Flavonoids for treating traumatic brain injury and alzheimer's disease

Abstract

Embodiments of the invention include the use of flavonoids to modulate inflammation of the CNS. Formulations and methods described herein can treat traumatic brain injuries (TBI) and Alzheimer's disease (AD) by reducing systematic inflammation and modulating immune dysregulation. The formulations and methods include antagonists that bind to receptors (CCR2 and GPR55) and a prostaglandin (PGE2). When administered therapeutically with 17-DHA and / or THEA, their combined activity can reduce systemic inflammation and post-trauma inflammation. In aspects, one or more of the compounds work synergistically with one another.

Description

FLAVONOIDS FOR TREATING TRAUMATIC BRAIN INJURY AND ALZHEIMER’S DISEASERELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application No. 63 / 551 ,868 filed on February 94, 2024, the contents of which are incorporated herein by reference.FIELD OF THE INVENTION

[0002] The invention relates to therapeutics, specifically, to botanically sourced molecules and methods to treat ailments such as traumatic brain injury and Alzheimer’s disease.BACKGROUND

[0003] Inflammation can be defined as part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells or irritants. It is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out damaged cells and tissues, and initiate tissue repair. The five cardinal signs of inflammation are heat, pain, redness, swelling and loss of function. Inflammation is a generic response and therefore is considered as a mechanism of innate immunity rather than adaptive immunity.

[0004] Without adequate inflammation, an organism can succumb to infection as too little inflammation can lead to progressive tissue destruction by bacteria or other harmful stimulus. In contrast, excess inflammation (i.e., chronic inflammation) is associated with various diseases, such as hay fever, periodontal disease, atherosclerosis and osteoarthritis.

[0005] Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (in particular granulocytes) from theblood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation (i.e. , chronic inflammation) can lead to a progressive shift in the type of cells present at the site of inflammation (e.g., mononuclear cells).

[0006] There is increasing evidence that inflammation contributes to clinical and functional outcomes in traumatic brain injury (TBI). After injury to the brain, the cellular cascade of inflammation can have beneficial effects. However, if inflammation is too intense, prolonged, and unremitting, it can be harmful. Secondary injury has a slower progression ranging from minutes to years following the mechanical insult and is driven by several pathways, including: 1 ) free radical generation causing damage to molecular structures of cellular membranes, 2) excitotoxicity secondary to excess of glutamate and 3) systemic and central nervous system (CNS) immune activation. It has been proposed that immune activation and modulation can significantly change the clinical and functional course in TBI.

[0007] Similarly, clinical evidence demonstrates that inflammation contributes to Alzheimer's disease (AD) and its progression. Studies into the specific inflammatory mechanisms that play roles in disease causation and progression have revealed lessons about inflammation-driven neurodegeneration that can be applied to other neurodegenerative diseases. An increasing number of immunotherapeutic strategies that have been successful in MS are now being applied to other neurodegenerative diseases. Some approaches suppress CNS immune mechanisms, while others harness the immune system to clear deleterious products and cells.

[0008] Conventional treatments for most neurological diseases such as TBI and AD are limited. Current treatments are focused on symptoms by, for example, improving mental function, controlling behavior and slowing progress of the disease. However, such treatments are generally considered ineffective. Accordingly, there is a need for more effective therapies for neurological disorders. Embodiments of the invention include molecules for treating traumatic brain injury (TBI) and Alzheimer’s disease (AD).SUMMARY OF THE INVENTION

[0009] The inventions described and claimed herein have many attributes and embodiments including, but not limited to, those set forth or described or referenced in this brief summary. The inventions described and claimed herein are not limited to, or by, the features or embodiments identified in this summary, which is included for purposes of illustration only and not restriction.

[0010] Applicants have characterized underlying mechanisms related to inflammation and neurological disorders. In embodiments described herein, Applicants present therapeutic methods against particular targets to treat such neurological disorders.

[0011] Embodiments of the invention include the use of flavonoids to modulate inflammation of the CSN and treat neurodegenerative diseases.

[0012] Embodiments of the invention include methods for prevention and treatment of inflammation using specific flavonoid pharmaceutical compositions. In aspects, the flavonoids include: a) kaempferol 3-(2,4-di-E-p-coumaroylrhamnoside), b) cannabidiol (CBD), cannabidiphorol (CBDP) and / or tetrahydromagnolol, and c) cannflavin A and / or cannflavin B.In aspects, the formulation also includes 17-hydroxy Docosahexaenoic Acid (17-DHA) and / or tetracosahexaenoylethanolamide (THEA). In aspects, the inflammation is central nervous system (CNS) inflammation.

[0013] Accordingly, one embodiment is a method of preventing or treating a neurological disorder by modulating or suppressing chronic inflammation in neural tissue. In aspects, the neurological disorder is associated with inflammation. In aspects, the neurological disorder is traumatic brain injury (TBI) and Alzheimer’s disease (AD).

[0014] In one embodiment, the formulations described herein are useful to reduce inflammation. In aspects, the inflammation is inflammation of the CNS. In aspects the formulations can treat neurodegenerative diseases of the CNS, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and the prototypic neuroinflammatory disease multiple sclerosis (MS).

[0015] In another embodiment the formulations described herein are useful to reduce inflammation to treat a neurological disorder such as TBI or AD.

[0016] One embodiment is a formulation that includes (a) CCR2 inhibitor, (b) a GPR55 inhibitor and (c) a PGE2 inhibitor. In aspects, the CCR2 inhibitor is kaempferol 3-(2,4-di-E-p-coumaroylrhamnoside). In aspects, the GPR55 inhibitor is cannabidiol (CBD), cannabidiphorol (CBDP) and / or tetrahydromagnolol. In aspects, the PGE2 inhibitor is cannflavin A and / or cannflavin B. In aspects, the formulation also includes 17-DHA and / or THEA.

[0017] Embodiments also include methods that are effective to simultaneously inhibit CCR2, GPR55 and PGE2 activity. In aspects, the combined inhibition decreases levels of inflammation of the CNS.

[0018] One embodiment is a method of reducing CNS inflammation and / or treating a neurological disorder using a GRAS botanical formulation.

[0019] One embodiment is a method of reducing CNS inflammation and / or treating a neurological disorder in a subject by inhibiting CCR2, GPR55 and PGE2. In aspects, the subject is also treated with 17-DHA and / or THEA.

[0020] One embodiment is a method of reducing CNS inflammation and / or treating a neurological disorder that includes administering a therapeutically effective amount of a formulation that includes (a) CCR2 inhibitor, (b) a GPR55 inhibitor and (c) a PGE2 inhibitor. In aspects, the CCR inhibitor is kaempferol 3-(2,4-di-E-p- coumaroylrhamnoside. In aspects, the GPR55 inhibitor is cannabidiol (CBD),cannabidiphorol (CBDP) and / or tetrahydromagnolol. In aspects, the PGE2 inhibitor is cannflavin A and / or cannflavin B. In aspects, the formulation also includes 17-DHA and / or THEA. In aspects, the neurological disorder is inflammation of the CNS, traumatic brain injury (TBS) or Alzheimer’s disease. In aspects, one or more of the compounds work synergistically with one another to reduce CNS inflammation.

[0021] Another embodiment is a formulation that includes (a) kaempferol 3-(2,4-di- E-p-coumaroylrhamnoside), (b) cannabidiol (CBD), cannabidiphorol (CBDP) and / or tetrahydromagnolol and (c) cannflavin A and / or cannflavin B. In aspects, the formulation also includes 17-DHA and / or THEA. It is also contemplated that one or more of the compounds can be chemically modified to improve its solubility, bioavailability, etc.

[0022] One embodiment is a method of treating a neurological disorder that includes administering a therapeutically effective amount of a formluation that includes (a) kaempferol 3-(2,4-di-E-p-coumaroylrhamnoside), (b) cannabidiol (CBD), cannabidiphorol (CBDP) and / or tetrahydromagnolol and (c) cannflavin A and / or cannflavin B. In aspects, the formulation also includes 17-DHA and / or THEA. In aspects, the neurological disorder is inflammation of the CNS, traumatic brain injury (TBI) or Alzheimer’s disease. In aspects, 17-DHA and THEA attenuate effects of inflammation-based damage by promotion of NPD1 pathway. In aspects, the formulation includes about 0.5 to 5 wt.% of each of each of the above compounds for either oral administration or injection.

[0023] One embodiment is a method of treating an ailment by administering a therapeutic amount of the formulation described herein. The ailment can be, for example, inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis (MS), muscular dystrophy, neurocutaneous syndromes, Parkinson's disease (PD), stroke, headaches, encephalitis or myasthenia gravis.

[0024] One embodiment is a method of reducing amyloid plaques by administering a therapeutically effective amount of a formulation described herein. One embodiment is a method improving neuroplasticity by administering a therapeutically effective amount of a formulation described herein.

[0025] In still another aspect, the present specification provides a use of the pharmaceutical composition including the same in the preparation of drugs for the prevention or treatment of a neurological disorder caused (at least in part) by inflammation of the CNS.

[0026] In aspects, the formulations described herein reduce CNS inflammation at one or more stages of the neurodegenerative cascade.

[0027] The methods described herein can use a GRAS botanical formulation that includes antagonists that bind two key receptors (i.e. , CCR2 and GPR55) and one important prostaglandin (i.e., PGE2). In aspects, the formulation includes CBD which is both a synergist and excellent carrier.

[0028] Other features and advantages of aspects of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of aspects of the invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The accompanying drawings illustrate aspects of the present invention. In such drawings:

[0030] FIG. 1 is a flowchart that depicts CNS inflammation, related disorders and compounds that can be administered to reduce / alleviate the inflammation and prevent / treat related disorders.Definitions

[0031] Reference in this specification to "one embodiment / aspect" or "an embodiment / aspect" means that a particular feature, structure, or characteristic described in connection with the embodiment / aspect is included in at least one embodiment / aspect of the disclosure. The use of the phrase "in one embodiment / aspect" or "in another embodiment / aspect" in various places in the specification are not necessarily all referring to the same embodiment / aspect, nor are separate or alternative embodiments / aspects mutually exclusive of other embodiments / aspects. Moreover, various features are described which may be exhibited by some embodiments / aspects and not by others. Similarly, various requirements are described which may be requirements for some embodiments / aspects but not other embodiments / aspects. Embodiment and aspect can be in certain instances be used interchangeably.

