the subject a therapeutically effective amount of ellagitannin or a combination of ellagic acid and phenacetin. In some embodiments, the method further includes administering to the subject nicotinamide nucleoside. In some embodiments, nicotinamide nucleoside is administered in an amount from about 100 mg to about 800 mg daily. In some embodiments, the method further includes administering to the subject quercetin. In some embodiments, quercetin is administered in an amount from about 50 mg to about 1000 mg. In some embodiments, the method further includes administering cat's claw extract to the subject. In some embodiments, cat's claw extract is administered in an amount from about 100 mg to about 1200 mg.

[0014] In some aspects, this document provides methods for treating or preventing neurodegenerative diseases in subjects of need, methods comprising administering to the subject a therapeutically effective amount of ellagitannin or ellagic acid, a therapeutically effective amount of a fisetin agent, and a composition comprising one or more bacterial species associated with urolithin A production. In some embodiments, the bacterial species are *Gordonella urolithi* or *Turkestanella turgenei*. In some embodiments, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, polyglutamine amplification syndrome, trinucleotide repeat amplification syndrome, Alexander disease, Alpert disease, ataxia-telangiectasia, Barten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, ischemic stroke, Crabb's disease, Lewy body dementia, multiple system atrophy, Peyre's disease, Pick's disease, primary lateral sclerosis, Rifsum disease, Sandhof's disease, Sheld's disease, spinal cord injury, spinal muscular atrophy, progressive supranuclear palsy, or tabes dorsalis. In some embodiments, ellagitannins or ellagic acid, fisetin, and a composition containing one or more bacterial species are administered simultaneously. In some embodiments, ellagitannins or ellagic acid, fisetin, and a composition containing one or more bacterial species are administered separately. In some embodiments, ellagitannin or ellagic acid and fisetin are administered daily. In some embodiments, ellagitannin or ellagic acid and fisetin are administered once daily, twice daily, or three or more times daily. In some embodiments, the fisetin is fisetin. In some embodiments, the method includes administering fisetin to the subject at a dose of about 0.5 mg to about 2500 mg. In some embodiments, fisetin is administered to the subject at a dose of about 1 mg to about 10 mg daily. In some embodiments, fisetin is administered to the subject once daily. In some embodiments, the method includes administering fisetin to the subject twice daily at a dose of about 1 mg to about 10 mg. In some embodiments, the method includes administering fisetin twice daily at a dose of about 2 mg to about 6 mg. In some embodiments, the subject has one or more symptoms associated with neurodegenerative diseases. In some embodiments, the subject is at risk of developing neurodegenerative diseases. In some embodiments, the method further includes determining, or having determined, that the subject has one or more symptoms associated with neurodegenerative diseases prior to administration. In some embodiments, the method further includes determining, or having determined, that the subject is at risk of developing a neurodegenerative disease prior to administration. In some embodiments, the method further includes administering to the subject one or more agents selected from nicotinamide nucleosides or pharmaceutically acceptable salts thereof, or cat's claw extract or components thereof.In some embodiments, the method includes administering to a subject a therapeutically effective amount of ellagitannin or ellagic acid, fisetin, and a combination comprising one or more bacterial species associated with urolithiasis A production. In some embodiments, the method further includes administering to a subject nicotinamide nucleoside. In some embodiments, nicotinamide nucleoside is administered in an amount from about 100 mg to about 800 mg daily. In some embodiments, the method further includes administering to a subject quercetin. In some embodiments, quercetin is administered in an amount from about 50 mg to about 1000 mg. In some embodiments, the method further includes administering cat's claw extract to a subject. In some embodiments, cat's claw extract is administered in an amount from about 100 mg to about 1200 mg.

[0015] This article also provides combinations of one or more agents as disclosed herein for the treatment or prevention of neurodegenerative diseases in subjects in need, including, for example, urolithiasis A agents, fisetin agents, nicotinamide nucleoside or pharmaceutically acceptable salts thereof, and cat's claw extract or components thereof.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The methods and materials described herein are exemplary, and similar or equivalent methods and materials may be used in the practice or testing of this invention. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In case of conflict, this application (including definitions) shall prevail. Materials, methods, and examples are illustrative only and are not intended to be limiting.

[0017] Where a range of values ​​is provided, it should be understood that, unless the context explicitly specifies otherwise, every interval value between the upper and lower limits of the range (to one-tenth of the lower limit unit), as well as any other value or interval value within the range, is encompassed within this disclosure. The upper and lower limits of these smaller ranges may be independently included within the smaller range and are also encompassed within this disclosure, subject to any specifically excluded limits within the range. Where the range includes one or both of the limits, the range excluding any or both of the included limits is also included in this disclosure.

[0018] This article presents certain ranges where numerical values ​​are preceded by the term "approximately". The term "approximately" is used in this article to provide literal support for the exact number that follows it, as well as numbers that are close to or approximate to the number that follows the term. In determining whether a number is close to or approximates a specifically listed number, the unlisted number that is close to or approximates can be a number that is a fundamental equivalent of the specifically listed number in the context in which it is presented.

[0019] The term "alkyl" as used alone or as part of a larger part refers to having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3 or 1-2 carbon atoms (e.g., C12, C23, C14, C23, C2 ... 1-12 C 1-10 C 1-8 C 1-6 C 1-4 C 1-3 Or C 1-2 A saturated, optionally substituted straight-chain or branched hydrocarbon group. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0020] The term "alkenyl" used alone or as part of a larger part refers to having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C12, C23, C14, C23, C24, C25, C26, C26, C27, C28, C28, C29, C29, C29 2-12 C 2-10 C 2-8 C 2-6 C 2-4 Or C 2-3 Alkenes can be optionally substituted with straight-chain, branched, or cyclic hydrocarbon groups. Exemplary alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0021] The term "alkoxy" refers to the -O-alkyl group, including straight-chain, branched, cyclic, and combinations thereof with 1 to 8 carbon atoms attached to the parent structure via oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, and cyclohexyloxy.

[0022] The term "aryl" refers to an aryl group having a total of six to fourteen ring members (e.g., C6-C). 14 The system comprises optionally substituted monocyclic and bicyclic systems, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains three to seven ring members. In some embodiments, the "aryl" group contains a total of six to twelve ring members (e.g., C6-C1). 12 The term "aryl" may be used interchangeably with the term "aromatic ring." In some embodiments, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, and anthracene, which may have one or more substituents. Unless otherwise stated, the "aryl" group is a hydrocarbon. In some embodiments, the "aryl" ring system is an aromatic ring (e.g., phenyl) fused with a non-aromatic ring (e.g., cycloalkyl). Examples of aromatic rings include fused aromatic rings, including...

[0023] As used herein, the term "cycloalkyl" refers to a saturated cyclic monocyclic or polycyclic system with optional substitution of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0024] The term "halogen" or "halogenated" refers to F, Cl, Br, or I.

[0025] Other features and advantages of the invention will become apparent from the following detailed description and claims. Attached Figure Description

[0026] Figure 1 This is a graph demonstrating the dose-responsive increase in Aβ42 uptake via urolithin A in microglia BV2 cells, as measured by Aβ ELISA.

[0027] Figure 2A and Figure 2B The graphs show how TNFα dose-responsiveness is reduced by urolithiasis A and fenestrone, respectively. Figure 2A A graph showing the reduction in TNFα dose-responsiveness via urolithin A. Figure 2B This is a graph showing the reduction in TNFα dose-responsiveness caused by fisetin.

[0028] Figure 3 This demonstrates microglial Aβ42 uptake / clearance in response to co-treatment with urolithin A and ferrolithin, compared to fisetin alone.

[0029] Figure 4A and Figure 4B This study showed the toxicity and TNFα levels in BV2 microglia in response to treatment with urolithiasis A alone or in combination with fenestrone. Figure 4A The toxicity measured using LDL assay is shown. Figure 4B This shows the TNFα level as measured by ELISA.

[0030] Figure 5 The study showed the levels of TNFα secreted by BV2 microglia in response to different doses of urolithin A and fenestrone (alone or in combination).

[0031] Figures 6A to 6E The concentrations of TNFα after treatment with 20 μM nicotinamide nucleoside (#101), 34 μg / mL cat's claw herb (#134), 10 μM urolithin A (#144), 5 μM fisetin (NP-82), or 7.5 μM quercetin (NP-162) alone or in combination are shown.

[0032] Figures 7A to 7CThe concentrations of TNFα after treatment with 20 μM nicotinamide nucleoside (#101), 25 μg / mL cat's claw herb (#134), 20 μM urolithin A (#144), 10 μM fisetin (NP-82), or 7.5 μM quercetin (NP-162) alone or in combination are shown.

[0033] Figure 8 The toxicity of treatment with 20 μM nicotinamide nucleoside (#101), 40 μg / mL cat's claw herb (#134), 10 μM urolithin A (#144), 5 μM fisetin (NP-82), or 7.5 μM quercetin (NP-162) alone or in combination was shown.

[0034] Figure 9 The results show Aβ uptake after treatment alone or in combination with 20 μM nicotinamide nucleoside (#101), 40 μg / mL cat's claw herb (#134), 10 μM urolithin A (#144), 5 μM fisetin (NP-82), or 7.5 μM quercetin (NP-162).

[0035] Figure 10A The Aβ uptake was shown after treatment with 25 μg / mL or 40 μg / mL of cat's claw herb in water or DMSO. Figure 10B The Aβ uptake was shown after treatment with a combination of 25 μg / mL or 40 μg / mL of cat's claw herb (#134) in water and 25 μM or 40 μM of urolithin A (#144). Figure 10C The Aβ uptake was shown after treatment with a combination of 25 μg / mL or 40 μg / mL of cat's claw herb (#134) and urolithin A (#144) in DMSO.

[0036] Figure 11A The toxicity of treatment with 20 μM nicotinamide nucleoside (#101), 30 μg / mL cat's claw herb (#134), 20 μM urolithin A (#144), 10 μM fisetin (NP-82), or 7.5 μM quercetin (NP-162) alone or in combination was shown.

[0037] Figures 11B-11D The levels of TNFα are shown after treatment with 20 μM urolithin A (#144), 7.5 μM fisetin (NP-82), or 10 μM quercetin (NP-162) and 30 μg / mL cat's claw herb (#134), alone or in combination.

[0038] Figures 12A-12FThe levels of TNFα are shown after treatment with 30 μg / mL of cat's claw herb (#134), 20 μM of urolithin A (#144), 7 μM of fisetin (NP-82), or 10 μM of quercetin (NP-162), alone or in combination.

[0039] Figures 13A-13E The levels of TNFα are shown after treatment with 25 μM nicotinamide nucleoside (#101), 30 μg / mL cat's claw herb (#134), 20 μM urolithin A (#144), and 7 μM fisetin (NP-82), alone or in combination. Detailed Implementation

[0040] Neurodegenerative diseases occur when nerve cells in the brain or peripheral nervous system lose function and eventually die over time. Although several drugs are currently approved for treating neurodegenerative diseases, most of them only help with the associated symptoms. Neurodegenerative diseases such as Alzheimer's disease and dementia remain clinical problems for most older adults.

