New use of 1-amino-3,5-dimethyladamantane hydrochloride

Abstract

New use of 1-amino-3,5-dimethyladamantane hydrochloride in treating or preventing cognitive impairment, reducing microglia in the cortex and hippocampus, reducing neuron loss in the cortex and hippocampus, and ameliorating the mitochondrial dysfunction state. The cognitive impairment includes cognitive impairment in systemic lupus erythematosus, Parkinson's disease, lateral sclerosis, stroke, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, attention deficit hyperactivity disorder, sepsis-related encephalopathy, or mild cognitive disorder. The present application also provides a corresponding drug and a treatment or prevention method.

Description

Novel Uses of 1-Amino-3,5-Dimethyladamantaneamine Hydrochloride

[0001] Cross-reference of related applications

[0002] This application claims priority to Chinese Patent Application No. 2024119505976, filed on December 26, 2024, entitled "Novel Use of 1-Amino-3,5-Dimethyladamantaneamine Hydrochloride", and also claims priority to Chinese Patent Application No. 202511528337.4, filed on October 24, 2025, entitled "Novel Use of 1-Amino-3,5-Dimethyladamantaneamine Hydrochloride", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application belongs to the pharmaceutical field, and specifically, this application provides a novel use of 1-amino-3,5-dimethyladamantaneamine hydrochloride for the treatment or prevention of diseases. Background Technology

[0004] Cognitive impairment is a syndrome characterized primarily by memory loss, accompanied by other cognitive impairments. Early detection is crucial for patient prognosis, but currently there are no approved drugs for cognitive impairment worldwide. Causes of cognitive impairment include inflammation, blood-brain barrier disruption, oxidative stress, and neuronal damage, and may be triggered by conditions such as systemic lupus erythematosus, Parkinson's disease, amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, attention deficit hyperactivity disorder (ADHD), and sepsis-associated encephalopathy.

[0005] Non-PSLE is a severe manifestation of systemic lupus erythematosus (SLE), affecting up to 80% of patients with cognitive impairment (“brain fog”), leading to severe disability, approximately a twofold increased risk of unemployment, reduced health-related quality of life (HRQoL), and a 2–14 times higher mortality rate than the general population. The prevalence of cognitive impairment in NPSLE patients is 39–88% (compared to 57.8% in overall SLE, mostly mild), accompanied by mood disorders (up to 65%), psychosis (up to 11%), and persistent SLICC / ACR impairment index (SDI) episodes, hospitalizations, and cumulative organ damage. The economic burden includes direct costs (hospitalization, loss of productivity) and approximately 65% ​​of working disabilities. Patient-reported outcomes (PROs) such as LupusQoL and Neuro-QoL show significant declines comparable to those of chronic disease, and the MCID emphasizes their clinical relevance.

[0006] There are no approved treatments for NPSLE cognitive impairment, representing a high-priority unmet need for this FDA-recognized serious disorder with major functional and psychosocial burdens. Heterogeneity (e.g., delayed diagnosis) amplifies morbidity, but quantitative measures are not adequately integrated in the PFDD-aligned merged table reconstruction submissions presented here. Summary of the Invention

[0007] EG501 (Memantine Hydrochloride) ) is a low-affinity, non-competitive NMDA receptor antagonist that selectively blocks pathological glutamate excitotoxicity caused by anti-NR2A autoantibodies, neuroinflammation (e.g., IL-6 / TNF-α), BBB damage, and microglial activation and expansion in NPSLE, while preserving physiological synaptic signaling for learning / memory (see Table 1). This targets the "inflammation + excitotoxicity" axis, reducing synaptic noise, oxidative stress, and hippocampal vulnerability.

[0008] Table 1. The mechanism of EG501 is uniquely consistent with the pathophysiology of NPSLE.

[0009] NMDA regulation has dual benefits:

[0010] Acute phase (symptom control): Improve cognitive speed and clarity within 4-8 weeks.