[0032] The terms used in this specification generally have their ordinary meanings in the art, within the context of the disclosure, and in the specific context where each term is used. Certain terms that are used to describe the disclosure are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the disclosure. It will be appreciated that the same thing can be said in more than one way.

[0033] Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein. Nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and is not intended to further limit the scope and meaning of the disclosure or of any exemplified term. Likewise, the disclosure is not limited to various embodiments given in this specification.

[0034] The term “chronic inflammation” refers to slow, long-term inflammation lasting for prolonged periods of several months to years. Generally, the extent andeffects of chronic inflammation vary with the cause of the injury and the ability of the body to repair and overcome the damage. Causes of chronic inflammation include autoimmune disorders, exposure to toxins, untreated acute inflammation, autoinflammatory disorders and repeated episodes of acute inflammation. Lifestyle factors can also contribute to chronic inflammation (e.g., heavy alcohol consumption, high body mass index and chronic stress.

[0035] Several types of diseases are associated with chronic inflammation such as cancer, neurological diseases (e.g., Alzheimer’s disease, multiple sclerosis and PD), pulmonary diseases (e.g., asthma, COPD, hay fever and bronchitis), bone / joint disease (e.g., osteoarthritis, osteopenia, osteoporosis and rheumatoid arthritis), metabolic disorders (e.g., T2 diabetes, renal failure and fatty liver disease), cardiovascular disease (e.g., atherosclerosis, heart failure, stroke and hypertension) and autoimmune disorders (e.g., IBD, Crohn’s disease, colitis, lupus, multiple sclerosis and T1 diabetes). Conventional treatments for chronic inflammation include dietary supplements, nonsteroidal anti-inflammatory drugs (NSAIDs) and steroid injections.

[0036] The term “active agent” or “active ingredient” refers to a substance, compound, or molecule, which is biologically active or otherwise, induces a biological or physiological effect on a subject to which it is administered to. In other words, “active agent” or “active ingredient” refers to a component or components of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a secondary agent, or in other words, the component(s) of a composition to which an additional part and / or other effect of the composition is attributed.

[0037] A “formulation” or a “pharmaceutical composition” can include the combination of an active agent, such as a therapeutic peptide, with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.

[0038] The term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.

[0039] The term “generally recognized as safe” or “GRAS” refers to a United States Food and Drug Administration (FDA) designation that a chemical or substance added to food is considered safe by experts under the conditions of its intended use. An ingredient with a GRAS designation is exempted from the usual Federal Food, Drug, and Cosmetic Act (FFDCA) food additive tolerance requirements.

[0040] The term “analog” or “chemical analog” refers to a compound having a structure similar to that of another compound, but differing from it in respect to a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced with other atoms, groups, or substructures.

[0041] The term “neurological disorder” broadly refers to a disorder of the nervous system. Neurological disorders can affect the brain as well as the nerves found throughout the human body and the spinal cord. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. Neurological disorders include, for example, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headaches, encephalitis and myasthenia gravis.

[0042] The term “post-traumatic stress disorder” or “PTSD” refers to a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, violence, etc. Symptoms can include disturbing thoughts, feelings, or dreams related to the events, mental or physical distress to trauma-related cues, attempts to avoid trauma-related cues, alterations in the way a person thinks and feels, and an increase in the fight-or-flight response. PTSDcauses biochemical changes in the brain and body that differ from other psychiatric disorders such as major depression.

[0043] The term “traumatic brain injury” or “TBI” refers to an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury [mTBI / concussion] to severe traumatic brain injury), mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area). TBI can lead to temporary or permanent impairment of cognitive, physical and psychosocial functions. TBI is not a single pathophysiological event but a complex disease process, and causes structural damage and functional deficits that are due to both primary and secondary injury mechanisms. The primary injury is the result of the immediate mechanical disruption of brain tissue that occurs at the time of exposure to the external force and includes contusion, damage to blood vessels (hemorrhage), and axonal shearing, in which the axons of neurons are stretched and torn. Secondary injury evolves over minutes to months after the primary injury, and is the result of cascades of metabolic, cellular and molecular events that ultimately lead to brain cell death, tissue damage and atrophy.

[0044] The term “Alzheimer’s disease” or “AD” refers to a neurodegenerative disease that usually starts slowly and progressively worsens as it proliferates. Alzheimer’s disease is estimated to be the cause of 60-70% dementia cases, ‘dementia’ referring to an umbrella term that comprises cognitive disorders that impair memory, thinking, behavior and negatively affect a person’s ability to perform everyday activities. Specifically referring to Alzheimer’s disease, the most common symptom that leads to prognosis is a patient’s difficulty in remembering recent events.

[0045] As Alzheimer’s disease progresses, symptoms can include problems with language, disorientation (including a loss of sense-of-direction), mood swings, loss of motivation, self-neglect and further behavioral issues. Another unfortunate downside of Alzheimer’s disease is that patients who are afflicted with the disease tend to withdraw from family and society as their condition worsens.

[0046] It is believed that there are several environmental and genetic risk factors associated with the development of Alzheimer’s disease. Other risk factors may include a history of head injury, clinical depression and high blood pressure. Alzheimer’s disease and its progression is largely believed to be associated with amyloid plaques, neurofibrillary tangles and weakening neuronal connections in the brain.

[0047] The term “alcohol dependency” refers to a chronic medical condition that typically includes a current or past history of excessive drinking, a strong craving for alcohol, continued use despite repeated problems with drinking and an inability to control alcohol consumption.

[0048] The term “multiple sclerosis” or “MS” refers to an inflammatory demyelinating disease of the central nervous system (CNS) which involves a complex interaction between immune system and neural cells.

[0049] The term “transcriptional regulation” refers to the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Transcription factors are proteins that bind to specific DNA sequences in order to regulate the expression of a given gene.

[0050] Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks in the brain to change through growth and reorganization. These changes range from individual neuron pathways making new connections, to systematic adjustments like cortical remapping. Examples of neuroplasticity include circuit and network changes that result from learning a new ability, environmental influences, practice, and psychological stress. Activity-dependent plasticity can have significant implications for healthy development, learning, memory and recovery from brain damage.

[0051] The term “Neuroprotectin D1” or “NPD1” refers to a stereoselective bioactive product of DHA that exerts neuroprotection in models of experimental stroke by downregulating brain ischemia reperfusion (BIR)-induced leukocyte infiltration, proinflammatory signaling and infarct size. Further, NPD1 inhibits cytokine-mediated cyclooxygenase-2 (COX-2) expression. Moreover, neurotrophins are NPD1 -synthesis agonists, and NPD1 content is decreased in the CA1 region of the hippocampus of Alzheimer’s patients. Overall, NPD1 promotes brain cell survival via the induction of antiapoptotic and neuroprotective gene-expression programs that suppress Ap42 production and its neurotoxicity. Thus, NPD1 elicits potent cell-protective, antiinflammatory, pro-survival repair signaling.

[0052] As used herein, the term "prevention" means all of the actions by which the occurrence of the disease is restrained or retarded.

[0053] The term “treating” or “treatment” refers to one or more of (1 ) inhibiting the disease (i.e. , arresting further development of the pathology and / or symptomatology); and (2) ameliorating the disease (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease.

[0054] The term “prophylactic treatment” refers to any of: halting the onset, reducing the risk of development, reducing the incidence, delaying the onset, reducing the development, as well as increasing the time to onset of symptoms of a particular disorder.

[0055] The term “prognosis” refers to the forecast or likely outcome of a disease. As used herein, it refers to the probable outcome of a neurodegenerative disease (e.g., AD or TBI) including whether the disease will respond to treatment or mitigation efforts and / or the likelihood that the disease will progress. The stage of AD can be considered in determining a prognosis of a subject.

[0056] The therapeutic agents in the pharmaceutical compositions can beformulated in a "therapeutically effective amount" or a "prophylactical ly effective amount." A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount may vary depending on the condition to be treated, the severity and course of the condition, the mode of administration, whether the agent is administered for preventive or therapeutic purposes, the bioavailability of the particular agent(s), the ability of the therapeutic small molecule to elicit a desired response in the individual, previous therapy, the age, weight and sex of the patient, the patient's clinical history and response to the agent, the type of the therapeutic small molecule used, discretion of the attending physician, etc. A therapeutically effective amount is also one in which any toxic or detrimental effects is outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result.

[0057] The term “dementia” generally refers to a range of conditions, diseases and disorders that affect the brain’s ability to think, remember and function normally.

[0058] The term “mild cognitive impairment” or “MCI” generally refers to the stage between the expected decline in memory and thinking that happens with age and the more serious decline of dementia. MCI may include problems with memory, language or judgment.

[0059] The term “Alzheimer’s disease” or “AD” generally refers to a neurodegenerative brain disorder that slowly destroys a person’s memory and thinking skills over time.

[0060] The term “preclinical Alzheimer’s disease” generally refers to the earliest stage of Alzheimer’s disease in which amyloid beta plaques form in the brain but do not present any outward and noticeable symptoms in the afflicted.

[0061] The term “early-stage Alzheimer’s disease” generally refers to individuals ofany age who are experiencing mild symptoms of Alzheimer’s disease such as memory loss, misplacing items, forgetting familiar places and the names of familiar people.

[0062] The term “middle-stage Alzheimer’s disease” or “Moderate-stage Alzheimer’s disease” or “Moderate Alzheimer’s disease” generally refers to a greater decline in a person’s cognitive and functional abilities as compared to early-stage Alzheimer’s disease. Symptoms such as memory loss, difficulty in problem solving, and changes in personality become more pronounced and prevalent.

[0063] The term “late-stage Alzheimer’s disease” generally refers to severe dementia caused by Alzheimer’s disease. Those afflicted lose the ability to communicate coherently and experience a decline in physical abilities. Those with latestage Alzheimer’s disease require daily assistance with personal care and display a complete loss of short- and long-term memory.