[0041] Amyloid-β (Aβ) plaque accumulation is considered one of the key drivers of the pathophysiology of Alzheimer's disease. Aβ clearance can be triggered by selectively activating microglia-mediated Aβ clearance. However, chronic and hyperresponsive microglia proliferation (the process of microglial expansion and activation) can also be detrimental in brain disorders such as Alzheimer's disease. For example, reactive microglia secrete pro-inflammatory cytokines that induce astrocyte proliferation and promote brain cell death in late Alzheimer's disease. Common anti-inflammatory drugs have been tested in Alzheimer's patients, but their efficacy in reducing reactive microglia proliferation has not yet been demonstrated.

[0042] The applicant has discovered that the combination of urolithin A and phenobarbital agents exhibits a synergistic effect in the treatment or prevention of neurodegenerative diseases in subjects of need. Surprisingly, the applicant has found that the combination of urolithin A and phenobarbital agents can simultaneously promote microglial Aβ clearance and reduce pathogenic microglial pro-inflammatory activation. The described combination therapy addresses issues associated with prior therapies (particularly the failure to achieve both promotion of microglial Aβ clearance and reduction of pathogenic microglial pro-inflammatory activation). The applicant has also found beneficial effects of nicotinamide nucleoside, quercetin, and cat's claw extract in promoting microglial Aβ clearance and reducing pathogenic microglial pro-inflammatory activation.

[0043] The applicant has surprisingly discovered that while each of the urolithin A agent or the fisetinone agent can individually provide some benefit in promoting microglial Aβ clearance or reducing pathogenic microglial pro-inflammatory activation, both effects are amplified in a manner exceeding simple additive when the two agents are combined. The effect of promoting microglial Aβ clearance can be illustrated by measuring Aβ concentrations in specific assays (e.g., those described in Examples 1 and 2). Furthermore, the effect of reducing pathogenic microglial pro-inflammatory activation can be illustrated by measuring TNFα concentrations in specific assays (e.g., those described in Examples 1 and 2). As illustrated in these examples, the applicant has demonstrated that this combination of agents is surprisingly synergistic, exhibiting an effect exceeding simple additive when comparing the effects of the urolithin A agent or the fisetinone agent on promoting microglial Aβ clearance or reducing pathogenic microglial pro-inflammatory activation, or on both.

[0044] Without being bound by theory, it should be understood that the synergistic effect of urolithiasis A and phenacetin agents, when used in combination to promote microglial Aβ clearance and reduce pathogenic microglial pro-inflammatory activation, can be used to treat neurodegenerative diseases, and particularly to achieve beneficial effects where other treatments to date have failed.

[0045] Therefore, this disclosure provides a method for treating or preventing (e.g., treating) neurodegenerative diseases, the method comprising administering to a subject a combination of a urolithiasis A agent and a fisetone agent.

[0046] In some embodiments, this disclosure provides methods for treating or preventing symptoms or features associated with neurodegenerative diseases. In some embodiments, the symptoms or features of neurodegenerative diseases are memory loss, cognitive decline, brain fog, increased Aβ plaque production, and / or increased Aβ plaque levels. In some embodiments, the symptom or feature of neurodegenerative diseases is memory loss. In some embodiments, the symptom or feature of neurodegenerative diseases is brain fog. In some embodiments, the symptom or feature of neurodegenerative diseases is increased Aβ plaque production. In some embodiments, the symptom or feature of neurodegenerative diseases is increased Aβ plaque levels.

[0047] In some embodiments, this disclosure provides methods for treating or preventing brain fog. In some embodiments, brain fog is not related to any specific clinical disease, symptom, or condition. In some embodiments, brain fog is associated with sleep deprivation and stress. Without wishing to be bound by any particular theory, this disclosure proposes combinations (e.g., those comprising and / or delivering urolithiasis A agents and fipronil agents, and optionally one or more other agents) that may be particularly useful and / or effective in reducing or improving brain fog. As described herein, brain fog can refer to confusion, forgetfulness, inattention, and unclear thinking, etc.

[0048] In some embodiments, this disclosure provides methods for treating, preventing, or reducing neuroinflammation. In some embodiments, neuroinflammation may be caused by or related to neurodegenerative conditions (e.g., those described herein), other diseases, conditions, and illnesses (such as viral infections, autoimmune diseases, psychological stress (e.g., stress caused by overwork and lack of sleep), metabolic disorders, and damage), or aging. In some embodiments, neuroinflammation is caused by or related to a viral infection. In some embodiments, the viral infection is SARS-CoV-2 infection. In some embodiments, neuroinflammation is characterized by microglial cell activation in the subject. In some embodiments, this disclosure provides methods for treating, preventing, or reducing neuroinflammation in a subject, the methods comprising administering to the subject a urolithiasis A agent and a fipronil agent. In some embodiments, this disclosure provides methods for treating, preventing, or reducing neuroinflammation in a subject, the methods comprising administering to the subject a combination of a urolithiasis A agent and a fipronil agent and one or more other components described herein.

[0049] This article also envisions methods for treating or preventing (e.g., treating) neurodegenerative diseases in subjects in need, methods comprising administering to the subject a combination of a urolithin A precursor (e.g., ellagitannin or ellagic acid) and a fisetone agent, wherein the methods may further comprise determining, or have been determined, that the subject is capable of metabolizing ellagitannin or ellagic acid into urolithin A.

[0050] This article also provides methods for treating or preventing (e.g., treating) neurodegenerative diseases in subjects in need, methods comprising administering to the subject ellagitannin or a combination of ellagic acid and fisetin, and one or more bacterial species associated with the production of urolithin A.

[0051] Urolithiasis A medication

[0052] Urolithiasis A agents can be used to treat or prevent (e.g., to treat) neurodegenerative diseases as disclosed herein.

[0053] In some embodiments, the urolithiasis A agent has the structure of Formula I:

[0054]

[0055] Or its pharmaceutically acceptable salt.

[0056] in:

[0057] R 1 Is it -H, -OH, or -OR? 4 ;

[0058] R 2 It is -H, -OH, -OR4 -NH2, -NHR 4 -SH, -SR 4 , -F, -Cl, -Br, -CN, -OCN, -O(CH2) n NH2, -O(CH2) n CH3、-C1-C 10 Alkyl, C3-C6 cycloalkyl, -C6-C 12 Aryl, -SOCH3, -SO2, -ONO2, -NO2, and -N3;

[0059] R 3 Is it -H, -OH, or -OR? 4 ;

[0060] R 5 Is it -H or -OR? 4 ;

[0061] R 4 It is C1-C 10 alkyl;

[0062] n is between 1 and 10,

[0063] Where R 2 Each alkyl, cycloalkyl, and aryl group may optionally be composed of one or more elements selected from halogens, C1-C2. 10 Alkyl, C3-C6 cycloalkyl and C6-C 12 Substituents of aryl groups.

[0064] In some implementations of Formula I, R 2 One example is -OH, R 2 Another example is -H,R 1 It is -H, and R 3 It is -OH.

[0065] In some implementations, the urolithin A agent is urolithin A or a pharmaceutically acceptable salt thereof.

[0066] Urolithin A (3,8-dihydroxy-6H-benzo[b,d]pyran-6-one) is produced, for example, as a metabolite of ellagitannins converted by intestinal bacteria. Ellagannins are hydrolyzed in the intestine to release ellagic acid, which is further processed by the intestinal microbiota into urolithin. Urolithin A has the following structure:

[0067]

[0068] Urolithin A is commercially available (see, for example, Sigma-Aldrich, SML 1791) and can also be obtained by methods known to those skilled in the art.

[0069] In some implementations, urolithin A is obtained from natural sources, including, for example, nuts, berries, and pomegranates, using conventional isolation methods.

[0070] In other embodiments, urolithin A is synthesized using conventional organic synthesis methods. For example, urolithin A can be prepared by combining the following starting materials and reagents in an alkaline aqueous solution: a copper-containing catalyst, 2-bromo-5-hydroxybenzoic acid, and resorcinol, which produces a salt of urolithin A, followed by protonation of this salt of urolithin A to produce urolithin A. (See, for example, WO2019168972).

[0071] In some embodiments, the urolithiasis A agent has the structure of formula Ia:

[0072]

[0073] Or its pharmaceutically acceptable salt.

[0074] Where R 2 Selected from -H, -OH, -OR 4 -NH2, -NHR 4 -SH, -SR 4 , -F, -Cl, -Br, -CN, -OCN, -O(CH2) n NH2, -O(CH2) n CH3、-C1-C 10 Alkyl, C3-C6 cycloalkyl, -C6-C 12 Aryl, -SOCH3, -SO2, -ONO2, -NO2, and -N3;

[0075] R 3 Is it OH or OR? 4 ;

[0076] R 4 It is RC1-C 10 alkyl;

[0077] n is 1-10; and

[0078] Where R 2 Each alkyl, cycloalkyl, and aryl group may optionally be composed of one or more elements selected from halogens, C1-C2. 10 Alkyl, C3-C6 cycloalkyl and C6-C 12 Substituents of aryl groups.

[0079] In some embodiments, the urolithin A agent is the urolithin A agent described in US2009 / 0326057 A1 (which is incorporated herein by reference in its entirety).

[0080] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof,

[0081] R 1 It is -H, -OH, or -OCH3;

[0082] R 2 It is -OH or -OCH3;

[0083] R 3 It is -H, -OH, or -OCH3; and

[0084] R 5 It is -H or -OCH3.

[0085] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 It is -H,R 2 It is -OH, R 3 It is -H, and R 5 Yes, it's -H.

[0086] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 It is -H,R 2 It is -OCH3, R 3 It is -H, and R 5 Yes, it's -H.

[0087] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 It is -OH, R 2 It is -OH, R 3 It is -H, and R 5 Yes, it's -H.

[0088] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 It is -OCH3, R 2 It is -OCH3, R 3 It is -H, and R 5 Yes, it's -H.

[0089] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 It is -H,R 2 It is -OH, R 3 It is -OH, and R 5 Yes, it's -H.

[0090] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 It is -H,R 2 It is -OCH3, R 3 It is -OCH3, and R 5Yes, it's -H.

[0091] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 It is -OH, R 2 It is -OH, R 3 It is -OCH3, and R 5 It is -OCH3.

[0092] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 It is -H,R 2 It is -OH, R 3 It is -OCH3, and R 5 Yes, it's -H.

[0093] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 It is -OH, R 2 It is -OH, R 3 It is -OH, and R 5 Yes, it's -H.

[0094] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 It is -OCH3, R 2 It is -OCH3, R 3 It is -OCH3, and R 5 Yes, it's -H.

[0095] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 It is -H,R 2 It is -OH, R 3 It is -OCH3, and R 5 It is -OCH3.

[0096] In certain embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 It is -OH, R 2 It is -OH, R 3 It is -OCH3, and R 5 Yes, it's -H.

[0097] In some embodiments, the urolithin A agent is the urolithin A agent described in Noshadi, B. et al., Chem. Biodiversity 2020, 17, e2000197 (which is incorporated herein by reference in its entirety).