[0011] Chronic phase (neuroprotection): Reduces structural deterioration and hippocampal damage, potentially delaying dementia progression (20-30% risk over 5-10 years).

[0012] The trial demonstrated that memantine hydrochloride, through its dual mechanism of action, provides immediate symptom relief and long-term neuroprotective effects, offering a compelling proof of concept for the treatment of cognitive impairment in NPSLE and strongly supporting the FDA's fast track and breakthrough treatment design considerations, as well as subsequent key developments to reduce risk.

[0013] 1-Amino-3,5-dimethylammonium hydrochloride (memantine) is a drug that targets NMDA receptors and 5HT3 receptors, and this application provides for a novel use of it.

[0014] On the one hand, this application provides the use of 1-amino-3,5-dimethylammonium hydrochloride (memantine) in the preparation of medicaments for the treatment or prevention of cognitive impairment.

[0015] Furthermore, the cognitive impairment refers to cognitive impairment in systemic lupus erythematosus (SLE), Parkinson's disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, attention deficit hyperactivity disorder, sepsis-associated encephalopathy, or mild cognitive impairment.

[0016] Furthermore, the cognitive impairment is cognitive impairment associated with systemic lupus erythematosus.

[0017] Furthermore, the drug has one or more of the following effects (1)-(6):

[0018] (1) Reduce, alleviate or restore neuronal lesions or degeneration in the hippocampus;

[0019] (2) Reduce, alleviate or restore the infiltration of inflammatory cells in the hippocampus;

[0020] (3) Reduce the number of microglia in the cortex and / or hippocampus;

[0021] (4) Reduce, alleviate or restore neuronal loss in the cortex and / or hippocampus;

[0022] (5) It relieves or restores edema in the white matter area of ​​the cortex, improves the local microcirculation, significantly widens the interneuronal gaps, and sparsely distributes cells.

[0023] (6) Relieves or restores nerve inflammation;

[0024] (7) Protects the integrity of brain tissue and improves the damage to the blood-brain barrier;

[0025] (8) Improves oxidative stress in the nervous system;

[0026] (9) Improves synaptic plasticity;

[0027] (10) Inhibits excessive activation of NMDA receptors and improves short-term neuronal overload and signal distortion;

[0028] (11) Increase acetylcholine and / or choline acetyltransferase levels.

[0029] Furthermore, the hippocampal region is the DG region.

[0030] Furthermore, the neuroinflammation is neuroinflammation of the cortex and / or hippocampus.

[0031] Furthermore, the drug has one or more of the following effects (1)-(5):

[0032] (1) Enhance memory;

[0033] (2) Enhance cognitive flexibility;

[0034] (3) Improve social behavior;

[0035] (4) Improves attention;

[0036] (5) Improve spatial memory and / or learning ability;

[0037] (6) Relieves symptoms of brain fog;

[0038] (7) Reduce the disease activity index of systemic lupus erythematosus;

[0039] (8) Improve symptoms of mental fatigue and / or mental confusion.

[0040] (9) Improve the patient’s overall impression.

[0041] Furthermore, the memory ability is delayed memory ability or delayed memory capacity.

[0042] Furthermore, the drug increases acetylcholine and / or choline acetyltransferase levels.

[0043] Furthermore, the drug regulates the expression of mitochondrial genes in brain tissue and improves mitochondrial dysfunction.

[0044] Furthermore, the drug improves mitochondrial metabolism.

[0045] Furthermore, the drug improves mitochondrial respiratory function.

[0046] Furthermore, the drug improves the mitochondrial electron transport chain.

[0047] Furthermore, the drug improves mitochondrial ATP production.

[0048] Furthermore, the drug increases the expression of mt-Nd4 and / or mt-Atp6 in mitochondria.

[0049] Furthermore, the drug reduces the expression of mt-Tm, mt-Tr and / or mt-CO1 in mitochondria.