[0064] The term “amyloid plaque” generally refers to sticky clumps of misfolded proteins that clog up the spaces in between brain cells.

[0065] The term “Lewy body” generally refers to a distinctive neuronal inclusion that is found in the substantia nigra and other specific brain regions in those who suffer from Parkinson’s disease and other disorders and diseases of dementia. Lewy bodies are abnormal aggregations of protein that develop inside nerve cells affected by Parkinson’s disease and dementia diseases such as AD and Lewy body dementia. Lewy bodies appear as spherical masses in the cytoplasm that displace other cell components.

[0066] The term “Protectin D1” or “neuroprotectin D1” (when it acts in the nervous system) abbreviated as PD1 or NPD1 is a member of the class of specialized proresolving mediators. Like other members of this class of polyunsaturated fatty acid metabolites, it possesses strong anti-inflammatory, anti-apoptotic and neuroprotective activity. PD1 is an aliphatic acyclic alkene 22 carbons in length with two hydroxyl groups at the 10 and 17 carbon positions and one carboxylic acid group at the onecarbon position.

[0067] The term “Docosahexaenoic acid” or “DHA” refers to the main omega-3 fatty acid that is concentrated and avidly retained in membrane phospholipids of the nervous system. DHA is involved in brain and retina function, aging and neurological and psychiatric / behavioral illnesses. Neuroprotectin D1 (NPD1 ), the first-identified stereoselective bioactive product of DHA, exerts neuroprotection in models of experimental stroke by down-regulating brain ischemia reperfusion (BIR)-induced leukocyte infiltration, proinflam matory signaling, and infarct size. Moreover, NPD1 inhibits cytokine-mediated cyclooxygenase-2 (COX-2) expression.

[0068] The term “neuronal autophagy,” “autophagy” or “type II programmed cell death” is characterized by the accumulation of autophagic vacuoles during cell death, along with toxic components such as proteins or damaged organelles. Excessive autophagy may lead to self-destruction and cell death. Autophagosomes have been identified in affected neurons of patients with AD, HD, and PD. Many stimuli also induce autophagy, including nutrient starvation, mitochondrial toxins, hypoxia, and oxidative stress.

[0069] The term “retrograde degeneration” refers to degeneration of the proximal neuronal cell body that can result from axonal injury or transection and may be associated with various pathological changes in the cell body, including apoptosis and chromatolysis of the neuronal perikaryon. The association of neuronal apoptosis with axonal damage suggests that inflammation-induced axotomy may produce retrograde (secondary) death of neuronal cell bodies via apoptosis.

[0070] The term “Wallerian degeneration” refers to proximal damage to the neuron or axon that can result in anterograde degeneration of the distal axon, termed Wallerian degeneration. Wallerian degeneration is a cascade of events that includes granular degeneration of the axonal cytoskeleton, accumulation of activated macrophages and microglia, and local changes in the immune environment. Evidence that Wallerian degeneration occurs in MS is seen in a histopathological study demonstrating inflammatory cervicomedullary junction lesion with distal axonal atrophy in the absenceof demyelination, as well as in MRI studies.

[0071] The term “demyelination” refers to loss of myelin with relative preservation of the axon. The relationship between the oligodendrocyte and axon is complex, with the provision of mutual support through trophic factors that can be disrupted in demyelinating diseases. In addition to protecting the axon from immune-mediated damage, myelin integrity protects the integrity of the developing axon. Myelin- associated glycoprotein and proteolipid protein deliver essential myelin-derived trophic signals to axons. Mice lacking proteolipid protein developed axonal swellings and degeneration, suggesting that local oligodendroglial support is critical for axon survival.

[0072] The term “astrogliopathy” refers to dysfunction of astrocytes. Aging-related tau astrogliopathy (ARTAG) describes the pathological accumulation of abnormally phosphorylated tau protein in astrocytes that is found in AD, frontal temporal lobe dementias, and corticobasal degeneration. Neuromyelitis optica (NMO) presents with optic neuritis and myelitis and can mimic MS. NMO is associated with the presence of aquaporin-4 (AQP4) antibodies, which target astrocyte water channels. Pathologically NMO is characterized by extensive loss of immunoreactivity for the astrocytic proteins AQP4 and glial fibrillary acidic protein (GFAP), perivascular deposition of immunoglobulins, and activation of complement even within lesions with relative preservation of myelin.

[0073] The term “apoptosis” refers to a caspase-mediated programmed cell death characterized by formation of membrane-enveloped apoptotic bodies that are rapidly phagocytosed by macrophages or neighboring cells. There is evidence of apoptotic mechanisms in animal models of several neurodegenerative diseases, but evidence in human tissues is limited. Caspase-1 , -3, -8, and -9 activation and cytochrome c release seen in models of Huntington’s disease (HD) were also demonstrated in human striatal brain tissue. Similarly, caspase activation and neuronal apoptosis have been demonstrated in ALS and HIV-associated neurodegeneration.

[0074] The term “necroptosis” refers to a form of programmed cell death that is independent from the caspase activation and involves loss of plasma membraneintegrity. Two main effector proteins of necroptosis are receptor-interacting serine / threonine-protein kinase 1 (RIPK1 ) and mixed-lineage kinase domain-like (MLKL). Astrocytes release TNF-a, FasL, and TRAIL, which can trigger necroptosis through RIPK1 and MLKL activation, and this mechanism has been demonstrated in murine models of ALS. RIPK1 -mediated axonal pathology was observed in pathological specimens from ALS patients. Necroptotic mechanisms were also observed in MS pathological samples.

[0075] The term “flavonoids” refers to phytochemical compounds present in many plants, fruits, vegetables, and leaves, with potential applications in medicinal chemistry. Flavonoids possess a number of medicinal benefits, including anticancer, antioxidant, anti-inflammatory and antiviral properties. They also have neuroprotective and cardioprotective effects. These biological activities depend upon the type of flavonoid, its (possible) mode of action, and its bioavailability. These cost-effective medicinal components have significant biological activities, and their effectiveness has been proved for a variety of diseases.

[0076] The term “cannabidiol” or “CBD” refers to a natural, non-psychoactive phytocannabinoid that occurs naturally in cannabis plants, including hemp. There are some 113 identified CBD’s in cannabis plants and CBD accounts for up to 40% of the cannabis plant's extract. CBD is known to act on cannabinoid receptors and several other neurotransmitters in the body. Clinical research has found that CBD showed efficacy in the treatment of different diseases and syndromes including anxiety, cognition, movement disorders, and pain.

[0077] The term “inhibitor” generally refers to chemical or biological molecules that regulate chemical reactions by slowing down or blocking them from occurring. Inhibitors often work to slow or stop enzymes. Accordingly, a CCR2 inhibitor is a substance that prevents the activation of the chemokine receptor CCR2 (e.g. PF-04136309, BMS CCR2 22 and BMS-813160). CCR2 inhibitors have been used to treat chronic diseases (e.g., hepatitis and cirrhosis). Similarly, a GPR55 inhibitor is a substance that reduces the activity of the G protein-coupled receptor 55 (GPR55). Examples includeCID16020046 and ML-193 (CID 1261822). A PGE2 inhibitor is a substance that reduces the production of prostaglandin E2 (PGE2). Examples include nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors and EP2 / EP4 antagonists.

[0078] The term “composition” or “pharmaceutical composition” refers to a product with the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from such combinations of the specified ingredients in the specified amounts and one or more pharmaceutically acceptable carriers therefor.

[0079] The term “pharmaceutically acceptable carrier” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0080] The term "administration" refers to the introduction of an amount of a predetermined substance into a patient by a certain suitable method. The composition disclosed herein may be administered via any of the common routes, as long as it is able to reach a desired tissue, for example, but is not limited to, inhaling, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrapulmonary, or intrarectal administration.

[0081] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are to be understood as approximations in accordance with common practice in the art. When used herein, the term “about” may connote variation (+) or (-) 1 %, 5% or 10% of the stated amount, as appropriate given the context. It is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0082] Many known and useful compounds and the like can be found in Remington’s Pharmaceutical Sciences (13thEd), Mack Publishing Company, Easton, PA — a standard reference for various types of administration. As used herein, the term “formulation(s)” means a combination of at least one active ingredient with one or more other ingredient, also commonly referred to as excipients, which may be independently active or inactive. The term “formulation” may or may not refer to a pharmaceutically acceptable composition for administration to humans or animals and may include compositions that are useful intermediates for storage or research purposes.

[0083] Other technical terms used herein have their ordinary meaning in the art that they are used, as exemplified by a variety of technical dictionaries. The particular values and configurations discussed in these non-limiting examples can be varied and are cited merely to illustrate at least one embodiment and are not intended to limit the scope thereof.DETAILED DESCRIPTION

[0084] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the subject technology as claimed. Additional features and advantages of the subject technology are set forth in the description below, and in part will be apparent from the description, or may be learned by practice of the subject technology. The advantages of the subject technology will be realized and attained by the structure particularly pointed out in the written description and claims hereof.

[0085] Studies have linked chronic inflammation with various diseases including hay fever, periodontal disease, atherosclerosis and osteoarthritis. Similarly, there is evidence that inflammation plays a critical role in neurodegenerative diseases of the CNS, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and multiple sclerosis (MS). Prolonged inflammation (i.e., chronic inflammation) leads to a progressive shift in the type of cells present at the siteof inflammation, such as mononuclear cells, and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. Several mechanisms that drive neurodegeneration may be triggered by inflammatory cells and their mediators at various stages of the neurodegenerative cascade including apoptosis, necroptosis, neuronal autophagy, retrograde degeneration, Wallerian degeneration, demyelination, astrogliopathy, apoptosis and necroptosis.Traumatic Brain Injury

[0086] Traumatic Brain Injury or “TBI” is not a single pathophysiological event but a complex disease process and causes structural damage and functional deficits that are due to both primary and secondary injury mechanisms. The primary injury is the result of the immediate mechanical disruption of brain tissue that occurs at the time of exposure to the external force and includes contusion, damage to blood vessels (hemorrhage), and axonal shearing, in which the axons of neurons are stretched and torn. Secondary injury evolves over minutes to months after the primary injury, and is the result of cascades of metabolic, cellular and molecular events that ultimately lead to brain cell death, tissue damage and atrophy.