[0098] In some implementations, urolithiasis A agents include, but are not limited to:

[0099] Having structure (8-hydroxy-6-oxo-6H-benzo[c]chromene-3-yl(tert-butoxycarbonyl)tryptophan ester), has the structure 6H-benzo[c]chromene-3,8-diol, 3-hydroxy-6H-benzo[c]chromene-6-one (=3-hydroxy-6H-dibenzo[b,d]pyran-6-one), 3-methoxy-6H-benzo[c]chromene-6-one (=3-methoxy-6H-dibenzo[b,d]pyran-6-one), 1,3-dihydroxy-6H-benzo[c]chromene-6-one (=1,3-dihydroxy-6H-dibenzo[b,d]pyran-6-one, 1,3 -Dimethoxy-6H-benzo[c]chromen-6-one (=1,3-dimethoxy-6H-dibenzo[b,d]pyran-6-one, 3,8-dimethoxy-6H-benzo[c]chromen-6-one (=3,8-dimethoxy-6H-dibenzo[b,d]pyran-6-one, 1,3-dihydroxy-8,9-dimethoxy-6H-benzo[c]chromen-6-one (=1,3-dihydroxy-8,9-dimethoxy-6H-dibenzo[b,d]pyran-6-one) 3-hydroxy-8-methoxy-6H-benzo[c]chromen-6-one (=3-hydroxy-8-methoxy-6H-dibenzo[b,d]pyran-6-one, 1,3,8-trihydroxy-6H-benzo[c]chromen-6-one (=1,3,8-trihydroxy-6H-dibenzo[b,d]pyran-6-one, 1,3,8-trimethoxy-6H-benzo[c]chromen-6-one (=1,3,8-trimethoxy-6H-dibenzo[b,d]pyran-6-one, 1,3,8-trimethoxy-6H-benzo[c]chromen-6-one (=1,3,8-trimethoxy-6H-dibenzo[b,d]pyran-6-one, 1,3,8-trimethoxy-6H-benzo[c]chromen-6-one (=1,3,8-trimethoxy-6H-dibenzo[b,d]pyran-6-one) d] Pyran-6-one, 3-hydroxy-8,9-dimethoxy-6H-benzo[c]chromene-6-one (=3-hydroxy-8,9-dimethoxy-6H-dibenzo[b,d]pyran-6-one, 1,3-dihydroxy-8-methoxy-6H-benzo[c]chromene-6-one (=1,3-dihydroxy-8-methoxy-6H-dibenzo[b,d]pyran-6-one, urolithin A-glucuronide, urolithin A-sulfate / ester and urolithin A-glycoside and methylated urolithin A.

[0100] In some embodiments, a urolithin A precursor or its analogue or metabolite may be used according to this disclosure. In some embodiments, this disclosure covers methods of delivering a urolithin A agent to a subject via a precursor, analogue, or metabolite. As used herein, the term "analyte" means a substance that shares one or more specific structural features, elements, components, or portions with a reference substance. Generally, an "analyte" exhibits significant structural similarity to a reference substance, such as sharing a parent nucleus or a consistent structure, but also differs in some individual aspects. In some embodiments, an analogue is a substance that can be produced from a reference substance, for example, through chemical manipulation of the reference substance. In some embodiments, an analogue is a substance that can be produced by performing a synthetic process substantially similar to that used to produce the reference substance (e.g., sharing multiple steps therewith). In some embodiments, an analogue is or can be produced by performing a synthetic process different from that used to produce the reference substance.

[0101] In some embodiments, the precursors of urolithin A include ellagitannins and ellagic acid. In some embodiments, analogues or metabolites of ellagitannins or ellagic acid may be useful according to this disclosure. Those skilled in the art will appreciate a wide variety of analogues or metabolites of ellagitannins or ellagic acid. Ellagannins that may be used in this disclosure may include monomeric ellagitannins, C-glycoside ellagitannins having an open-chain glucose core, condensates of C-glycoside tannins with flavan-3-ols (complex tannins), and oligomers formed by intermolecular CO or CC bonds between monomers. Exemplary ellagitannins include punicalagin, sanguiin H6, lambertianin C, pedunculagin, vescalagin, castalagin, casuarictin, and potentillin.

[0102] In some embodiments, one or more urolithin A precursors (e.g., ellagitannins or ellagic acid) or their analogues and metabolites are administered to a urolithin A producer, said urolithin A producer being an individual capable of metabolizing ellagitannins or ellagic acid into urolithin A. For example, some individuals are capable of producing urolithin A via their gut bacteria, while others may also produce isourolithin A and urolithin B. Bacterial species associated with urolithin A production are known in the art. For example, bacterial species belonging to the order Clostridium and family Ruminococcus are known to exhibit increased abundance in urolithin A producers, as well as *Gordonella urolithogene*, *Turtanobacterium tumefaciens*, and *Akkermansia muciniphilia*. Therefore, this disclosure also provides a method comprising administering ellagitannins and / or ellagic acid to a subject, said method further comprising determining, or having determined, that the subject is a urolithin A producer. By analyzing the gut microbiota of subjects through blood, urine, or fecal samples and detecting one or more bacterial species associated with urolithin A production, subjects can be identified as urolithin A producers.

[0103] Fesedon

[0104] Fesedon agents can be used to treat or prevent (e.g., to treat) neurodegenerative diseases as disclosed herein.

[0105] In some embodiments, the fisetin agent has the structure of Formula II:

[0106]

[0107] Or its pharmaceutically acceptable salt.

[0108] in:

[0109] R 7 It consists of H, CF3, OCH3, Cl, and Br;

[0110] R 8 It is H, CF3, OH, OCH3, F, Cl, Br, or tert-butyl (t-Bu);

[0111] R 9 It is H, CF3, Cl, Br, OH, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkyl, or SCF3;

[0112] R 10 It is H, CF3, C1-C6 alkoxy, C3-C6 cycloalkyl, or C1-C6 alkyl;

[0113] R 11It is H or NO2;

[0114] R 12 It is H, CH3, OH, OCH3, Cl, or Br;

[0115] R 13 It is H, CH3, F, Cl or Br; and

[0116] R 14 It is H or OH.

[0117] In certain embodiments of the compound of formula II or its pharmaceutically acceptable salt,

[0118] R 7 It consists of H, CF3, OCH3, Cl, and Br;

[0119] R 8 It is H, CF3, OH, OCH3, F, Cl, Br, or tert-butyl (t-Bu);

[0120] R 9 It is H, CF3, Cl, Br, OH, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkyl, or SCF3;

[0121] R 10 It is H, CF3, C1-C6 alkoxy, C3-C6 cycloalkyl, or C1-C6 alkyl;

[0122] R 11 It is H or NO2;

[0123] R 12 It is H, CH3, OH, OCH3, Cl, or Br;

[0124] R 13 It is H, CH3, F, Cl or Br; and

[0125] R 14 It is H or OH.

[0126] In some implementations, the fisetin agent is fisetin or a pharmaceutically acceptable salt thereof.

[0127] Feselon (3,3',4',7-tetrahydroxyflavone) is a plant flavonol derived from the flavonoid group of polyphenols, and has the following structure:

[0128]

[0129] Fesetone is commercially available (see, for example, Sigma-Aldrich, PHL82542) and can be obtained by methods known to those skilled in the art.

[0130] In some implementations, fisetin is obtained from natural sources, including fruits and vegetables such as strawberries, apples, persimmons, grapes, onions, and cucumbers.

[0131] In other embodiments, conventional organic synthesis methods are used to synthesize fisetin. For example, fisetin can be prepared using the method described in Grynkiewicz and Demchuk, New Perspectives for Fisetin, Front Chem. 7:697 (2019).

[0132] In some implementations, the fisetin agent is quercetin or a pharmaceutically acceptable salt thereof.

[0133] Quercetin (3,3',4',5,7-pentahydroxyflavone) is an antioxidant flavonoid with the following structure:

[0134]

[0135] Quercetin is commercially available and can be obtained by methods known to those skilled in the art.

[0136] In some implementations, quercetin is derived from natural sources, including fruits and vegetables such as apples, onions, grapes, berries, cherries, broccoli, and citrus fruits.

[0137] In some embodiments, the fisetin agent has the structure of formula IIa:

[0138]

[0139] Where R 9 It is H, C1-C6 alkoxy or C3-C6 cycloalkyl.

[0140] R 10 It is H, C1-C6 alkoxy or C3-C6 cycloalkyl.

[0141] In some embodiments, the urolithin A agent is the urolithin A agent described in US11591305B2 (which is incorporated herein by reference in its entirety).

[0142] In some embodiments, the fisetin agent is a glucuronide conjugate of fisetin or its 3'-methoxylated metabolite (e.g., 3'-methoxy-3,7,4'-trihydroxyflavone (geraldol)).

[0143] In some embodiments, the fisetin agent has the structure of formula IIb:

[0144]

[0145] Or its pharmaceutically acceptable salt.

[0146] In certain embodiments of compounds of formula IIb or pharmaceutically acceptable salts thereof, R 7 It is H, R 8 It is H, R 9 It's H, and R 10 It's H.

[0147] In certain embodiments of compounds of formula IIb or pharmaceutically acceptable salts thereof, R 7 It is H, R 8 It is OCH3, R 9 It's H, and R 10 It's H.

[0148] In certain embodiments of compounds of formula IIb or pharmaceutically acceptable salts thereof, R 7 It is H, R 8 It is H, R 9 It's SCF3, and R 10 It's H.

[0149] In certain embodiments of compounds of formula IIb or pharmaceutically acceptable salts thereof, R 7 It is Cl, R 8 It is H, R 9 It is Br, and R 10 It's H.

[0150] In certain embodiments of compounds of formula IIb or pharmaceutically acceptable salts thereof, R 7 It's CF3, R 8 It is H, R 9 It's CF3, and R 10 It's H.

[0151] In certain embodiments of compounds of formula IIb or pharmaceutically acceptable salts thereof, R 7 It is H, R 8 It's CF3, R 9 It's H, and R 10 It's CF3.

[0152] In certain embodiments of compounds of formula IIb or pharmaceutically acceptable salts thereof, R 7 It is H, R 8 It is H, R 9 It is OBn, and R 10 It's H.

[0153] In certain embodiments of compounds of formula IIb or pharmaceutically acceptable salts thereof, R 7 It is OCH3, R 8 It is H, R 9It's OCH3, and R 10 It is OCH3.

[0154] In some embodiments, the fisetin agent has the structure of formula IIc:

[0155]

[0156] Or its pharmaceutically acceptable salt.

[0157] In certain embodiments of compounds of formula IIc or pharmaceutically acceptable salts thereof, R 8 It is H, R 9 It is Cl, and R 10 It's H.

[0158] In certain embodiments of compounds of formula IIc or pharmaceutically acceptable salts thereof, R 8 It is H, R 9 It's OCH3, and R 10 It is H. In certain embodiments of compounds of formula IIc or pharmaceutically acceptable salts thereof, R 8 It is Br, R 9 It's OCH3, and R 10 It is OCH3. In certain embodiments of compounds of formula IIc or their pharmaceutically acceptable salts, R 8 It is H, R 9 It's H, and R 10 It is tert-butyl (t-Bu). In some embodiments, the fisetin agent has the structure of formula IId:

[0159]

[0160] Or its pharmaceutically acceptable salt.

[0161] In certain embodiments of compounds of formula IIc or pharmaceutically acceptable salts thereof, R 9 It is Br.

[0162] In certain embodiments of compounds of formula IIc or pharmaceutically acceptable salts thereof, R 9 It is tert-butyl (t-Bu).

[0163] In some embodiments, the fisetin agent has the structure of formula IIe:

[0164]

[0165] Or its pharmaceutically acceptable salt.

[0166] In certain embodiments of the compound of formula IIe or its pharmaceutically acceptable salt, R 7 It is H, R8 It is H, R 9 It is H, R 10 It's H, and R 12 It is Br.