[0050] Furthermore, the drug improves synaptic plasticity.

[0051] Furthermore, the drug inhibits the overactivation of NMDA receptors, improving short-term neuronal overload and signal distortion.

[0052] Furthermore, the drug improves neuropsychological states, depression and / or anxiety, and inflammatory states.

[0053] Furthermore, the drug may also contain other drugs, such as other drugs used to treat cognitive impairment.

[0054] Furthermore, the other drugs selected include cholinesterase inhibitors, excitatory amino acid receptor antagonists, vasodilators, anti-inflammatory drugs, antioxidant drugs, mitochondrial regulators, and traditional Chinese medicines for treating cognitive impairment.

[0055] On the other hand, a pharmaceutical composition for treating or preventing cognitive impairment is characterized in that the pharmaceutical composition comprises an anti-inflammatory agent, an antioxidant, and a mitochondrial regulator.

[0056] Furthermore, the mitochondrial regulator is 1-amino-3,5-dimethyladamantaneamine hydrochloride.

[0057] On the other hand, this application provides a medicament for treating or preventing cognitive impairment, the medicament comprising 1-amino-3,5-dimethylammonium hydrochloride.

[0058] Furthermore, the cognitive impairment refers to cognitive impairment in systemic lupus erythematosus, Parkinson's disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, attention deficit hyperactivity disorder, sepsis-associated encephalopathy, or mild cognitive impairment.

[0059] Furthermore, the cognitive impairment is cognitive impairment associated with systemic lupus erythematosus.

[0060] Furthermore, the drug has one or more of the following effects (1)-(6):

[0061] (1) Reduce, alleviate or restore neuronal lesions or degeneration in the hippocampus;

[0062] (2) Reduce, alleviate or restore the infiltration of inflammatory cells in the hippocampus;

[0063] (3) Reduce, alleviate or restore the increase in the number of microglia in the cortex and / or hippocampus;

[0064] (4) Reduce, alleviate or restore neuronal loss in the cortex and / or hippocampus;

[0065] (5) Relieves or restores edema in the white matter area of ​​the cortex, significantly widens the interneuronal gaps, and sparsely distributes cells;

[0066] (6) Relieves or restores nerve inflammation;

[0067] (7) Improves the condition of the blood-brain barrier;

[0068] (8) Improves oxidative stress in the nervous system;

[0069] (9) Improves synaptic plasticity;

[0070] (10) Inhibits excessive activation of NMDA receptors and improves short-term neuronal overload and signal distortion;

[0071] (11) Increase acetylcholine and / or choline acetyltransferase levels.

[0072] Furthermore, the hippocampal region is the DG region.

[0073] Furthermore, the neuroinflammation is neuroinflammation of the cortex and / or hippocampus.

[0074] Furthermore, the drug has one or more of the following effects (1)-(5):

[0075] (1) Enhance memory;

[0076] (2) Enhance cognitive flexibility;

[0077] (3) Improve social behavior;

[0078] (4) Improves attention;

[0079] (5) Improve spatial memory and / or learning ability;

[0080] (6) Relieves symptoms of brain fog;

[0081] (7) Reduce the disease activity index of systemic lupus erythematosus;

[0082] (8) Improve symptoms of mental fatigue and / or mental confusion.

[0083] (9) Improve the patient’s overall impression.

[0084] Furthermore, the memory ability is delayed memory ability or delayed memory capacity.

[0085] Furthermore, the drug increases acetylcholine and / or choline acetyltransferase levels.

[0086] Furthermore, the drug regulates the expression of mitochondrial genes in brain tissue and improves mitochondrial dysfunction.

[0087] Furthermore, the drug improves mitochondrial metabolism.

[0088] Furthermore, the drug improves mitochondrial respiratory function.

[0089] Furthermore, the drug improves the mitochondrial electron transport chain.