[0087] There is increasing evidence that inflammation contributes to clinical and functional outcomes in traumatic brain injury (TBI). Timing and immunological context are paramount for the direction, quality, and intensity of immune responses to TBI and the resulting neuroanatom ical, clinical, and functional course. After injury (i.e. , TBI), the cellular cascade of inflammation can have beneficial effects. However, inflammation can be harmful if it is intense and / or prolonged. Secondary injury has a slower progression ranging from minutes to years following the mechanical insult and is driven by several pathways, including: a) free radical generation causing damage to molecular structures of cellular membranes, b) excitotoxicity secondary to excess of glutamate and 3) systemic and central nervous system (CNS) immune activation. Applicants have recognized that immune modulation can significantly change the clinical and functional course in TBI.Alzheimer’s disease

[0088] Alzheimer’s disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens as it proliferates. Alzheimer’s disease is estimated to be the cause of 60 - 70% of dementia cases. The most common symptom that leads to prognosis is difficulty remembering recent events. As Alzheimer’s disease progresses, symptoms can include problems with language, disorientation (including a loss of sense-of-direction), mood swings, loss of motivation, self-neglect and further behavioral issues. Another unfortunate downside of Alzheimer’s disease is that patients who are afflicted with the disease tend to withdraw from family and society as their condition worsens.

[0089] It is believed that there are several environmental and genetic risk factors associated with the development of Alzheimer’s disease. Other risk factors may include a history of head injury, clinical depression and high blood pressure. Alzheimer’s disease and its progression is largely believed to be associated with amyloid plaques, neurofibrillary tangles and weakening neuronal connections in the brain.

[0090] Recent studies have linked inflammation of the CSN with onset and progression of AD. For example, the sustained activation of the brain's resident macrophages (i.e. , microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder.Flavonoids

[0091] Flavonoids are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed by humans. Chemically, flavonoids have the general structure of a 15-carbon skeleton, which includes two phenyl rings (A and B) and a heterocyclic ring (C, the ring containing the embedded oxygen).

[0092] Flavonoids may have pharmacological activities and are often used for antioxidant, antidiabetic, anti-inflammatory, antiallergic, antibiotic, antidiarrheal and anticancer properties. While many plats are rich in flavonoids, studies have identified over twenty flavonoids in the Cannabis plant, including cannflavin A, cannflavin B, cannflavinC, chrysoeril, cosmosiin, flavocannabiside, vitexin, isovitexin, apigenin, kaempferol, myricetin, quercetin, luteolin, homoorientin and orientin. Cannabis flavonoids have been shown to have several pharmacological properties especially the most common flavonoids such as quercetin, apigenin, luteolin and kaempferol. Recent studies suggest potential therapeutic use cannflavins and other related flavonoids isolated either from cannabis or from other plants to reduce inflammation.

[0093] Applicants present methods of reducing inflammation or treating a neurodegenerative disease by inhibiting (a) chemokine receptor CCR2, (b) g protein- coupled receptor 55 and (c) prostoglanden E2 receptor activity. In aspects, flavonoids are administered as receptor antagonists. Inhibition of the receptors can reduce CNS inflammation to prevent / treat neurodegenerative diseases such as TBI and AD. In aspects, 17-hydroxy Docosahexaenoic Acid (17-DHA) and / or tetracosahexaenoylethanolamide (THEA) are also included in the methods described herein to enhance action of receptor antagonists.

[0094] Chemokine receptor CCR2 (CCR2) is the receptor for C-C motif chemokine 2 (CCL2) and is associated with various inflammatory diseases and cancer metastasis. CCR2 deficient mice have been shown to develop an accelerated Alzheimer's-like pathology in comparison to wild type mice. Animal model studies of chronic inflammatory diseases have demonstrated that inhibition of binding between CCL2 and CCR2 by an antagonist suppresses the inflammatory response. The interaction between CCL2 and CCR2 has been implicated in several inflammatory diseases.CCR2 antagonists include, for example, kaempferol 3-(2,4-di-E-p- coumaroylrhamnoside, CCX872, BMS-741672 and Cenicriviroc (TAK-652).

[0095] G protein-coupled receptor 55 (GPR55) is a cannabinoid receptor that increases intracellular calcium and inhibits M current. GPR55, along with GPR119 and GPR18, have been implicated as novel cannabinoid receptors. GPR55 antagonists include, for example, CBD, KIT 10, CID16020046 and 2-arachidonoyl-3-glycero- phosphoinositol.

[0096] Prostaglandin E2 (PGE2) is a terminal prostaglandin in the cyclooxygenase (COX) pathway. Inhibition of PGE2 production may relieve inflammatory symptoms such as fever, arthritis and inflammatory pain. Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. It is used in labor induction, bleeding after delivery, termination of pregnancy, and in newborn babies to keep the ductus arteriosus open. PGE2 antagonists include, for example, cannflavin A, cannflavin B, SC-19220, E7046 and TG6-129.

[0097] Accordingly, embodiments include methods of reducing inflammation or treating an ailment that includes administering (a) a CCR inhibitor, (b) a GPR55 inhibitor and (c) a PGE2 inhibitor. In aspects, a formulation is administered includes the flavonoids (a) kaempferol 3-(2,4-di-E-p-coumaroylrhamnoside, (b) cannabidiol (CBD), cannabidiphorol (CBDP) or tetrahydromagnolol and (c) cannflavin A and cannflavin B.

[0098] FIG. 1 is a flowchart that depicts CNS inflammation, related disorders and compounds that can be administered to reduce / alleviate the inflammation and prevent / treat the disorders. CNS inflammation can cause and / or exasperate conditions such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), traumatic brain injury (TBI) and multiple sclerosis (MS). The CNS inflammation can be prevented or reduced by administering a formulation that includes (a) CCR2 antagonist, (b) a GPR55 antagonist and (c) a PGE2 antagonist. Also shown are chemical structres of kaempferol 3-(2,4-di-E-p-coumaroylrhamnoside), cannabidiol (CBD), cannflavin, 17-hydroxy Docosahexaenoic Acid (17-DHA) and tetracosahexaenoylethanolamide (THEA). One or more of the compounds can be administered in a formulation to reduce CNS inflammation and treat ailments such as ALS, MS, TBI, PD and AD.Methods of Treatment

[0099] Embodiments include formulations to treat neurodegenerative diseases suchas traumatic brain injuries (TBI) and Alzheimer’s disease (AD). In aspects, the formulations reduce systematic inflammation and / or modulate immune dysregulation.

[0100] The compounds described herein can be administered in various forms, depending on the disorder to be treated and the age, condition, and body weight of the patient, as is well known in the art. For example, where the compositions are to be administered orally, they may be formulated as tablets, capsules, granules, powders, or syrups; or for parenteral administration, they may be formulated as injections (intravenous, intramuscular, or subcutaneous), drop infusion preparations, or suppositories. Any suitable route or mode of administration can be employed for providing the patient with a therapeutically or prophylactically effective dose of the therapeutic peptide. Exemplary routes or modes of administration include parenteral (e.g., intravenous, intraarterial, intramuscular, subcutaneous, intratumoral), oral, topical (nasal, transdermal, intradermal or intraocular), mucosal (e.g., nasal, sublingual, buccal, rectal, vaginal), inhalation, intralymphatic, intraspinal, intracranial, intraperitoneal, intratracheal, intravesical, intrathecal, enteral, intrapulmonary, intralymphatic, intracavital, intraorbital, intracapsular and transurethral, as well as local delivery by catheter or stent.

[0101] The methods described herein can be used to treat numerous disorders related to CNS inflammation including post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headaches, encephalitis and myasthenia gravis.

[0102] A pharmaceutical formulation in accordance with the present disclosure can be formulated in any pharmaceutically acceptable carrier(s) or excipient(s). Pharmaceutical compositions can include suitable solid or gel phase carriers or excipients. Exemplary carriers or excipients include calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers suchas polyethylene glycols. Exemplary pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. In many cases it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers can further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the therapeutic agents.

[0103] The therapeutic compounds can be incorporated into a pharmaceutical composition suitable for parenteral administration. Suitable buffers include but are not limited to, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate. Sodium chloride can be used to modify the toxicity of the solution at a concentration of 0 - 300 mM (optimally 150 mM for a liquid dosage form).Cryoprotectants can be included for a lyophilized dosage form, principally 0 - 10% sucrose (optimally 0.5 - 1 .0%). Other suitable cryoprotectants include trehalose and lactose. Bulking agents can be included for a lyophilized dosage form, principally 1 - 10% mannitol (optimally 2 - 4%). Stabilizers can be used in both liquid and lyophilized dosage forms, principally 1 - 50 mM L-Methionine (optimally 5 - 10 mM). Other suitable bulking agents include glycine, arginine, can be included as 0 - 0.05%> polysorbate-80 (optimally 0.005 - 0.0 1 %). Additional surfactants include but are not limited to polysorbate 20 and BRIJ surfactants.

[0104] Therapeutic preparations can be lyophilized and stored as sterile powders, preferably under vacuum, and then reconstituted in bacteriostatic water (containing, for example, benzyl alcohol preservative) or in sterile water prior to injection.Pharmaceutical compositions can be formulated for parenteral administration by injection e.g., by bolus injection or continuous infusion.

[0105] The therapeutic compounds can be administered as a preventive measure (i.e. , to avoid an ailment) at one time or multiple times. Alternatively, the therapeutic small molecule is suitably administered to the patient at one time or over a series oftreatments and may be administered to the patient at any time from diagnosis onwards. The therapeutic small molecule may be administered as the sole treatment or in conjunction with other drugs or therapies useful in treating the condition in question.