[0167] In certain embodiments of the compound of formula IIe or its pharmaceutically acceptable salt, R 7 It is H, R 8 It is OCH3, R 9 It is H, R 10 It's H, and R 12 It is Br.

[0168] In certain embodiments of the compound of formula IIe or its pharmaceutically acceptable salt, R 7 It is H, R 8 It is F, R 9 It is OEt, R 10 It's H, and R 12 It is Cl.

[0169] In certain embodiments of the compound of formula IIe or its pharmaceutically acceptable salt, R 7 It is OCH3, R 8 It is H, R 9 It is OCH3, R 10 It's OCH3, and R 12 It is Cl.

[0170] In some embodiments, the fisetin agent has the structure of formula IIf:

[0171]

[0172] Or its pharmaceutically acceptable salt.

[0173] In certain embodiments of compounds of formula IIf or pharmaceutically acceptable salts thereof, R 8 It is H, R 9 It is OCH3, R 10 It's OCH3, and R 13 It is Br.

[0174] In certain embodiments of compounds of formula IIf or pharmaceutically acceptable salts thereof, R 8 It is H, R 9 It is Cl, R 10 It's H, and R 13 It is F.

[0175] In certain embodiments of compounds of formula IIf or pharmaceutically acceptable salts thereof, R 8 It is OCH3, R 9 It is OCH3, R 10 It's OCH3, and R13 It is F.

[0176] In some embodiments, the fisetin agent has the structure of formula IIg:

[0177]

[0178] Or its pharmaceutically acceptable salt.

[0179] In certain embodiments of the compound of formula IIg or its pharmaceutically acceptable salt, R 9 It is tert-butyl (t-Bu).

[0180] In certain embodiments of the compound of formula IIg or its pharmaceutically acceptable salt, R 9 It is OBn.

[0181] In some embodiments, the fisetin agent has the structure of formula IIh:

[0182]

[0183] Or its pharmaceutically acceptable salt.

[0184] Nicotinamide Riboside

[0185] Nicotinamide nucleoside or a pharmaceutically acceptable salt thereof may be used to treat or prevent (e.g., to treat) neurodegenerative diseases as disclosed herein.

[0186] Nicotinamide nucleoside is a member of the vitamin B3 family and has the following structure:

[0187]

[0188] Nicotinamide nucleoside is NAD + Precursor, it is an essential coenzyme that plays an important role in various metabolic pathways. NAD + The importance of NAD + NAD+ depletion enzyme (NAD) + The activity of NAD+ depleting enzymes reflects the activity of NAD+. + Depletion enzymes are mediators of aging, primarily induced by stress factors such as DNA damage, oxidative stress, and inflammation. Pharmaceutically acceptable salts of nicotinamide nucleosides include, for example, nicotinamide-β-d-nucleoside chloride, nicotinamide-β-d-nucleoside bromide, thionicotinamide-β-d-nucleoside bromide, nicotinamide-β-d-riboside triacetate bromide, and thionicotinamide-β-d-nucleoside triacetate bromide.

[0189] Nicotinamide nucleoside or a pharmaceutically acceptable salt thereof is commercially available (e.g., Tru). And can be obtained by methods known to those skilled in the art.

[0190] Cat's claw

[0191] Cat's Claw (Uncaria tomentosa) is a woody vine found in the Amazon rainforest. Cat's Claw extract or components thereof may be used to treat or prevent (e.g., to treat) neurodegenerative diseases as disclosed herein.

[0192] Cat's Claw extract can be prepared from cat's claw bark using conventional extraction methods. For example, the extraction process may include using 70% ethanol / distilled water in a 5:1 ratio. Components from the cat's claw extract can be separated using conventional methods, including, for example, affinity fractionation and high-performance liquid chromatography (HPLC). The method may also include assessing the purity of each component using HPLC, mass spectrometry, and / or nuclear magnetic resonance (NMR) spectroscopy. HPLC, β-VE ion electrospray spectroscopy (relative intensities of molecular ions given as percentages), Fourier transform mass spectrometry, and ultraviolet spectroscopy can be used. 1 HNMR, 13 C10 NMR, electrospray ionization time-of-flight mass spectrometry (ESI-TOF), electron impact (EI) induced mass spectrometry, fast atom impact (FAB) mass spectrometry, homonuclear correlation spectroscopy (COSY), constant time inverse-detection gradient accordion rescaled heteronuclear multiple bond correlation spectroscopy (CIGAR), and / or heteronuclear correlation spectroscopy (HETCOR) are used to assess the identity of each component.

[0193] In some embodiments, the cat's claw component is a polyphenol. In some embodiments, the cat's claw component is an epicatechin dimer or its variants (called proanthocyanidins). For example, the cat's claw component may be proanthocyanidin B2 (epicatechin-4β-8-epicatechin), proanthocyanidin B4 (i.e., catechin-4α→8-epicatechin), or proanthocyanidin C1 (i.e., epicatechin-4β→8-epicatechin-4β→8-epicatechin). In some embodiments, the cat's claw component is an epicatechin trimer (i.e., epicatechin-4β→8-epicatechin-4β→8-epicatechin), epiafzelechin-4β→8-epicatechin, or an epicatechin tetramer (i.e., epicatechin-4β→8-epicatechin-4β→8-epicatechin-4β→8-epicatechin). In some implementations, the cat's claw extract is PTI-00703 (Percepta).

[0194] Treatment

[0195] This document provides methods for treating or preventing (e.g., treating) neurodegenerative diseases in subjects in need by administering, alone or in combination, a urolithin A agent or a fisetinone agent to a subject. In some embodiments, this disclosure provides a method for reducing pathogenic microglial pro-inflammatory activation in a subject, the method comprising administering to the subject a therapeutically effective amount of a urolithin A agent and a therapeutically effective amount of a fisetinone agent. In some embodiments, this disclosure provides a method for promoting microglial Aβ clearance in a subject, the method comprising administering to the subject a therapeutically effective amount of a urolithin A agent and a therapeutically effective amount of a fisetinone agent. In some embodiments, this disclosure provides a method for reducing pathogenic microglial pro-inflammatory activation and promoting microglial Aβ clearance in a subject, the method comprising administering to the subject a therapeutically effective amount of a urolithin A agent and a therapeutically effective amount of a fisetinone agent.

[0196] Therefore, in addition to this, this disclosure describes techniques (e.g., combinations of urolithiasis A agents and fisetin agents) that reduce inflammation, particularly microglial inflammation. In some embodiments, this disclosure describes such techniques that reduce pro-inflammatory activation, such as microglial pro-inflammatory activation, particularly including pathogenic microglial pro-inflammatory activation.

[0197] In many embodiments, the provided methods involve combination therapy using at least a urolithin A agent and a fexone agent. Those skilled in the art will understand that combination therapy (e.g., a combination therapy of urolithin A and fexone agents) involves administering or otherwise delivering one or more of a plurality of agents to a subject, thereby exposing the subject to all the agents. In some embodiments, each agent in the combination is administered or otherwise delivered to the subject. In some embodiments, one or more agents are administered or otherwise delivered (e.g., via an overlap administration regimen) to a subject who has received, is receiving, or will receive the remaining agents in the combination.

[0198] In some embodiments, combination therapy involves administering one or more pharmaceutical compositions as described herein (i.e., comprising and / or otherwise delivering related agents as described herein), each pharmaceutical composition comprising and / or delivering one or more agents in the combination. In some embodiments, different agents are delivered from different pharmaceutical compositions (i.e., from different dosage forms). In some embodiments, two or more agents may be delivered from the same pharmaceutical composition (i.e., may be contained in the same dosage form). In some embodiments, pharmaceutical compositions delivering different agents are administered according to an overlapping dosing regimen to determine the achievement of exposure to all agents in the combination.

[0199] In some embodiments, the provided method includes applying or otherwise delivering one or more agents other than urolithin A and fisetin; in particular embodiments, such one or more additional agents are one or both of nicotinamide nucleoside or a pharmaceutically acceptable salt thereof and cat's claw extract or a component thereof. In some embodiments, the provided method includes applying a combination of urolithin A and fisetin. In some embodiments, the provided method includes applying a combination of urolithin A, fisetin, and cat's claw extract or a component thereof. In some embodiments, the provided method includes applying a combination of urolithin A, fisetin, and nicotinamide nucleoside or a pharmaceutically acceptable salt thereof. In some embodiments, the provided method includes applying a combination of urolithin A, fisetin, nicotinamide nucleoside or a pharmaceutically acceptable salt thereof, and cat's claw extract or a component thereof. For example, in some embodiments, the provided method includes applying a combination of urolithin A, fisetin, and quercetin. In some embodiments, the provided method includes applying a combination of urolithin A, fisetin, and cat's claw extract or a component thereof. In some embodiments, the provided method includes applying a combination of urolithin A, fisetin, quercetin, and cat's claw extract or components thereof. In some embodiments, the provided method includes applying a combination of urolithin A, fisetin, quercetin, and nicotinamide nucleoside or a pharmaceutically acceptable salt thereof. In some embodiments, the provided method includes applying a combination of urolithin A, fisetin, nicotinamide nucleoside or a pharmaceutically acceptable salt thereof, and cat's claw extract or components thereof. In some embodiments, the provided method includes applying a combination of urolithin A, fisetin, quercetin, nicotinamide nucleoside or a pharmaceutically acceptable salt thereof, and cat's claw extract or components thereof.

[0200] This document also provides methods for treating or preventing (e.g., treating) neurodegenerative diseases in subjects in need, methods comprising administering or otherwise delivering to the subject ellagitannins or ellagic acid, or their analogues or metabolites, alone or in combination with a fisetin agent, wherein the methods may further comprise determining, or have been determined, that the subject is a producer of urolithiasis A. In some embodiments, the provided methods comprise administering or otherwise delivering one or more agents other than ellagitannins or ellagic acid, or their analogues or metabolites, and a fisetin agent; in particular embodiments, such one or more additional agents are one or both of nicotinamide nucleoside or its pharmaceutically acceptable salt and cat's claw extract or components thereof.

[0201] In some embodiments, the provided method includes applying a combination of ellagitannin or ellagic acid or its analogues or metabolites, and a fisetin agent. In some embodiments, the provided method includes applying a combination of ellagitannin or ellagic acid or its analogues or metabolites, a fisetin agent, and cat's claw extract or a component thereof. In some embodiments, the provided method includes applying a combination of ellagitannin or ellagic acid or its analogues or metabolites, a fisetin agent, and nicotinamide nucleoside or a pharmaceutically acceptable salt thereof. In some embodiments, the provided method includes applying a combination of ellagitannin or ellagic acid or its analogues or metabolites, a fisetin agent, nicotinamide nucleoside or a pharmaceutically acceptable salt thereof, and cat's claw extract or a component thereof. For example, in some embodiments, the provided method includes applying a combination of ellagitannin or ellagic acid or its analogues or metabolites, fisetin, and quercetin. In some embodiments, the provided method includes applying a combination of ellagitannin or ellagic acid or its analogues or metabolites, fisetin, and cat's claw extract or a component thereof. In some embodiments, the provided method includes applying a combination of ellagitannins or ellagic acid or their analogues or metabolites, fisetin, quercetin, and cat's claw extract or components thereof. In some embodiments, the provided method includes applying a combination of ellagitannins or ellagic acid or their analogues or metabolites, fisetin, quercetin, and nicotinamide nucleoside or their pharmaceutically acceptable salts. In some embodiments, the provided method includes applying a combination of ellagitannins or ellagic acid or their analogues or metabolites, fisetin, nicotinamide nucleoside or their pharmaceutically acceptable salts, and cat's claw extract or components thereof. In some embodiments, the provided method includes applying a combination of ellagitannins or ellagic acid or their analogues or metabolites, fisetin, quercetin, nicotinamide nucleoside or their pharmaceutically acceptable salts, and cat's claw extract or components thereof.