[0090] Furthermore, the drug increases the expression of mt-Nd4 and / or mt-Atp6 in mitochondria.

[0091] Furthermore, the drug reduces the expression of mt-Tm, mt-Tr and / or mt-CO1 in mitochondria.

[0092] Furthermore, the drug improves mitochondrial ATP production.

[0093] Furthermore, the drug improves synaptic plasticity.

[0094] Furthermore, the drug inhibits the overactivation of NMDA receptors, improving short-term neuronal overload and signal distortion.

[0095] Furthermore, the drug improves neuropsychological states, depression and / or anxiety, and inflammatory states.

[0096] Furthermore, the drug also contains other medications used to treat cognitive impairment.

[0097] Furthermore, other drug options for treating cognitive impairment include cholinesterase inhibitors, excitatory amino acid receptor antagonists, vasodilators, anti-inflammatory drugs, antioxidant drugs, mitochondrial regulators, and traditional Chinese medicine for treating cognitive impairment.

[0098] On the other hand, this application provides the use of 1-amino-3,5-dimethyladamantaneamine hydrochloride in the preparation of a medicament for reducing microglia in the cortex and hippocampus.

[0099] On the other hand, this application provides the use of 1-amino-3,5-dimethyladamantaneamine hydrochloride in the preparation of drugs that reduce neuronal loss in the cortex and hippocampus.

[0100] On the other hand, this application provides the use of 1-amino-3,5-dimethylammonium hydrochloride in the preparation of a medicament for regulating the expression of mitochondrial genes in brain tissue and / or improving mitochondrial dysfunction.

[0101] Furthermore, the drug improves mitochondrial metabolism.

[0102] Furthermore, the drug improves mitochondrial respiratory function.

[0103] Furthermore, the drug improves the mitochondrial electron transport chain.

[0104] Furthermore, the drug increases the expression of mt-Nd4 and / or mt-Atp6 in mitochondria.

[0105] Furthermore, the drug reduces the expression of mt-Tm, mt-Tr, and / or mt-CO1 in mitochondria. Furthermore, the drug is used in mammals.

[0106] Furthermore, the drug was used on Homo sapiens.

[0107] Furthermore, the drug contains pharmaceutically acceptable excipients.

[0108] Furthermore, the drug is an injectable, oral, or topical preparation.

[0109] Furthermore, injectable preparations include injection solutions and powder injections; oral preparations include tablets, capsules, oral liquids, powders, granules, and suspensions; and topical preparations include ointments, sprays, and transdermal patches; furthermore, the drug is a sustained-release preparation, a transdermal patch, or a nanoparticle drug.

[0110] Furthermore, pharmaceutically acceptable excipients are selected from fillers, binders, coating agents, disintegrants, lubricants, flavor masking agents, sustained-release agents, controlled-release agents, flavoring agents, solvents, cosolvents, osmotic pressure regulators, pH regulators, stabilizers, dispersants, viscosity modifiers, and antioxidants.

[0111] Furthermore, the daily dose of the drug is 1-60 mg.

[0112] Furthermore, the daily dose of the drug is 5-40 mg.

[0113] Furthermore, the daily dose of the drug is 5-20 mg.

[0114] Furthermore, the medication is taken 1-3 times daily.

[0115] Furthermore, the medication is taken once or twice daily.

[0116] Furthermore, the drug is administered continuously for more than 2 weeks.

[0117] Furthermore, the drug is administered continuously for more than 4 weeks.

[0118] Furthermore, the drug is administered continuously for more than 8 weeks.

[0119] Furthermore, the medication needs to be taken long-term.

[0120] On the other hand, this application provides a method for treating or preventing cognitive impairment in a subject, the method comprising administering 1-amino-3,5-dimethylammonium hydrochloride to the subject.

[0121] Furthermore, the cognitive impairment refers to cognitive impairment in systemic lupus erythematosus, Parkinson's disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, attention deficit hyperactivity disorder, sepsis-associated encephalopathy, or mild cognitive impairment.