[0106] Certain embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0107] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.Administration

[0108] The formulations described herein can be suitably administered to the patient at one time or over a series of treatments and may be administered to the patient at any time from diagnosis onwards. Alternatively, it can be administered as a preventive measure (i.e. to avoid infection). The solution can be administered as the sole treatment or in conjunction with other drugs or therapies useful in treating the condition in question.

[0109] As a general proposition, a therapeutically effective amount or prophylactical ly effective amount of therapeutic agents in the pharmaceutical compositions will be each administered in a range from about 1 ng / kg body weight to about 100 mg / kg body weight whether by one or more administrations. In a particular embodiment, each therapeutic small molecule is administered in the range of from about 1 ng / kg body weight to about 10 mg / kg body weight, about 1 ng / kg body weight to about 1 mg / kg body weight, about 1 ng / kg body weight to about 100 g / kg body weight, about 1 ng / kg body weight to about 10 g / kg body weight, about 1 ng / kg body weight / day to about 1 g / kg body weight, about 1 ng / kg body weight to about 100 ng / kg body weight, about 1 ng / kg body weight to about 10 ng / kg body weight, about 10 ng / kg body weight to about 100 mg / kg body weight, about 10 ng / kg body weight to about 10 mg / kg body weight, about 10 ng / kg body weight to about 1 mg / kg body weight, about 10 ng / kg body weight / to about 100 g / kg body weight, about 10 ng / kg body weight to about 10 mg / kg body weight, about 10 ng / kg body weight to about 1 mg / kg body weight, 10 ng / kg body weight to about 100 ng / kg body weight / , about 100 ng / kg body weight to about 100 mg / kg body weight, about 100 ng / kg body weight to about 10 mg / kg body weight, about 100 ng / kg body weight to about 1 mg / kg body weight, about 100 ng / kg body weight to about 100 mg / kg body weight, about 100 ng / kg body weight to about 10 mg / kg body weight, about 100 ng / kg body weight to about 1 mg / kg body weight, about 1 mg / kg body weight to about 100 mg / kg body weight, about 1 mg / kg body weight to about 10 mg / kg body weight / day, about 1 mg / kg body weight to about 1 mg / kg body weight, about 1 mg / kg body weight to about 100 mg / kg body weight, about 1 mg / kg body weight to about 10 mg / kg body weight, about 10 mg / kg body weight to about 100 mg / kg body weight, about 10 mg / kg body weight to about 10 mg / kg body weight, about 10 mg / kg body weight to about 1 mg / kg body weight / day, about 10 mg / kg body weight to about 100 mg / kg body weight, about 100 mg / kg body weight / day to about 100 mg / kg body weight, about 100 mg / kg body weight / day to about 10 mg / kg body weight, about 100 mg / kg body weight / day to about 1 mg / kg body weight, about 1 mg / kg body weight to about 100 mg / kg body weight, about 1 mg / kg body weight to about 10 mg / kg body weight, about 10 mg / kg body weight to about 100 mg / kg body weight / day.

[0110] In other embodiments, the compounds described herein are eachadministered in the range of about 10 ng to about 100 ng per individual administration, about 10 ng to about 1 g per individual administration, about 10 ng to about 10 g per individual administration, about 10 ng to about 100 mg per individual administration, about 10 ng to about 1 mg per individual administration, about 10 ng to about 10 mg per individual administration, about 10 ng to about 100 mg per individual administration, about 10 ng to about 1000 mg per injection, about 10 ng to about 10,000 mg per individual administration, about 100 ng to about 1 mg per individual administration, about 100 ng to about 10 mg per individual administration, about 100 ng to about 100 mg per individual administration, about 100 ng to about 1 mg per individual administration, about 100 ng to about 10 mg per individual administration, about 100 ng to about 100 mg per individual administration, about 100 ng to about 1000 mg per injection, about 100 ng to about 10,000 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 1 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 1000 mg per injection, about 1 mg to about 10,000 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1 mg per individual administration, about 10 mg to about 10 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1000 mg per injection, about 10 mg to about 10,000 mg per individual administration, about 100 mg to about 1 mg per individual administration, about 100 mg to about 10 mg per individual administration, about 100 mg to about 100 mg per individual administration, about 100 mg to about 1000 mg per injection, about 100 mg to about 10,000 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 1000 mg per injection, about 1 mg to about 10,000 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1000 mg per injection, about 10 mg to about 10,000 mg per individual administration, about 100 mg to about 1000 mg per injection, about 100 mg to about 10,000 mg per individual administration and about 1000 mg to about 10,000 mg per individual administration. The therapeutic small molecule may beadministered daily, every 2, 3, 4, 5, 6, 7 or 10 days, or every 1 , 2, 3 or 4 weeks.

[0111] In other particular embodiments, the amount of the compounds described herein can each be administered at a dose of about 0.0006 mg, 0.001 mg, 0.003 mg, 0.006 mg, 0.01 mg, 0.03 mg, 0.06 mg, 0.1 mg, 0.3 mg, 0.6 mg, 1 mg, 3 mg, 6 mg, 10 mg, 30 mg, 60 mg, 100 mg, 300 mg, 600 mg, 1000 mg, 2000 mg, 5000 mg or 10,000 mg. As expected, the dosage will be dependent on the condition, size, age and condition of the patient.

[0112] Alternatively, the formulations described herein can include equal amounts of each compound. In aspects, the total amount administered for a therapeutic effect is 250 mg / day to 500 mg / day. In other embodiments, the total (combined) amount of the compounds described herein is administered at a dose of about 0.0006 mg, 0.001 mg, 0.003 mg, 0.006 mg, 0.01 mg, 0.03 mg, 0.06 mg, 0.1 mg, 0.3 mg, 0.6 mg, 1 mg, 3 mg, 6 mg, 10 mg, 30 mg, 60 mg, 100 mg, 300 mg, 600 mg, 1000 mg, 2000 mg, 5000 mg or 10,000 mg.

[0113] In other aspects of this embodiment, a pharmaceutical composition compound disclosed herein reduces signs / symptoms of an ailment such as a neurological disorder by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In yet other aspects of this embodiment, a pharmaceutical composition disclosed herein reduces signs / symptoms of an ailment such as a neurological disorder from, e.g., about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0114] A pharmaceutical composition disclosed herein is in an amount sufficient to allow customary administration to an individual. In aspects of this embodiment, a pharmaceutical composition disclosed herein can be, e.g., at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a pharmaceutical composition. In other aspects of this embodiment, a pharmaceutical composition disclosed herein may be, e.g., at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 ,000 mg, at least 1 ,100 mg, at least 1 ,200 mg, at least 1 ,300 mg, at least 1 ,400 mg, or at least 1 ,500 mg of a pharmaceutical composition. In yet other aspects of this embodiment, a pharmaceutical composition disclosed herein may be in the range of, e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1 ,000 mg, about 850 mg to about 1 ,200 mg, or about 1 ,000 mg to about 1 ,500 mg. In still other aspects of this embodiment, a pharmaceutical composition disclosed herein may be in the range of, e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1 ,000 mg, about 10 mg to about 1 ,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1 ,000 mg, about 50 mg to about 1 ,500 mg, about 100 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1 ,000 mg, about 100 mg to about 1 ,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1 ,000 mg, about 200 mg to about 1 ,500 mg, about 5 mg to about 1 ,500 mg, about 5 mg to about 1 ,000 mg, or about 5 mg to about 250 mg.

[0115] A pharmaceutical composition disclosed herein can include a solvent, emulsion or other diluent in an amount sufficient to dissolve a pharmaceutical composition disclosed herein. In other aspects of this embodiment, a pharmaceutical composition disclosed herein may comprise a solvent, emulsion or a diluent in an amount of, e.g., less than about 90% (v / v), less than about 80% (v / v), less than about 70% (v / v), less than about 65% (v / v), less than about 60% (v / v), less than about 55% (v / v), less than about 50% (v / v), less than about 45% (v / v), less than about 40% (v / v), less than about 35% (v / v), less than about 30% (v / v), less than about 25% (v / v), less than about 20% (v / v), less than about 15% (v / v), less than about 10% (v / v), less than about 5% (v / v), or less than about 1 % (v / v). In other aspects of this embodiment, a pharmaceutical composition disclosed herein may comprise a solvent, emulsion or other diluent in an amount in a range of, e.g., about 1 % (v / v) to 90% (v / v), about 1 % (v / v) to 70% (v / v), about 1 % (v / v) to 60% (v / v), about 1 % (v / v) to 50% (v / v), about 1 % (v / v) to40% (v / v), about 1 % (v / v) to 30% (v / v), about 1 % (v / v) to 20% (v / v), about 1 % (v / v) to10% (v / v), about 2% (v / v) to 50% (v / v), about 2% (v / v) to 40% (v / v), about 2% (v / v) to30% (v / v), about 2% (v / v) to 20% (v / v), about 2% (v / v) to 10% (v / v), about 4% (v / v) to50% (v / v), about 4% (v / v) to 40% (v / v), about 4% (v / v) to 30% (v / v), about 4% (v / v) to20% (v / v), about 4% (v / v) to 10% (v / v), about 6% (v / v) to 50% (v / v), about 6% (v / v) to40% (v / v), about 6% (v / v) to 30% (v / v), about 6% (v / v) to 20% (v / v), about 6% (v / v) to10% (v / v), about 8% (v / v) to 50% (v / v), about 8% (v / v) to 40% (v / v), about 8% (v / v) to30% (v / v), about 8% (v / v) to 20% (v / v), about 8% (v / v) to 15% (v / v), or about 8% (v / v) to 12% (v / v).