[0202] This disclosure also provides a method of treating neurodegenerative diseases in a subject in need, the method comprising administering or otherwise delivering to the subject ellagitannins or ellagic acid, alone or in combination with a fisetin agent, or an analogue or metabolite thereof, wherein the method may further comprise administering a composition comprising one or more bacterial species associated with urolithiasis A production. In some embodiments, the provided method comprises administering or otherwise delivering one or more agents other than ellagitannins or ellagic acid, or an analogue or metabolite thereof, and a fisetin agent; in particular embodiments, such one or more additional agents are one or both of nicotinamide nucleoside or a pharmaceutically acceptable salt thereof and cat's claw extract or components thereof.

[0203] In some embodiments, the provided method includes applying a combination of ellagitannin or ellagic acid or its analogues or metabolites, and a fisetin agent. In some embodiments, the provided method includes applying a combination of ellagitannin or ellagic acid or its analogues or metabolites, a fisetin agent, and cat's claw extract or a component thereof. In some embodiments, the provided method includes applying a combination of ellagitannin or ellagic acid or its analogues or metabolites, a fisetin agent, and nicotinamide nucleoside or a pharmaceutically acceptable salt thereof. In some embodiments, the provided method includes applying a combination of ellagitannin or ellagic acid or its analogues or metabolites, a fisetin agent, nicotinamide nucleoside or a pharmaceutically acceptable salt thereof, and cat's claw extract or a component thereof. For example, in some embodiments, the provided method includes applying a combination of ellagitannin or ellagic acid or its analogues or metabolites, fisetin, and quercetin. In some embodiments, the provided method includes applying a combination of ellagitannin or ellagic acid or its analogues or metabolites, fisetin, and cat's claw extract or a component thereof. In some embodiments, the provided method includes applying a combination of ellagitannins or ellagic acid or their analogues or metabolites, fisetin, quercetin, and cat's claw extract or components thereof. In some embodiments, the provided method includes applying a combination of ellagitannins or ellagic acid or their analogues or metabolites, fisetin, quercetin, and nicotinamide nucleoside or their pharmaceutically acceptable salts. In some embodiments, the provided method includes applying a combination of ellagitannins or ellagic acid or their analogues or metabolites, fisetin, nicotinamide nucleoside or their pharmaceutically acceptable salts, and cat's claw extract or components thereof. In some embodiments, the provided method includes applying a combination of ellagitannins or ellagic acid or their analogues or metabolites, fisetin, quercetin, nicotinamide nucleoside or their pharmaceutically acceptable salts, and cat's claw extract or components thereof.

[0204] This article also provides methods for treating or preventing (e.g., treating) neurodegenerative diseases in subjects in need by administering or otherwise delivering two or more agents selected from urolithin A agents, fisetin agents, nicotinamide nucleoside or pharmaceutically acceptable salts thereof, or cat's claw extract or components thereof. For example, the method may include administering urolithin A agents in combination with cat's claw extract or components thereof, with or without nicotinamide nucleoside or pharmaceutically acceptable salts thereof.

[0205] Non-limiting examples of neurodegenerative diseases that can be treated or prevented using the methods disclosed herein include Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, polyglutamine amplification disorders (e.g., HD, dentatorubropallidoluysianatrophy, Kennedy's disease (also known as spinobulbar muscular atrophy), spinocerebellar ataxia (e.g., types 1, 2, 3 (also known as Machado-Joseph disease), 6, 7, and 17)), and other trinucleotide repeat amplification disorders (e.g., fragile X syndrome, fragile XE mental retardation, Friedreich's ataxia). (ataxia), myotonic dystrophy, spinocerebellar ataxia type 8 and spinocerebellar ataxia type 12), Alexander disease, Alpert disease, ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, ischemic stroke, Krabby disease, Lewy body dementia, multiple system atrophy, Peyre's disease, Pick's disease, primary lateral sclerosis, Rifsum disease, Sandhof disease, Sheld disease, spinal cord injury, spinal muscular atrophy, progressive supranuclear palsy or tabes dorsalis.

[0206] As understood by those skilled in the art, effective prevention may involve delaying the onset of one or more features of a related disease, symptom, or condition (e.g., a neurodegenerative disease as described herein) (e.g., an expected onset that can be determined, for example, based on genetics, lifestyle, biomarkers, or other factors); effective treatment may involve delaying the onset (e.g., an expected onset) and / or reducing the frequency and / or severity of one or more such features.

[0207] The methods described in this disclosure may include treating the disease or condition itself, and treating one or more symptoms of the disease or condition. “Treating” a disease does not require 100% elimination of the subject’s disease or disease symptoms. In some embodiments, the treatment achieves relief or reduction of the severity of one or more symptoms or features of the disease; typically, the relevant relief or reduction is determined, for example, by significant effects in an appropriate system (e.g., a model system) and / or an appropriate population (e.g., a population of human subjects or animal models). In some embodiments, “treatment” may be or include a delay in the onset of symptoms or a delay in symptom progression or disease-related functional loss; optionally or additionally, in some embodiments, “treatment” may be or include a reduction in the frequency and / or severity of one or more symptoms or features of the disease; optionally or additionally, “treatment” may be or include eliminating or reducing one or more side effects of the treatment, or eliminating or reducing one or more direct or indirect effects of disease progression. In some embodiments, a subject receiving treatment according to this disclosure may not exhibit signs of the disease but may be at risk of developing the disease.

[0208] In some implementations, the provided method includes selecting subjects, for example, by obtaining and testing samples from candidate subjects to indicate suitability for selection. In some cases, subjects may be identified or determined by, for example, a healthcare professional to have a condition or disease or to be at risk of developing a condition or disease. In some cases, subject selection may involve multiple parties. For example, a first party may obtain samples from candidate subjects, and a second party may test the samples. In some cases, subjects may be selected and / or submitted by a healthcare practitioner (e.g., a general practitioner). Samples may include, for example, cells or cell populations.

[0209] As used herein, the terms “administer,” “administering,” or “administration” refer to administering (i.e., exposing) a subject to an applicable pharmaceutical agent, and in some embodiments, may involve one or more of the following methods: ingestion, injection, implantation, absorption, or inhalation, but are not limited to a particular form. In some embodiments, one or more compounds disclosed herein may be administered to a subject by oral and / or topical (e.g., nasal) intake. For example, in some embodiments, the provided method includes administering an effective amount of the pharmaceutical agent or a combination of pharmaceutical agents to achieve the desired or claimed effect. The specific dosage and treatment regimen for any particular subject may depend on a wide range of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, rate of excretion, combination of drugs, severity and progression of the disease, condition, or symptoms, the subject’s predisposition to the disease, condition, or symptoms, and the judgment of the treating physician.

[0210] Those skilled in the art who read this specification will understand that, in cases involving combination therapy, the “effective amount” of a particular agent included in the combination therapy is an effective amount (e.g., one that has been proven effective through appropriate testing in the relevant system [e.g., a model system] and / or population [e.g., a patient population]); where the amount has been proven effective in a particular model system, those skilled in the art will recognize that appropriate adjustments establish a corresponding amount for delivery [e.g., administration] to a subject [e.g., a human subject] in the case of such a combination; this amount may differ and, in a particular embodiment, may be lower and / or less frequently than the amount required to achieve a particular effect if the agent were not delivered as part of the relevant combination therapy.

[0211] In some implementations, the subject may be evaluated after administration to detect, assess, or determine their disease level. In some implementations, treatment may continue until a change in the disease level (e.g., a decrease) is detected in the subject. In some implementations, the treatment method may include assessing the subject's disease level before, during, and / or after treatment.

[0212] After improvement in a patient's condition (e.g., a change in disease level in the subject (e.g., a decrease)), a maintenance dose of the compounds, compositions, or combinations of the present disclosure may be administered if needed or desired. Subsequently, the dose or frequency of administration, or both, may be reduced to a level that maintains the improved condition, depending on the symptoms. However, in the event of any recurrence of disease symptoms, the patient may require long-term intermittent treatment.

[0213] As used herein, the term "subject" refers to any animal. In some cases, the subject is a mammal. In other cases, as used herein, the term "subject" refers to a human (e.g., a male, female, or child).

[0214] Alzheimer's disease

[0215] In some implementations, the neurodegenerative disease is Alzheimer's disease (AD). Alzheimer's disease is characterized by the loss of neurons and synapses in the cerebral cortex, as well as atrophy of the temporal and parietal lobes. Histopathological findings in AD may include abnormal aggregates of amyloid plaques and neurofibrillary tangles.

[0216] This article provides a method for treating Alzheimer's disease in subjects in need, comprising administering a combination of urolithiasis A and fenestrone to the subject. This method can be used to treat at least one symptom of AD, reduce the progression of AD, reduce the deterioration of one or more physical functions affected by AD, maintain or improve one or more physical functions affected by AD, treat dementia or mild cognitive impairment (MCI) (e.g., dementia or MIC due to AD), or reduce progressive cognitive decline (including loss of declarative and procedural memory, reduced learning ability, reduced attention span, and severe impairment in thinking, judgment, and decision-making). Methods for increasing survival in subjects with one or more symptoms of AD or reducing the levels of one or more biomarkers (e.g., total tau or phosphorylated tau) in subjects with AD are also provided.

[0217] In some implementations, the subject exhibits one or more symptoms associated with AD, has been diagnosed with AD, is suspected of having AD, or is at risk of developing AD. Treatment may further include determining or having determined that the subject has AD, has one or more symptoms associated with AD, or is at risk of developing AD.

[0218] Methods for diagnosing AD are known in the art. A subject may be diagnosed based on clinical history, family history, physical examination, or neurological examination. A subject may be identified or diagnosed with AD by a healthcare professional. The diagnosis of AD or the determination of the risk of developing AD may be based on neuroimaging, one or more cognitive tests (e.g., ADAS-Cog, MoCA, DSRS, MADCOMS, FAQ, or NPI-Q), or the presence of one or more biomarkers in a subject's cerebrospinal fluid or blood sample. Exemplary biomarkers include amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau), the Aβ42 / 40 or amyloid precursor protein (APP) 669-711 / Aβ42 ratio, neurogranules, neurofilament light chains, and soluble insulin receptors. Diagnosis may also be based on detecting mutations in one or more genes associated with AD, such as the presence of the APOEε4 allele or mutation in APP, presenilin 1 (PSEN1), or presenilin 2 (PSEN2). Intense inflammation in the brain (including increased responsiveness of resident microglia to amyloid deposits) is associated with the pathogenesis and progression of Alzheimer's disease (AD). Therefore, diagnosis can also be based on the presence of neuroinflammatory markers.