[0122] Furthermore, the cognitive impairment is cognitive impairment associated with systemic lupus erythematosus.

[0123] Furthermore, the treatment achieves one or more of the following effects (1)-(6):

[0124] (1) Reduce, alleviate or restore neuronal lesions or degeneration in the hippocampus;

[0125] (2) Reduce, alleviate or restore the infiltration of inflammatory cells in the hippocampus;

[0126] (3) Reduce the number of microglia in the cortex and / or hippocampus;

[0127] (4) Reduce, alleviate or restore neuronal loss in the cortex and / or hippocampus;

[0128] (5) It relieves or restores edema in the white matter area of ​​the cortex, improves the local microcirculation, significantly widens the interneuronal gaps, and sparsely distributes cells.

[0129] (6) Relieves or restores nerve inflammation;

[0130] (7) Protects the integrity of brain tissue and improves the damage to the blood-brain barrier;

[0131] (8) Improves oxidative stress in the nervous system;

[0132] (9) Improves synaptic plasticity;

[0133] (10) Inhibits excessive activation of NMDA receptors and improves short-term neuronal overload and signal distortion;

[0134] (11) Increase acetylcholine and / or choline acetyltransferase levels.

[0135] Furthermore, the neuroinflammation is neuroinflammation of the cortex and / or hippocampus.

[0136] Furthermore, the treatment achieves one or more of the following effects (1)-(5):

[0137] (1) Enhance memory;

[0138] (2) Enhance cognitive flexibility;

[0139] (3) Improve social behavior;

[0140] (4) Improves attention;

[0141] (5) Improve spatial memory and / or learning ability.

[0142] Furthermore, the treatment increases acetylcholine and / or choline acetyltransferase levels.

[0143] Furthermore, the treatment regulates the expression of mitochondrial genes in brain tissue and improves mitochondrial dysfunction.

[0144] Furthermore, the treatment improves mitochondrial metabolism.

[0145] Furthermore, the treatment improves the mitochondrial electron transport chain.

[0146] Furthermore, the drug improves mitochondrial ATP production.

[0147] Furthermore, the treatment reduces, alleviates, or restores the decreased expression of mt-Nd4 and / or mt-Atp6 in the cortex.

[0148] Furthermore, the treatment reduces, alleviates, or restores the increased expression of mt-Tm and / or mt-CO1 in the hippocampus.

[0149] Furthermore, the treatment improves synaptic plasticity.

[0150] Furthermore, the treatment inhibits excessive activation of NMDA receptors, improving short-term neuronal overload and signal distortion.

[0151] Furthermore, the treatment improves neuropsychological states, depression and / or anxiety, and inflammatory states.

[0152] Furthermore, the treatment also includes the administration of other medications.

[0153] Furthermore, the other drugs selected include cholinesterase inhibitors, excitatory amino acid receptor antagonists, vasodilators, anti-inflammatory drugs, antioxidant drugs, mitochondrial regulators, and traditional Chinese medicines for treating cognitive impairment.

[0154] Furthermore, the daily dose of 1-amino-3,5-dimethylammonium hydrochloride is 1-60 mg.

[0155] Furthermore, the daily dose of 1-amino-3,5-dimethylammonium hydrochloride is 5-40 mg.

[0156] Furthermore, the daily dose of 1-amino-3,5-dimethylammonium hydrochloride is 5-20 mg.

[0157] Furthermore, 1-amino-3,5-dimethylammonium hydrochloride is taken 1-3 times daily.

[0158] Furthermore, 1-amino-3,5-dimethylammonium hydrochloride is taken 1-2 times daily.

[0159] Furthermore, 1-amino-3,5-dimethyladamantane hydrochloride was continuously applied for more than 2 weeks.

[0160] Furthermore, 1-amino-3,5-dimethyladamantaneamine hydrochloride was continuously applied for more than 4 weeks.