[0116] The final concentration of a pharmaceutical composition disclosed herein in a pharmaceutical composition disclosed herein can be of any concentration desired. In an aspect of this embodiment, the final concentration of a pharmaceutical composition in a pharmaceutical composition may be a therapeutically effective amount. In other aspects of this embodiment, the final concentration of a pharmaceutical composition in a pharmaceutical composition may be, e.g., at least 0.00001 mg / mL, at least 0.0001 mg / mL, at least 0.001 mg / mL, at least 0.01 mg / mL, at least 0.1 mg / mL, at least 1 mg / mL, at least 10 mg / mL, at least 25 mg / mL, at least 50 mg / mL, at least 100 mg / mL, at least 200 mg / mL or at least 500 mg / mL. In other aspects of this embodiment, thefinal concentration of a pharmaceutical composition in a pharmaceutical composition may be in a range of, e.g., about 0.00001 mg / mL to about 3,000 mg / mL, about 0.0001 mg / mL to about 3,000 mg / mL, about 0.01 mg / mL to about 3,000 mg / mL, about 0.1 mg / mL to about 3,000 mg / mL, about 1 mg / mL to about 3,000 mg / mL, about 250 mg / mL to about 3,000 mg / mL, about 500 mg / mL to about 3,000 mg / mL, about 750 mg / mL to about 3,000 mg / mL, about 1 ,000 mg / mL to about 3,000 mg / mL, about 100 mg / mL to about 2,000 mg / mL, about 250 mg / mL to about 2,000 mg / mL, about 500 mg / mL to about 2,000 mg / mL, about 750 mg / mL to about 2,000 mg / mL, about 1 ,000 mg / mL to about 2,000 mg / mL, about 100 mg / mL to about 1 ,500 mg / mL, about 250 mg / mL to about 1 ,500 mg / mL, about 500 mg / mL to about 1 ,500 mg / mL, about 750 mg / mL to about 1 ,500 mg / mL, about 1 ,000 mg / mL to about 1 ,500 mg / mL, about 100 mg / mL to about 1 ,200 mg / mL, about 250 mg / mL to about 1 ,200 mg / mL, about 500 mg / mL to about 1 ,200 mg / mL, about 750 mg / mL to about 1 ,200 mg / mL, about 1 ,000 mg / mL to about 1 ,200 mg / mL, about 100 mg / mL to about 1 ,000 mg / mL, about 250 mg / mL to about 1 ,000 mg / mL, about 500 mg / mL to about 1 ,000 mg / mL, about 750 mg / mL to about 1 ,000 mg / mL, about 100 mg / mL to about 750 mg / mL, about 250 mg / mL to about 750 mg / mL, about 500 mg / mL to about 750 mg / mL, about 100 mg / mL to about 500 mg / mL, about 250 mg / mL to about 500 mg / mL, about 0.00001 mg / mL to about 0.0001 mg / mL, about 0.00001 mg / mL to about 0.001 mg / mL, about 0.00001 mg / mL to about 0.01 mg / mL, about 0.00001 mg / mL to about 0.1 mg / mL, about 0.00001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 0.01 mg / mL, about 0.001 mg / mL to about 0.1 mg / mL, about 0.001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 10 mg / mL, or about 0.001 mg / mL to about 100 mg / mL.

[0117] Aspects of the present specification disclose, in part, treating an individual who is susceptible to an ailment (e.g., a neurological disorder) or suffering from an ailment. As used herein, the term "treating," refers to reducing or eliminating the signs / symptoms of the ailment; or lowering or depleting signs / symptoms. For example, the term "treating" can mean reducing a symptom of a condition characterized by an ailment, by, e.g., at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or at least 100%. Those ofskill in the art will know the appropriate symptoms or indicators associated with a specific type of ailment and will know how to determine if an individual is a candidate for treatment as disclosed herein.

[0118] In aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces signs / symptoms of an ailment, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces signs / symptoms of an ailment by, e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95% or at most 100%. In yet other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces signs / symptoms of an ailment by, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0119] In yet other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein generally is in the range of about 0.001 mg / kg to about 100 mg / kg and administered, for example, every 3, 5, 7, 10 or 14 days. In aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be, e.g., at least 0.001 mg / kg, at least 0.01 mg / kg, at least 0.1 mg / kg, at least 1 .0 mg / kg, at least 5.0 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, or at least 50 mg / kg and administered, for example, every 3,5, 7, 10 or 14 days. In other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be in the range of, e.g., about 0.001 mg / kg to about 10 mg / kg, about 0.001 mg / kg / day to about 15 mg / kg, about 0.001 mg / kg to about 20 mg / kg, about 0.001 mg / kg to about 25 mg / kg, about 0.001 mg / kg to about 30 mg / kg, about 0.001 mg / kg to about 35 mg / kg, about 0.001 mg / kg to about 40 mg / kg, about 0.001 mg / kg to about 45 mg / kg, about 0.001 mg / kg to about 50 mg / kg, about 0.001 mg / kg to about 75 mg / kg, or about 0.001 mg / kg to about 100 mg / kg and administered, for example, every 3, 5, 7, 10 or 14 days. In yet other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be in the range of, e.g., about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 15 mg / kg, about 0.01 mg / kg to about 20 mg / kg, about 0.01 mg / kg to about 25 mg / kg, about 0.01 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 35 mg / kg, about 0.01 mg / kg to about 40 mg / kg, about 0.01 mg / kg to about 45 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.01 mg / kg to about 75 mg / kg, or about 0.01 mg / kg to about 100 mg / kg and administered, for example, every 3, 5, 7, 10 or 14 days. In still other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be in the range of, e.g., about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 35 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.1 mg / kg to about 45 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 75 mg / kg, or about 0.1 mg / kg to about 100 mg / kg and administered, for example, every 3, 5, 7, 10 or 14 days.

[0120] Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art. For example, treatment of an ailment or addiction infection can comprise a one-time administration of an effective dose of a pharmaceutical composition disclosed herein. Alternatively, treatment of an ailment or addiction may include multiple administrations of an effective dose of a pharmaceutical composition carried out over a range of time periods, such as, e.g., once daily, twice daily, trice daily, once every few days, or once weekly. The timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual's symptoms. For example, an effective dose of a pharmaceutical compositiondisclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy. A person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a pharmaceutical composition disclosed herein that is administered can be adjusted accordingly.

[0121] In a further embodiment, the therapeutic compounds described herein have half-lives of 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, one month, two months, three months, four months or more.

[0122] In an embodiment, the period of administration of the formulations described herein therapeutic is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0123] In aspects of this embodiment, a therapeutically effective amount of a therapeutic disclosed herein reduces the signs / symptoms of an ailment such as a neurological disorder by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a therapeutic disclosed herein reduces the signs / symptoms of an ailment such as a neurological disorder by, e.g., at most 10%, at most 15%, at most20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95% or at most 100%. In yet other aspects of this embodiment, a therapeutically effective amount of a therapeutic disclosed herein reduces the signs / symptoms of an ailment such as a neurological disorder, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0124] In an embodiment, treatment with a formulation described herein decreases the severity of a neurological disorder, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0125] In an embodiment, treatment with a formulation described herein decreases the signs / symptoms of a neurodegenerative disease, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0126] In an embodiment, treatment with a formulation described herein decreasesCNS inflammation in a patient, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0127] In one embodiment, the dose of the compositions are administered daily, semi-weekly, weekly, bi-weekly, or monthly. The period of treatment may be for a week, two weeks, a month, two months, four months, six months, eight months, a year, or longer. The initial dose may be larger than a sustaining dose. In one embodiment, the dose (of each compound) ranges from a weekly dose of at least 0.01 mg / kg, at least 0.25 mg / kg, at least 0.3 mg / kg, at least 0.5 mg / kg, at least 0.75 mg / kg, at least 1 mg / kg, at least 2 mg / kg, at least 3 mg / kg, at least 4 mg / kg, at least 5 mg / kg, at least 6 mg / kg, at least 7 mg / kg, at least 8 mg / kg, at least 9 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, or at least 30 mg / kg In one embodiment, a weekly dose may be at most 1 .5 mg / kg, at most 2 mg / kg, at most 2.5 mg / kg, at most 3 mg / kg, at most 4 mg / kg, at most 5 mg / kg, at most 6 mg / kg, at most 7 mg / kg, at most 8 mg / kg, at most 9 mg / kg, at most 10 mg / kg, at most 15 mg / kg, at most 20 mg / kg, at most 25 mg / kg, or at most 30 mg / kg. In a particular aspect, the weekly dose may range from 5 mg / kg to 20 mg / kg. In an alternative aspect, the weekly dose may range from 10 mg / kg to 15 mg / kg.EXAMPLES

[0128] The following non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples are intended to be a mere subset of all possible contexts in which the components of the formulation may be combined. Thus, these examples should not be construed to limit any of the embodiments described in the present specification, including those pertaining to the type and amounts of componentsof the formulation and / or methods and uses thereofExample 1Rodent Model for Traumatic Brain Injury (TBI) Assessment

[0129] Recent studies have demonstrated that rodent models can simulate stress induction and traumatic brain injury (TBI). See, for example, Verbitsky et al. Translational Psychiatry (2020) 10:132. Physical stressors used to develop TBI models include electric shock, underwater trauma, restraint / immobilization stress, and single prolonged stress. By manipulating stress type, intensity, duration, and frequency, preclinical models reflect core TBI phenotypes, measured through various behavioral assays.

[0130] In this example, a fluid percussion injury model (FPI) is used to study the effect of the below formulation on rats after FPI. In FPI models, the insult is inflicted by a pendulum striking the piston of a reservoir of fluid to generate a fluid pressure pulse to the intact dura through a craniotomy, which is made either centrally around the midline. In rats, LFPI produces a combination of focal cortical contusion and diffuse subcortical (such as hippocampus and thalamus) neuronal injury, which occurs within minutes of the impact, progresses to a loss of neurons by 12 hours, and does not markedly expand into other brain regions by 7 days post injury. The contused cortex beneath the injury site enlarges over weeks to become a cavity lined with glia and continues to expand up to one year post-injury due to ongoing cell death. Over days to months, progressive degenerative cascades persist in selectively vulnerable brain regions, including the ipsilateral hippocampus, thalamus, medial septum, striatum and amygdala. LFPI produces neurobehavioural and cognitive deficits such as difficulties with movement and memory that are commonly seen in patients with TBI. Cognitive dysfunction and neurological impairments persist for more than a year following severe LFPI.

[0131] This approach produced acute and chronic TBI features similar to that observed in the LFPI literature, as quantified by histological changes, structural changes seen on MRI and chronic behavioural sequelae.