[0219] The treatments provided in this disclosure can be initiated at any stage of disease progression. For example, treatment can be initiated before an onset (e.g., for a subject at risk of developing AD), at the onset of symptoms, immediately after the detection of AD symptoms, or when any one or more symptoms (e.g., cognitive decline, memory loss, reduced attention span) are observed that would lead a skilled practitioner to suspect that the subject may be developing AD. Treatment can also be initiated at a later stage.

[0220] Application of ellagitannins or ellagic acid

[0221] This disclosure also provides methods for treating or preventing (e.g., treating) neurodegenerative diseases in subjects in need, the methods comprising administering or otherwise delivering to the subject ellagitannins (e.g., any ellagitannins disclosed herein or known in the art) or ellagic acid or its analogues or metabolites, and fisetone agents, wherein the methods may further comprise determining, or have been determined, that the subject is a producer of urolithiasis A.

[0222] Whether a subject is a urolithin A producer can be determined based on the presence of one or more bacterial species associated with urolithin A production in their gut microbiota (e.g., from blood, urine, or fecal samples). Bacterial species associated with urolithin A production can be bacterial species known in the art, including, for example, bacterial species belonging to the order Clostridium and family Ruminococci, as well as *Gordonella urolithi*, *Turkmenistanella turbidiforme*, and *Ackermania fasciolita*.

[0223] This document also provides methods for treating or preventing (e.g., treating) neurodegenerative diseases in subjects in need, methods comprising administering to the subject a combination of ellagitannin or ellagic acid or its analogues or metabolites with a fisetin agent, and a composition comprising one or more bacterial species associated with urolithin A production (e.g., any bacterial species disclosed herein or known in the art). The bacterial composition may be prepared in a wide variety of forms, such as capsules, tablets, suppositories, foods, or beverages. The ellagitannin or ellagic acid or its analogues or metabolites, the fisetin agent, and the composition comprising one or more bacterial species may be administered simultaneously or separately, and may be administered at the same or different frequencies.

[0224] Dosage

[0225] The compounds disclosed herein are generally administered in therapeutically effective amounts. An "effective amount" is an amount sufficient to achieve a beneficial or desired outcome. For example, a therapeutically effective amount may be an amount that achieves a desired therapeutic effect. This amount may be the same as or different from a preventatively effective amount, which is the amount required to prevent the onset of disease or disease symptoms. Effective amounts may be administered in a single or multiple dose, application, or dosage. The therapeutically effective amount (i.e., effective dose) of a therapeutic compound depends on the selected therapeutic compound. Those skilled in the art will understand that certain factors may influence the dose and timing required for effective treatment of a subject, including, but not limited to, the severity of the disease or condition, prior treatment, the subject's overall health and / or age, and any other pre-existing conditions. Furthermore, treatment of a subject with a therapeutically effective amount of the therapeutic compound described herein may comprise a single treatment or a series of treatments.

[0226] In some implementations, the provided therapy is a regulated therapy, wherein its commercialization is supported by clinical trials and / or otherwise regulated and / or supervised by government. Optionally or additionally, in some implementations, the provided therapy may be commercialized without regulatory review and / or approval.

[0227] Data obtained from cell culture assays and animal studies can be used to determine dosage ranges for human use. For any compound used in the methods of this invention, the therapeutically effective dose can be initially estimated from cell culture assays. Doses can be determined in animal models to achieve a range of circulating plasma concentrations including the IC50 (i.e., the concentration of the test compound that achieves half-maximal inhibition of symptoms) as determined in cell cultures. Such information can be used to more accurately determine the useful dose in humans. Plasma levels can be measured, for example, by high-performance liquid chromatography.

[0228] The agents provided herein can be administered separately or concurrently, including as part of a treatment regimen. For example, the urolithiasis A agent, fisetin agent, and one or more other agents (e.g., nicotinamide nucleoside or a pharmaceutically acceptable salt thereof, or cat's claw extract or a component thereof) disclosed herein can be administered separately in individual dosage forms or concurrently as part of a single dosage form. The agents provided herein can be administered daily, weekly, monthly, or quarterly. In some embodiments, they are administered once daily, twice daily, or three or more times daily. They can be administered over periods of weeks, months, or years. For example, the compounds can be administered for at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or at least or about 5 years or longer.

[0229] Urolithin A has been reported to be safe and / or effective when administered in doses ranging from 500 mg to 1000 mg daily (see, for example, Cell Rep Med. 2022 May 17; 3(5):100633). In some embodiments, urolithin A may be administered or delivered in such doses and / or according to such regimens as disclosed herein. Optionally or additionally, in some embodiments, urolithin A may be used according to alternative doses and / or according to alternative regimens as disclosed herein; for example, in some embodiments, urolithin A may be used at a lower dose and / or a lower frequency of administration than when administered alone.

[0230] Urolithiasis A can be obtained from approximately 1 mg to approximately 2500 mg (e.g., approximately 1 mg to approximately 1000 mg, approximately 50 mg to approximately 2500 mg, approximately 10 mg to approximately 2400 mg, approximately 100 mg to approximately 2300 mg, approximately 130 mg to approximately 2100 mg, approximately 160 mg to approximately 1900 mg, approximately 190 mg to approximately 1700 mg, approximately 220 mg to approximately 1500 mg, approximately 240 mg to approximately 1300 mg, approximately 260 mg to approximately 1100 mg, approximately 280 mg to approximately 1000 mg). Urolithiasis A can be administered in doses ranging from about 300 mg to about 900 mg, about 1 mg, about 10 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. Urolithiasis A can be administered once daily, twice daily, or three or more times daily. For example, urolithiasis A can be administered twice daily in doses ranging from about 50 mg to about 2500 mg (e.g., any subrange or dose within this range disclosed herein). Urolithin A can be administered in doses of about 100 mg to about 5000 mg daily (e.g., about 200 mg to about 4000 mg, about 300 mg to about 3000 mg, about 400 mg to about 2500 mg, about 500 mg to about 2000 mg, about 550 mg to about 1500 mg, about 600 mg to about 1200 mg, about 700 mg to about 1100 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). In some embodiments, urolithin A is administered in doses of about 1000 mg daily (e.g., about 500 mg twice daily). In some embodiments, urolithin A is administered in doses of about 1 mg to about 1000 mg daily.

[0231] In some implementations, urolithiasis A is administered at a dose of about 0.5 to about 65 mg / kg of subject body weight (e.g., about 1 to about 60, about 1.5 to about 55, about 2 to about 50, about 2.5 to about 45, about 3 to about 40, about 3.5 to about 35, about 4 to about 30, about 4.5 to about 25, about 5 to about 20, about 5.5 to about 15, about 6 to about 12, or about 6.5 to about 10 mg / kg of subject body weight).

[0232] Urolithiasis A agents other than urolithiasis A can be administered at doses corresponding to the doses of urolithiasis A disclosed herein, wherein, as those skilled in the art will understand, such correspondences can be established, for example, through comparable results and in appropriate assessments.

[0233] Fesedon can be administered in doses of about 0.5 mg to about 2500 mg (e.g., about 0.5 mg to about 20 mg, about 1 mg to about 10 mg, about 2 mg to about 6 mg, about 25 mg to about 500 mg, about 50 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 1500 mg, about 300 mg to about 1200 mg, or about 400 mg to about 750 mg). Fesedon can be administered once daily, twice daily, or three or more times daily. For example, fesedon can be administered twice daily in doses of about 0.5 mg to about 2000 mg (e.g., any subrange or dose within the range disclosed herein). Fiseridone can be administered in doses of about 1 mg to about 5000 mg daily (e.g., about 1 mg to about 40 mg, about 2 mg to about 20 mg, about 4 mg to about 12 mg, about 50 mg to about 1000 mg, about 100 mg to about 800 mg, about 150 mg to about 500 mg, about 200 mg to about 400 mg, about 500 mg to about 2000 mg, about 700 mg to about 1800 mg, or about 800 mg to about 1500 mg). In some embodiments, fisetone is administered in doses of about 8 mg daily (e.g., about 4 mg twice daily).

[0234] Other fisetin agents may be administered at doses corresponding to those of fisetin disclosed herein, wherein, as those skilled in the art will understand, such correspondences may be established, for example, through comparable results and in appropriate evaluations.

[0235] In some embodiments, fisetin is administered at an amount of about 0.05 to about 60 mg / kg of subject body weight (e.g., about 0.05 to about 0.15, about 0.4 to about 12, about 0.6 to about 10, about 0.8 to about 8, about 1 to about 6, about 1.5 to about 26, about 2 to about 24, about 2.5 to about 22, or about 3 to about 20 mg / kg of subject body weight).

[0236] In some implementations, when used in combination with urolithin A to treat or prevent (e.g., treat) neurodegenerative diseases, the dose of fisetin may be reduced compared to the dose used when fisetin is used alone. For example, the amount of fisetin used in combination with urolithin A may be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, or about 55% compared to the dose used when fisetin is used alone.

[0237] In some implementations, when used in combination with fisetin to treat or prevent (e.g., treat) neurodegenerative diseases, the dose of urolithin A can be reduced compared to the dose used when urolithin A is used alone. For example, the amount of urolithin A administered in combination with fisetin A can be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, or about 55% compared to the dose used when urolithin A is used alone.

[0238] In some embodiments, urolithin A is administered at a dose of about 1 mg to about 1100 mg per day, and fisetin is administered at a dose of about 4 mg to about 12 mg per day. In some embodiments, urolithin A is administered at a dose of about 100 mg to about 1000 mg per day, and fisetin is administered at a dose of about 4 mg to about 12 mg per day.

[0239] Nicotinamide nucleoside can be administered in doses of about 1 mg to about 2500 mg (e.g., about 10 mg to about 1000 mg, about 50 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 500 mg). For example, nicotinamide nucleoside can be administered in doses of about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg daily.

[0240] Cat's claw extract can be administered in doses of about 1 mg to about 2500 mg (e.g., about 100 mg to about 1200 mg, about 200 mg to about 1100 mg, about 300 mg to about 1000 mg, about 400 mg to about 900 mg, about 600 mg to about 800 mg, or about 750 mg).

[0241] Quercetin can be administered in doses of about 1 mg to about 2500 mg (e.g., about 50 mg to about 1000 mg, about 50 mg to about 800 mg, about 100 mg to about 600 mg, about 150 mg to about 500 mg, about 200 mg to about 300 mg, or about 250 mg). For example, quercetin can be administered once daily or twice daily in doses of about 200 mg, about 250 mg, about 300 mg, or about 400 mg.

[0242] In some implementations, when urolithin A and ferrous ketone are administered in combination with one or more of nicotinamide nucleoside, cat's claw, or quercetin to treat neurodegenerative diseases, the dose of urolithin A or ferrous ketone may be reduced compared to the dose used when urolithin A and ferrous ketone are administered alone. For example, the amount of urolithin A or ferrous ketone may be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, or about 55%.

[0243] Pharmaceutical Composition

[0244] When used as a medicine, the pharmaceutical agents disclosed herein may be administered in the form of a pharmaceutical composition comprising and / or delivering the relevant compound.

[0245] A pharmaceutical composition refers to a combination of one or more compounds disclosed herein and at least one pharmaceutically acceptable carrier.