[0132] In this example, rats are subject to inflicted by a pendulum striking. Rats are then treated with the below formulation and tested for signs / symptoms of TBI. The treated population of rats is compared with a control group. The results demonstrated that rats treated with the formulation below recover from TBI faster with less (or no) long-term effects than those in a control group.Table 1 - Flavonoid FormulationExample 2 Formulation for Treating Alzheimer's Disease

[0133] In this example, a patient complains of symptoms characteristic of Alzheimer's disease (AD) including problems with language, disorientation, mood swings, loss of motivation and self-neglect. The treating physician diagnoses the patient with early to mid-onset AD. To prevent progression of the disease, the patient is administered the flavonoid formulation described below. The patient is administered the formulation orally and approximately equal amounts of each ingredient (combined total of 500 mg / day).

[0134] Within two weeks, the signs / symptoms of AD diminish and the patient appears in good health. The patient resumes the treatment and is periodically monitored for changes in her condition.Table 2 - Flavonoid FormulationExample 3 Formulation for Treating Traumatic Brain Injury (TBI)

[0135] In this example, a patient suffers a head injury from a motor vehicle accident. The treating physician recognizes that the patient is likely to suffer long term damage from TBI. To prevent excessive and prolonged CNS inflammation, the patient is administered the flavonoid formulation described above (Table 2). The patient is administered the formulation orally (i.e. , 50 ml, once per day). After two months, the patient is evaluated for TBI. Signs / symptoms are negligible and the patient appears in good health. The patient resumes the treatment for an additional 30 days and is thereafter evaluated again for changes in her condition.* * *

[0136] Embodiments of the invention include botanical formulations useful to treat ailments such as traumatic brain injury (TBI) and Alzheimer’s disease (AD) by reducing systematic inflammation and modulating immune dysregulation. In aspects, systematic inflammation is reduced using a GRAS botanical formulation that includes antagonists which bind to receptors (CCR2 & GPR55) and prostaglandin (PGE2), all of which possess related mechanisms and alterations. The GRAS formulations described herein can also include CBD which is both a synergist and excellent carrier.

[0137] Although not to be bound by theory, Applicants propose that the triple activity of CCR2, GPR55 and PGE2 antagonism facilitates reduction of post trauma inflammation and overall reduction of systemic inflammation.

[0138] Kaempferol 3-(2,4-di-E-p-coumaroylrhamnoside is a botanically-derived compound is a CCR2 antagonist which results in direct and indirect inhibition of CCR2 via pathway modulation. The compound is naturally found in Abeies species.

[0139] The following botanically-derived compounds are GPR55 antagonists which can directly or indirectly inhibit the GPR55 via pathway modulation. The compounds are naturally found in Cannabis and Magnolia species. a) Cannabidiol (CBD) b) Cannabidiphorol (CBDP) c) Tetrahydromagnolol

[0140] The following botanically-derived compounds are PGE2 antagonists which can directly or indirectly inhibit the PGE2 via pathway modulation. The compounds are naturally found in Cannabis species. a) Cannflavin A b) Cannflavin B

[0141] When the three components above are combined with (17-DHA) and THEA, the resulting formulation can be used to effectively reduce inflammation related to ailments such as AD. The formulations can attenuate effects of inflammation-based damage in more aggressive cases of AD via promotion of NPD1 pathway. The compounds are two chain short lipids and can be naturally derived: a) (±)17-hydroxy-4Z,7Z, 10Z, 13Z, 15E, 19Z-docosahexaenoic acid (17-DHA) b) tetracosahexaenoylethanolamide (THEA)

[0142] The present specification also provides pharmaceutical compositions for the administration to treat an ailment in a subject. The pharmaceutical composition disclosed herein may further include a pharmaceutically acceptable carrier, excipient, or diluent. As used herein, the term "pharmaceutically acceptable" means that the composition is sufficient to achieve the therapeutic effects without deleterious side effects, and may be readily determined depending on the type of the diseases, the patient's age, body weight, health conditions, gender, and drug sensitivity,administration route, administration mode, administration frequency, duration of treatment, drugs used in combination or coincident with the composition disclosed herein, and other factors known in medicine.

[0143] The pharmaceutical composition herein may further include a pharmaceutically acceptable carrier. For oral administration, the carrier may include, but is not limited to, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersing agent, a stabilizer, a suspending agent, a colorant, and a flavorant. For injectable preparations, the carrier may include a buffering agent, a preserving agent, an analgesic, a solubilizer, an isotonic agent, and a stabilizer. For preparations for topical administration, the carrier may include a base, an excipient, a lubricant, and a preserving agent.

[0144] The disclosed compositions may be formulated into a variety of dosage forms in combination with the aforementioned pharmaceutically acceptable carriers. For example, for oral administration, the pharmaceutical composition may be formulated into tablets, troches, capsules, elixirs, suspensions, syrups or wafers. For injectable preparations, the pharmaceutical composition may be formulated into an ampule as a single dosage form or a multidose container. The pharmaceutical composition may also be formulated into solutions, suspensions, tablets, pills, capsules and long-acting preparations.

[0145] On the other hand, examples of the carrier, the excipient, and the diluent suitable for the pharmaceutical formulations include, without limitation, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oils. In addition, the pharmaceutical formulations may further include fillers, anti-coagulating agents, lubricants, humectants, flavorants, and antiseptics.

[0146] Further, the pharmaceutical composition disclosed herein may have any formulation selected from the group consisting of tablets, pills, powders, granules,capsules, suspensions, liquids for internal use, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, lyophilized formulations and suppositories.

[0147] The composition may be formulated into a single dosage form suitable for the patient's body, and preferably is formulated into a preparation useful for small molecule drugs according to the typical method in the pharmaceutical field so as to be administered by an oral or parenteral route such as through skin, intravenous, intramuscular, intra-arterial, intramedullary, intramedullary, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, intracolonic, topical, sublingual, vaginal, or rectal administration, but is not limited thereto.

[0148] The composition may be used by blending with a variety of pharmaceutically acceptable carriers such as physiological saline or organic solvents. In order to increase the stability or absorptivity, carbohydrates such as glucose, sucrose or dextrans, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers may be used.

[0149] The administration dose and frequency of the pharmaceutical composition disclosed herein are determined by the type of active ingredient, together with various factors such as the disease to be treated, administration route, patient's age, gender, and body weight, and disease severity.

[0150] The total effective dose of the compositions disclosed herein may be administered to a patient in a single dose or may be administered for a long period of time in multiple doses according to a fractionated treatment protocol. In the pharmaceutical composition disclosed herein, the content of active ingredient may vary depending on the disease severity. Preferably, the total daily dose of the small molecule disclosed herein may be approximately 0.0001 g to 500 mg per 1 kg of body weight of a patient. However, the effective dose of the small molecule is determined considering various factors including patient's age, body weight, health conditions, gender, disease severity, diet, and secretion rate, in addition to administration route and treatment frequency of the pharmaceutical composition. In view of this, those skilled in the art mayeasily determine an effective dose suitable for the particular use of the pharmaceutical composition disclosed herein. The pharmaceutical composition disclosed herein is not particularly limited to the formulation, and administration route and mode, as long as it shows suitable effects.

[0151] Moreover, the pharmaceutical composition may be administered alone or in combination or coincident with other pharmaceutical formulations showing prophylactic or therapeutic efficacy.

[0152] In various embodiments, a formulation can include, without limitation, combinations of bioactive agents (such as viruses, proteins, antibodies, peptides and the like as described herein) in the formulation. For example, a formulation as described herein can include a single bioactive agent for treatment of one or more conditions, including without limitation, disease. A formulation as described herein also can include, in an embodiment, without limitation, two or more different bioactive agents for a single or multiple conditions. Use of multiple bioactive agents in a formulation can be directed to, for example, the same or different indications. Similarly, in another embodiment, multiple bioactive agents can be used in a formulation to treat, for example, both a pathological condition and one or more side effects caused by the primary treatment. In a further embodiment, multiple bioactive agents also can be included, without limitation, in a formulation as described herein to accomplish different medical purposes including, for example, simultaneous treatment and monitoring of the progression of the pathological condition. In an additional embodiment, multiple, concurrent therapies such as those exemplified herein as well as other combinations well known in the art are particularly useful for patient compliance because a single formulation can be sufficient for some or all suggested treatments and / or diagnosis. Those skilled in the art will know those bioactive agents that can be admixed for a wide range of combination therapies. Similarly, in various embodiments, a formulation can be used with a small molecule drug and combinations of one or more bioactive agents together with one or more small molecule pharmaceuticals. Therefore, in various embodiments a formulation is provided containing 1 , 2, 3, 4, 5 or 6 or more different bioactive agents, as well as, for one or more bioactive agents combined with one ormore small molecule pharmaceuticals.

[0153] In various embodiments, a formulation can include, one or more preservatives and / or additives known in the art. Similarly, a formulation can further be formulated, without limitation, into any of various known delivery formulations. For example, in an embodiment, a formulation can include, surfactants, adjuvant, biodegradable polymers, hydrogels, etc., such optional components, their chemical and functional characteristics are known in the art. Similarly known in the art are formulations that facilitate rapid, sustained or delayed release of the bioactive agents after administration. A formulation as described can be produced to include these or other formulation components known in the art.

[0154] The composition can therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages may be ascertained through use of appropriate dose-response data. In various embodiments, the bioactive agents in formulations described herein can, without limitation, be administered to patients throughout an extended time period, such as chronic administration for a chronic condition. The composition can be a solid, a semi-solid or an aerosol and a pharmaceutical compositions is formulated as a tablet, geltab, lozenge, orally dissolved strip, capsule, syrup, oral suspension, emulsion, granule, sprinkle or pellet.

[0155] In an embodiment, for oral, rectal, vaginal, parenteral, pulmonary, sublingual and / or intranasal delivery formulations, tablets can be made by compression or molding, optionally with one or more accessory ingredients or additives. In an embodiment, compressed tablets are prepared, for example, by compressing in a suitable tableting machine, the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (for example, without limitation, povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (forexample, without limitation, sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) and / or surface-active or dispersing agent.

[0156] In an embodiment, molded tablets are made, for example, without limitation, by molding in a suitable tableting machine, a mixture of powdered compounds moistened with an inert liquid diluent. In an embodiment, the tablets may optionally be coated or scored, and may be formulated so as to provide slow or controlled release of the active ingredients, using, for example, without limitation, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. In an embodiment, tablets may optionally be provided with a coating, without limitation, such as a thin film, sugar coating, or an enteric coating to provide release in parts of the gut other than the stomach. In an embodiment, processes, equipment, and toll manufacturers for tablet and capsule making are well-known in the art.

[0157] In an embodiment, capsule formulations can utilize either hard or soft capsules, including, without limitation, gelatin capsules or vegetarian capsules such as those made out of hydroxymethylpropylcellulose (HMPC). In an embodiment, a type of capsule is a gelatin capsule. In an embodiment, capsules may be filled using a capsule filling machine such as, without limitation, those available from commercial suppliers such as Miranda International or employing capsule manufacturing techniques well- known in the industry, as described in detail in Pharmaceutical Capules, 2. sup. nd Ed., F. Podczeck and B. Jones, 2004. In an embodiment, capsule formulations may be prepared, without limitation, using a toll manufacturing center such as the Chao Center for Industrial Pharmacy & Contract Manufacturing, located at Purdue Research Park.

[0158] Packaging and instruments for administration may be determined by a variety of considerations, such as, without limitation, the volume of material to be administered, the conditions for storage, whether skilled healthcare practitioners will administer or patient self-compliance, the dosage regime, the geopolitical environment (e.g., exposure to extreme conditions of temperature for developing nations), and other practical considerations.

[0159] Injection devices include pen injectors, auto injectors, safety syringes,injection pumps, infusion pumps, glass prefilled syringes, plastic prefilled syringes and needle free injectors syringes may be prefilled with liquid, or may be dual chambered, for example, for use with lyophilized material. An example of a syringe for such use is the Lyo-Ject™, a dual-chamber pre-filled lyosyringe available from Vetter GmbH, Ravensburg, Germany. Another example is the LyoTip which is a prefilled syringe designed to conveniently deliver lyophilized formulations available from LyoTip, Inc., Camarillo, California, U.S.A. Administration by injection may be, without limitation intravenous, intramuscular, intraperitoneal, or subcutaneous, as appropriate. Administrations by non-injection route may be, without limitation, nasal, oral, cocular, dermal, or pulmonary, as appropriate.

[0160] In certain embodiments, kits can include one or more single or multichambered syringes (e.g., liquid syringes and lyosyringes) for administering one or more formulations described herein. In various embodiments, the kit can comprise formulation components for parenteral, subcutaneous, intramuscular or IV administration, sealed in a vial under partial vacuum in a form ready for loading into a syringe and administration to a subject. In this regard, the composition can be disposed therein under partial vacuum. In all of these embodiments and others, the kits can contain one or more vials in accordance with any of the foregoing, wherein each vial contains a single unit dose for administration to a subject.

[0161] The kits can comprise lyophilates, disposed as herein, that upon reconstitution provide compositions in accordance therewith. In various embodiment the kits can contain a lyophilate and a sterile diluent for reconstituting the lyophilate.

[0162] Also described herein, are methods for treating a subject in need of therapy, comprising administering to the subject an effective amount of a formulation as described herein. The therapeutically effective amount or dose of a formulation will depend on the disease or condition of the subject and actual clinical setting.

[0163] In an embodiment, a formulation as described herein can be administered by any suitable route, specifically by parental (including subcutaneous, intramuscular, intravenous and intradermal) administration. It will also be appreciated that thepreferred route will vary with the condition and age of the recipient, and the disease being treated. Methods of determining the most effective means and dosage of administration are known to those of skill in the art and will vary, without limitation, with the composition used for therapy, the purpose of the therapy, and the subject being treated. Single or multiple administrations can be carried out, without limitation, the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the agents are known in the art.

[0164] The formulations as described herein can be used in the manufacture of medicaments and for the treatment of humans and other animals by administration in accordance with conventional procedures.

[0165] Also provided herein are combinatorial methods for developing suitable virus formulations using combinations of amino acids. These methods are effective for developing stable liquid or lyophilized formulations, and particularly pharmaceutical virus formulations.

[0166] Compositions in accordance with embodiments described herein have desirable properties, such as desirable solubility, viscosity, syringeability and stability. Lyophilates in accordance with embodiments described herein have desirable properties, as well, such as desirable recovery, stability and reconstitution.

[0167] In an embodiment, the pH of the pharmaceutical formulation is at least about 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, or 9.

[0168] In an embodiment, the pH of the pharmaceutical formulation is from about 3 to about 9, about 4 to about 19, about 5 to about 9, about 6 to about 8, about 6 to about 7, about 6 to about 9, about 5 to about 6, about 5 to about 7, about 5 to about 8, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about5, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 7 to about 8, about 7 to about 9, about 7 to about 10.

[0169] Certain embodiments of the present invention are described herein,including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0170] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0171] Unless otherwise indicated, all numbers expressing a characteristic, item, quantity, parameter, property, term, and so forth used in the present specification and claims are to be understood as being modified in all instances by the term “about.” As used herein, the term “about” means that the characteristic, item, quantity, parameter, property, or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values setting forth the broad scope ofthe invention are approximations, the numerical ranges and values set forth in the specific examples are reported as precisely as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the present specification as if it were individually recited herein.

[0172] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s).Embodiments of the present invention so claimed are inherently or expressly described and enabled herein.

[0173] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0174] All patents, patent publications, and other publications referenced and identified in the present specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for theirdisclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

[0175] In closing, it is to be understood that although aspects of the present specification are highlighted by referring to specific embodiments, one skilled in the art will readily appreciate that these disclosed embodiments are only illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to a particular methodology, protocol, and / or reagent, etc., described herein. As such, various modifications or changes to or alternative configurations of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of the present specification. Lastly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims

CLAIMSWhat is claimed is:1 . A formulation comprising: a) a OCR inhibitor, b) a GPR55 inhibitor, and c) a PGE2 inhibitor.

2. The formulation of claim 1 , wherein the CCR inhibitor is kaempferol 3-(2,4-di-E-p- coumaroylrham noside).

3. The formulation of claim 1 , wherein the GPR55 inhibitor is one or more of cannabidiol (CBD), cannabidiphorol (CBDP) and tetrahydromagnolol.

4. The formulation of claim 1 , wherein the PGE2 inhibitor is one or more of cannflavin A and cannflavin B.

5. The formulation of claim 1 , further comprising 17-hydroxy Docosahexaenoic Acid (17-DHA) and / or tetracosahexaenoylethanolam ide (THEA).

6. A method of treating an ailment, the method comprising administering a therapeutic amount of the formulation of claim 1 to a subject.

7. The method of claim 6, wherein the ailment is a neurological disorder.

8. The method of claim 7, wherein the neurological disorder is one or more of inflammation, traumatic brain injury (TBI) and Alzheimer’s disease.

9. A method of reducing or modulating inflammation of the CNS to treat an ailment in a subject, the method comprising administering a therapeutic amount of the formulation of claim 1 to the subject.

10. The method of claim 9, wherein the ailment is one or more of inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain- Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headaches, encephalitis and myasthenia gravis.

11. A method of treating an ailment comprising administration of an effective amount of a formulation comprising: a) a CCR inhibitor, b) a GPR55 inhibitor, and c) a PGE2 inhibitor.

12. The method of claim 11 , wherein the CCR inhibitor is kaempferol 3-(2,4-di-E-p- coumaroylrhamnoside.

13. The method of claim 11 , wherein the GPR55 inhibitor is one or more of cannabidiol (CBD), cannabidiphorol (CBDP) and tetrahydromagnolol.

14. The method of claim 11 , wherein the PGE2 inhibitor is one or more of cannflavin A and cannflavin B.

15. The method of claim 11 , wherein the formulation further comprises 17-hydroxy Docosahexaenoic Acid (17-DHA) and / or tetracosahexaenoylethanolam ide (THEA).

16. The method of claim 11 , wherein the ailment is one or more of inflammation, traumatic brain injury (TBI) and Alzheimer’s disease.

17. The method of claim 11 , wherein the ailment is one or more of inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain- Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headaches, encephalitis and myasthenia gravis.

18. A formulation comprising: a) kaempferol 3-(2,4-di-E-p-coumaroylrhamnoside, b) one or more of cannabidiol (CBD), cannabidiphorol (CBDP) and tetrahydromagnolol, and c) one or more of cannflavin A and cannflavin B.

19. The formulation of claim 18, further comprising 17-hydroxy Docosahexaenoic Acid (17-DHA) and / or tetracosahexaenoylethanolam ide (THEA).

20. A method of treating an ailment, the method comprising administering a therapeutic amount of the formulation of claim 18 or 19 to a subject.21 . The method of claim 20, wherein the ailment is a neurological disorder.

22. The method of claim 20, wherein the ailment is inflammation.

23. The method of claim 21 , wherein the neurological disorder is one or more of inflammation, traumatic brain injury (TBI) and Alzheimer’s disease.

24. A method of increasing neuroplasticity or improving neural function to treat an ailment in a subject in need thereof, the method comprising administering a therapeutic amount of the formulation of claim 19 to the subject.

25. The method of claim 20, wherein the ailment is one or more of inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain- Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headaches, encephalitis and myasthenia gravis.

26. A method of reducing inflammation comprising administration of an effective amount of the formulation of claim 19 to a subject.

27. A method of treating a neurological disorder comprising steps of (a) identifying a subject with a neurological disorder associated with inflammation and (b) administering a therapeutic amount of the formulation of claim 19 to the subject.

28. The method of claim 27, wherein the neurological disorder associated with inflammation is traumatic brain injury (TBI) or Alzheimer’s disease.

29. The method of claim 27, wherein the neurological disorder associated with inflammation is one or more of acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headaches, encephalitis and myasthenia gravis.

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