[0246] For example, this disclosure provides pharmaceutical compositions that, individually or in combination, comprise one or more agents selected from urolithin A, fisetin, nicotinamide nucleoside, or pharmaceutically acceptable salts thereof, and cat's claw extract or components thereof, and optionally comprise one or more excipients. In some embodiments, the provided pharmaceutical compositions comprise a combination of urolithin A and fisetin, and optionally comprise one or more excipients. In some embodiments, the provided pharmaceutical compositions comprise urolithin A, fisetin, and optionally one or more excipients. In some embodiments, the provided pharmaceutical compositions comprise urolithin A, fisetin, and one or more agents selected from quercetin, nicotinamide nucleoside, or pharmaceutically acceptable salts thereof, and cat's claw extract or components thereof, and optionally one or more excipients. These compositions can be prepared in a manner known in the pharmaceutical industry and can be administered via a variety of routes, depending on whether local or systemic treatment is required and depending on the area to be treated.

[0247] Pharmaceutical compositions are typically formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral (subcutaneous, intradermal, intravenous, intradermal, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intralesional, and intracranial injection or infusion techniques), oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.

[0248] The pharmaceutical composition may be in the form of a solution or a powder. Suitable powders may include those that are substantially soluble in water. The pharmaceutical composition may be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents in accordance with techniques known in the art.

[0249] Pharmaceutical compositions can be administered orally in any orally acceptable dosage form, including but not limited to powders, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions, or hydrogel formulations. In the case of powders for oral administration, the powder can be substantially dissolved in water prior to administration. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, may be added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When oral administration is achieved with aqueous suspensions and / or emulsions, the active ingredient can be suspended or dissolved in an oil phase in combination with emulsifiers and / or suspending agents. Certain sweeteners, flavoring agents, or coloring agents may be added if desired.

[0250] Pharmaceutical compositions can also be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons and / or other solubilizers or dispersants known in the art.

[0251] In some embodiments, this document provides oral compositions comprising one or more agents selected from urolithiasis A agents, fisetin agents, nicotinamide nucleoside or pharmaceutically acceptable salts thereof, and cat's claw extract or components thereof, optionally comprising one or more excipients. In some embodiments, the oral composition is a capsule, soft gel, or tablet.

[0252] The pharmaceutical composition may be included in a container, package, or dispenser along with instructions for use. In some embodiments, the present invention provides a kit comprising bile acids and phenylbutyrate compounds. The kit may also include instructions for use to physicians and / or patients, syringes, needles, boxes, bottles, vials, etc.

[0253] Combination therapy

[0254] As discussed herein and as understood by those skilled in the art, combination therapies (e.g., urolithiasis A and fenestrone combination therapy) involve administering or otherwise delivering one or more of a variety of agents to a subject, thereby exposing the subject to all agents. In some embodiments, each agent in the combination is administered or otherwise delivered to the subject. In some embodiments, one or more agents are administered or otherwise delivered to a subject who has received, is receiving, or will receive (e.g., via an overlap administration regimen) the remaining agents in the combination.

[0255] In some embodiments, combination therapy involves administering one or more pharmaceutical compositions (i.e., containing and / or otherwise delivering, for example, the active pharmaceutical agents described herein), each pharmaceutical composition containing and / or delivering one or more agents in the combination. In some embodiments, different agents are delivered from different pharmaceutical compositions (i.e., from different dosage forms). In some embodiments, two or more agents may be delivered from the same pharmaceutical composition (i.e., may be contained in the same dosage form). In some embodiments, pharmaceutical compositions delivering different agents are administered according to an overlapping dosing regimen to determine the achievement of exposure to all agents in the combination.

[0256] In some embodiments, the combination therapy according to this disclosure is a combination therapy of urolithiasis A and ferrousone agents or a combination therapy comprising urolithiasis A and ferrousone agents. In some embodiments, the combination therapy involves a combination of urolithiasis A agents and / or ferrousone agents with one or more additional therapeutic agents. As noted, in some embodiments, such additional therapeutic agents may be combined with the compounds disclosed herein in a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms. In some embodiments, the additional agents include those known for the treatment or prevention (e.g., treatment) of neurodegenerative diseases. For example, in some embodiments, suitable agents for the combination therapy as described herein may include donepezil. Taklin Cabraladine Galantham ( and ), Megistrar One or more of the following: anti-amyloid vaccines, Aβ-lowering therapy, and mental exercises or stimulation.

[0257] In some cases, treatment with urolithiasis A agents and / or fisetin agents as described herein may reduce the need for treatment with one or more additional therapeutic agents, or reduce the dose or frequency required to achieve the same therapeutic effect with additional therapeutic agents. For example, the amount of additional therapeutic agent administered to the subject may be reduced by at least about 10% (e.g., at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55%) compared to the dose used when the additional therapeutic agent is administered alone.

[0258] Example

[0259] The following examples are provided by way of illustrating certain embodiments of this disclosure and are not intended to limit the scope of this disclosure or the claims in any way.

[0260] Example 1: Effects of urolithiasis A and phenothione on microglial Aβ clearance and pro-inflammatory cytokine release.

[0261] In unbiased (and biased) screening of natural product compounds, urolithin A was identified as a top enhancer of Aβ clearance by microglia. A BV2 microglia-based cytoscopy model was used to assess the ability of microglia to phagocytose and synthesize Aβ42 peptide (the major pathogenic Aβ isoform of Alzheimer's disease Aβ substance) (microglia uptake / clearance). Figure 1 This study demonstrates representative results of urolithin A increasing Aβ uptake / clearance in microglia in a dose-dependent manner in a cell culture model. In this model system, Aβ42 uptake of EC 50 It is 1.243e-005M. For example... Figure 3 As shown, co-treatment with urolithin A and urolithin significantly increased microglial Aβ uptake / clearance compared to fisetin alone.

[0262] The effects of urolithiasis A and fisetin on reducing the levels of pro-inflammatory cytokines such as TNFα were evaluated in an unbiased library screening. BV2 microglia were converted to a pro-inflammatory activated state by acute treatment with 1 μg / mL lipopolysaccharide (LPS) for 5 h in the presence of solvent or urolithiasis A or fisetin. The effect on inflammation was assessed by measuring the levels of the representative pro-inflammatory cytokine TNFα on conditioned cell culture medium via ELISA. Figure 2A and Figure 2B Representative results of dose-responsive reductions in TNFα following treatment with LPS and urolithin A and fisetin are shown, respectively. While urolithin A and fisetin A each reduced TNFα release from LPS-activated microglia in a dose-dependent manner, fisetin A significantly reduced ECG... 50 The concentration was 8 μM, and the EC50 of urolithiasis A was... 50 The value was 21 μM, indicating that fisetin was a more effective drug in this assay.

[0263] Next, BV2 microglia were treated with 10 μM urolithin A and 7.5 μM fisetin, alone or in combination. Drug toxicity during cell treatment was measured (expressed as solvent %) by monitoring the level of lactate dehydrogenase released in the conditioned medium. Figure 4A ).like Figure 4A As shown, the combined treatment did not affect cell viability. The reduction in TNFα in BV2 microglia was measured by ELISA. Figure 4B ).

[0264] Next, BV2 microglia were treated with 1 μg / mL LPS for 5 hours in the presence of different concentrations of urolithin A and fenestrone, alone or in combination. Figure 5 The level of TNFα secreted by microglia into conditioned cell culture medium was measured using ELISA.

[0265] As measured by TNFα levels, co-treatment with urolithiasis A and phenobarbital significantly reduced LPS-induced pro-inflammatory activation of microglia. Figure 4B and Figure 5 As measured by TNFα levels, the combination of urolithin A and ferrous ketone unexpectedly and significantly increased the ability of ferrous ketone to reduce LPS-induced pro-inflammatory activation of microglia, significantly exceeding the effect of ferrous ketone alone. This combination produced a more than additive effect in reducing LPS-induced pro-inflammatory activation of microglia. Specifically, as... Figure 4B As shown, although fisetin alone significantly reduced TNFα levels by about 75% in LPS-treated BV2 microglia, the combination of 10 μM urolithin A and 7.5 μM fisetin reduced TNFα levels to almost undetectable levels, indicating a synergistic effect of using this co-treatment.

[0266] As the results described in this article demonstrate, the combination of urolithin A and fisetin promotes the beneficial role of microglia in mediating Aβ clearance while limiting harmful pro-inflammatory microglial activation, and the combination significantly enhances the two distinct therapeutic benefits compared to monotherapy with either urolithin A or fisetin alone.

[0267] Example 2: Effects of urolithin A, fisetin, nicotinamide nucleoside, cat's claw herb and quercetin on microglial Aβ clearance and pro-inflammatory cytokine release

[0268] The effects of urolithin A, fisetin, nicotinamide nucleoside, cat's claw, and quercetin alone or in combination on TNFα concentration were evaluated. Figures 6A-6E (and 7A-7C). BV2 microglia were converted to a pro-inflammatory activated state by acute treatment with 1 μg / mL lipopolysaccharide (LPS) for 5 h in the presence of solvent or alone or in combination with nicotinamide nucleoside (#101), cat's claw (#134), urolithin A (#144), fisetin (NP-82), or quercetin (NP-162). The effect on inflammation was assessed by measuring TNFα levels by ELISA on conditioned cell culture medium. Figures 6A-6E As shown in 7A-7C, the combination of five agents reduced TNFα release to a greater extent compared to each agent alone. Furthermore, as... Figure 6C-6E As shown, the combination of urolithin A (#144), fisetin (NP-82), and quercetin (NP-162) reduced TNFα release to a greater extent compared to each of the three agents alone. Toxicity was assessed by monitoring the level of lactate dehydrogenase released in the conditioned medium, and the results indicated that activity was unaffected by treatment. Figure 8 ).

[0269] The ability of single or combined agents to increase Aβ uptake in microglia was also evaluated. Figure 9 Compared to the solvent, cat's claw significantly increased Aβ uptake. Figure 9 and 10A Furthermore, the combination of cat's claw (#134) and urolithin A (#144) increased Aβ uptake more than cat's claw and urolithin A alone. Figure 10B and 10C ). Figure 11B-11D and Figure 12A-12F The levels of TNFα in response to treatment with cat's claw herb (#134), urolithin A (#144), fisetin (NP-82), and quercetin (NP-162), alone or in various combinations, are shown. Figure 12A-12F As shown, the combination of urolithin A, fisetin, and quercetin reduced TNFα levels to a greater extent than urolithin A, fisetin, or quercetin alone; the combination of urolithin A, fisetin, and cat's claw reduced TNFα levels to a greater extent than urolithin A, fisetin, or cat's claw alone.

[0270] Figures 13A-13E The study showed TNFα levels in response to treatment with nicotinamide nucleoside (#101), cat's claw herb (#134), urolithin A (#144), and phenoxylide (NP-82), alone or in various combinations. These results indicated that the combination of urolithin A, phenoxylide, and nicotinamide nucleoside reduced TNFα levels to a greater extent than urolithin A, phenoxylide, or nicotinamide nucleoside alone; and the combination of urolithin A, phenoxylide, and cat's claw herb reduced TNFα levels to a greater extent than urolithin A, phenoxylide, or cat's claw herb alone. Furthermore, the combination of urolithin A, phenoxylide, and nicotinamide nucleoside reduced TNFα levels to a greater extent than the combination of urolithin A and nicotinamide nucleoside or the combination of phenoxylide and nicotinamide nucleoside. Figure 13C and 13D The combination of urolithin A, fisetin, and cat's claw herb reduced TNFα levels to a greater extent than either the combination of urolithin A and cat's claw herb or fisetin and cat's claw herb. Figure 13E ).

Claims

1. A method for treating or preventing neurodegenerative diseases in a subject in need, the method comprising administering to the subject a therapeutically effective amount of urolithiasis A and a therapeutically effective amount of fisetin.

2. The method according to claim 1, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, polyglutamine amplification syndrome, trinucleotide repeat amplification syndrome, Alexander disease, Alpert disease, ataxia-telangiectasia, Barten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, ischemic stroke, Crabb disease, Lewy body dementia, multiple system atrophy, Peyre's disease, Pick's disease, primary lateral sclerosis, Rifsum disease, Sandhof disease, Sheld disease, spinal cord injury, spinal muscular atrophy, progressive supranuclear palsy, or tabes dorsalis.

3. The method according to claim 1 or 2, wherein the urolithiasis A agent and the fisetin agent are administered simultaneously.

4. The method according to claim 1 or 2, wherein the urolithiasis A agent and the fisetin agent are administered separately.

5. The method according to any one of claims 1-4, wherein the urolithiasis A agent and the fisetin agent are administered daily.

6. The method according to any one of claims 1-5, wherein the urolithin A agent and the fisetin agent are applied once a day, twice a day, or three or more times a day.

7. The method according to any one of claims 1-6, wherein the urolithin A agent is urolithin A.

8. The method of claim 7, wherein the urolithiasis A is administered to the subject at a dose of about 1 mg to about 2500 mg.

9. The method of claim 8, wherein urolithiasis A is administered to the subject in an amount of about 1 mg to about 1000 mg per day.

10. The method according to any one of claims 7-9, wherein urolithin A is administered to the subject once daily.

11. The method of claim 8, wherein the subject is administered urolithiasis A twice daily at a dose of about 300 mg to about 900 mg.

12. The method according to claims 1-11, wherein the fisetin agent is fisetin.

13. The method of claim 12, wherein fisetin is administered to the subject at a dose of about 0.5 mg to about 2500 mg.

14. The method of claim 13, wherein fisetin is administered to the subject in an amount of about 1 mg to about 10 mg per day.

15. The method according to claims 12-14, wherein fisetin is administered to the subject once daily.

16. The method of claim 12, wherein the method comprises administering fisetin to the subject twice daily at a dose of about 1 mg to about 10 mg.

17. The method of claim 12, wherein fisetin is administered to the subject twice daily at a dose of about 2 mg to about 6 mg.

18. The method according to any one of claims 1-17, wherein the subject has one or more symptoms associated with the neurodegenerative disease.

19. The method according to any one of claims 1-17, wherein the subject is at risk of developing the neurodegenerative disease.

20. The method according to any one of claims 1-18, the method further comprising determining, or having determined, that the subject has one or more symptoms associated with the neurodegenerative disease prior to administration.

21. The method according to any one of claims 1-17 and 19, the method further comprising determining, or having determined, that the subject is at risk of developing the neurodegenerative disease prior to administration.

22. The method according to any one of claims 1-21, wherein the method further comprises administering to the subject nicotinamide nucleoside or a pharmaceutically acceptable salt thereof and one or both of cat's claw extract or components thereof.

23. The method according to any one of claims 1-21, wherein the method comprises administering to the subject a therapeutically effective amount of a combination of urolithin A and fenestrone.

24. The method of claim 23, wherein the method further comprises administering nicotinamide nucleoside to the subject.

25. The method of claim 24, wherein nicotinamide nucleoside is administered in an amount of about 100 mg to about 800 mg per day.

26. The method of claim 23, wherein the method further comprises administering quercetin to the subject.

27. The method of claim 26, wherein quercetin is administered in an amount of about 50 mg to about 1000 mg.

28. The method of claim 23, wherein the method further comprises administering cat's claw extract to the subject.

29. The method of claim 28, wherein the cat's claw extract is applied in an amount of about 100 mg to about 1200 mg.

30. A method for treating or preventing neurodegenerative diseases in a subject in need, the method comprising administering to the subject a therapeutically effective amount of ellagitannin or ellagic acid and a therapeutically effective amount of fisetin.

31. The method of claim 30, wherein the subject is a producer of urolithin A.

32. The method of claim 30 or 31, the method further comprising determining, or having determined, that the subject is a producer of urolithiasis A prior to administration.

33. The method of claim 32, further comprising detecting or having detected one or more bacterial species associated with the production of urolithin A in a biological sample of the subject.

34. The method of claim 33, wherein the bacterial species is *Gordonella urolithogenes* or *Turkestanella turgenei*, which produces isourolithogenes.

35. The method according to any one of claims 30-34, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, polyglutamine amplification syndrome, trinucleotide repeat amplification syndrome, Alexander disease, Alpert disease, ataxia-telangiectasia, Barten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, ischemic stroke, Crabb disease, Lewy body dementia, multiple system atrophy, Peyre's disease, Pick's disease, primary lateral sclerosis, Rifsum disease, Sandhof disease, Sheld disease, spinal cord injury, spinal muscular atrophy, progressive supranuclear palsy, or tabes dorsalis.

36. The method according to any one of claims 30-35, wherein the ellagitannin or ellagic acid and the fisetin agent are administered simultaneously.

37. The method according to any one of claims 30-35, wherein the ellagitannin or ellagic acid and the fisetin are administered separately.

38. The method according to any one of claims 30-37, wherein the ellagitannin or ellagic acid and the fisetin agent are applied daily.

39. The method according to any one of claims 30-38, wherein the ellagitannin or ellagic acid and the fisetin are applied once a day, twice a day, or three or more times a day.

40. The method according to any one of claims 30-39, wherein the fisetin agent is fisetin.

41. The method of claim 40, wherein fisetin is administered to the subject at a dose of about 0.5 mg to about 2500 mg.

42. The method of claim 41, wherein fisetin is administered to the subject in an amount of about 1 mg to about 10 mg per day.

43. The method according to any one of claims 40-42, wherein fisetin is administered to the subject once daily.

44. The method of claim 40, wherein fisetin is administered to the subject twice daily at a dose of about 1 mg to about 10 mg.

45. The method of claim 44, wherein fisetin is administered to the subject twice daily at a dose of about 2 mg to about 6 mg.

46. ​​The method according to any one of claims 30-45, wherein the subject has one or more symptoms associated with the neurodegenerative disease.

47. The method according to any one of claims 30-45, wherein the subject is at risk of developing the neurodegenerative disease.

48. The method according to any one of claims 30-46, the method further comprising determining, or having determined, that the subject has one or more symptoms associated with the neurodegenerative disease prior to administration.

49. The method according to any one of claims 30-45 and 47, the method further comprising determining, or having determined, that the subject is at risk of developing the neurodegenerative disease prior to administration.

50. The method according to any one of claims 30-49, wherein the method further comprises administering to the subject one or both of nicotinamide nucleoside or a pharmaceutically acceptable salt thereof and cat's claw extract or a component thereof.

51. The method according to any one of claims 30-49, wherein the method comprises administering to the subject a therapeutically effective amount of ellagitannin or a combination of ellagic acid and phenacetin.

52. The method of claim 51, wherein the method further comprises administering nicotinamide nucleoside to the subject.

53. The method of claim 52, wherein nicotinamide nucleoside is administered in an amount of about 100 mg to about 800 mg per day.

54. The method of claim 51, wherein the method further comprises administering quercetin to the subject.

55. The method of claim 54, wherein quercetin is applied in an amount of about 50 mg to about 1000 mg.

56. The method of claim 51, wherein the method further comprises administering cat's claw extract to the subject.

57. The method of claim 56, wherein the cat's claw extract is applied in an amount of about 100 mg to about 1200 mg.

58. A method of treating or preventing neurodegenerative diseases in a subject in need, the method comprising administering to the subject a therapeutically effective amount of ellagitannin or ellagic acid, a therapeutically effective amount of a fisetin agent, and a composition comprising one or more bacterial species associated with the production of urolithiasis A.

59. The method of claim 58, wherein the bacterial species is *Gordonella urolithogenes* or *Turkestanella truncatella*.

60. The method according to claim 58 or 59, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, polyglutamine amplification syndrome, trinucleotide repeat amplification syndrome, Alexander disease, Alpert disease, ataxia-telangiectasia, Barten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, ischemic stroke, Crabb disease, Lewy body dementia, multiple system atrophy, Peyre's disease, Pick's disease, primary lateral sclerosis, Rifsum disease, Sandhof disease, Sheld disease, spinal cord injury, spinal muscular atrophy, progressive supranuclear palsy, or tabes dorsalis.

61. The method according to any one of claims 58-60, wherein the ellagitannin or ellagic acid, the fisetin agent, and the composition comprising one or more bacterial species are administered simultaneously.

62. The method according to any one of claims 58-60, wherein the ellagitannin or ellagic acid, the fisetin agent, and the composition comprising one or more bacterial species are administered separately.

63. The method according to any one of claims 58-62, wherein the ellagitannin or ellagic acid and the fisetin agent are administered daily.

64. The method according to any one of claims 58-63, wherein the ellagitannin or ellagic acid and the fisetin agent are applied once a day, twice a day, or three or more times a day.

65. The method according to any one of claims 58-64, wherein the fisetin agent is fisetin.

66. The method of claim 65, wherein fisetin is administered to the subject at a dose of about 0.5 mg to about 2500 mg.

67. The method of claim 66, wherein fisetin is administered to the subject in an amount of about 1 mg to about 10 mg per day.

68. The method according to any one of claims 65-67, wherein fisetin is administered to the subject once daily.

69. The method of claim 65, wherein fisetin is administered to the subject twice daily at a dose of about 1 mg to about 10 mg.

70. The method of claim 69, wherein the method comprises administering fisetin to the subject twice daily at a dose of about 2 mg to about 6 mg.

71. The method according to any one of claims 58-70, wherein the subject has one or more symptoms associated with the neurodegenerative disease.

72. The method according to any one of claims 58-70, wherein the subject is at risk of developing the neurodegenerative disease.

73. The method according to any one of claims 58-71, the method further comprising determining, or having determined, that the subject has one or more symptoms associated with the neurodegenerative disease prior to administration.

74. The method according to any one of claims 58-70 and 72, the method further comprising determining, or having determined, that the subject is at risk of developing the neurodegenerative disease prior to administration.

75. The method according to any one of claims 58-74, wherein the method further comprises administering to the subject one or more agents selected from nicotinamide nucleoside or a pharmaceutically acceptable salt thereof or cat's claw extract or a component thereof.

76. The method according to any one of claims 58-74, the method comprising administering to the subject a therapeutically effective amount of ellagitannin or ellagic acid, fisetin, and a combination comprising one or more bacterial species associated with urolithiasis A production.

77. The method of claim 76, wherein the method further comprises administering nicotinamide nucleoside to the subject.

78. The method of claim 77, wherein nicotinamide nucleoside is administered in an amount of about 100 mg to about 800 mg per day.

79. The method of claim 76, wherein the method further comprises administering quercetin to the subject.

80. The method of claim 79, wherein quercetin is applied in an amount of about 50 mg to about 1000 mg.

81. The method of claim 76, wherein the method further comprises administering cat's claw extract to the subject.

82. The method of claim 81, wherein the cat's claw extract is applied in an amount of about 100 mg to about 1200 mg.

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