[0161] Furthermore, 1-amino-3,5-dimethyladamantaneamine hydrochloride was continuously applied for more than 8 weeks.

[0162] Furthermore, the medication needs to be taken long-term.

[0163] [Amended 22.12.2025 according to Rule 26] The drug of this application is preferably used for patients of the Black race.

[0164] In this application and technical solution practice, 1-amino-3,5-dimethyladamantaneamine hydrochloride, memantine hydrochloride, memantine, Memantine Hydrochloride, Memantine, and EG-501 have the same meaning and can be used interchangeably, all representing compounds with the following chemical formulas:

[0165] Molecular formula: C 12 H 21 N·HCl, molecular weight: 215.7.

[0166] In this application, "reduction" means a decrease in quantity or percentage, "mitigation" means a slowing down or reducing the trend of change, "restoration" means to restore an already occurred change to its original state, "enhancement" means an increase in quantity or degree, and "improvement" means to change a quantity or state for the better. These terms can be used interchangeably with similar terms in Chinese or English.

[0167] Neuropsychological status, depression and / or anxiety, and inflammatory status can be assessed using known methods, including but not limited to imaging tests, biochemical tests, and scale assessments (including but not limited to RBANS score, BDI, HADS, SLEDAI-2K scale).

[0168] Other medications used to treat cognitive impairment include: cholinesterase inhibitors such as donepezil, rivastigmine, galantamine, and huperzine A; excitatory amino acid receptor antagonists such as NMDA receptor antagonists, glutamate receptor antagonists, or serotonin selective reuptake inhibitors; vasodilators such as nimodipine, ginkgo biloba extract, and acetaminophen; traditional Chinese medicines such as Liuwei Dihuang Wan, Buzhong Yiqi Tang, Guipi Tang, Tianwang Buxin Dan, and Huatuo Zaizao Wan; and anti-inflammatory drugs such as NLRP3 inflammasome inhibitors. The broad categories and specific types of these drugs may change as research progresses.

[0169] Other medications used to treat cognitive impairment may be prepared into the same pharmaceutical composition as 1-amino-3,5-dimethyladamantane hydrochloride, or placed in the same package, or provided separately for combined administration.

[0170] The dosage of the drug may vary with the stage of treatment, for example, using a lower dose at the beginning of treatment to reduce side effects, and then increasing to a maintenance dose after a certain period, such as 4 weeks. A non-limiting example is a dose of 5 mg daily in the first week of treatment, 10 mg twice daily in the second week, 15 mg twice daily in the third week, and the recommended maintenance dose of 20 mg twice daily thereafter starting in the fourth week.

[0171] The term "brain fog" as used in this application refers to a collection of cognitive symptoms, including inattention, forgetfulness, and slowed thinking; it may be associated with various conditions, including menopause, COVID-19, and autoimmune diseases such as lupus. Furthermore, such symptoms may also occur when the brain processes too much information simultaneously.

[0172] This application reveals that mimantine demonstrates expanded indications across multiple diseases by improving mitochondrial function, reducing oxidative stress, and inhibiting neuroinflammation. This application not only validates the significant role of mimantine in SLE-related cognitive impairment but also identifies its broad applicability in cognitive impairment in systemic lupus erythematosus, Parkinson's disease, amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, attention deficit hyperactivity disorder (ADHD), sepsis-associated encephalopathy, or mild cognitive impairment. Mimantine could serve as a breakthrough treatment for cognitive impairment, bringing tangible clinical benefits to more patients. Attached Figure Description

[0173] Figure 1 shows the experimental design of the mouse model.

[0174] Figure 2 shows a pathological section of hippocampal tissue, with neurons marked by blue arrows exhibiting typical lesion characteristics.

[0175] Figure 3 shows a pathological section of hippocampal tissue; the red arrows indicate neuronal degeneration.

[0176] Figure 4 shows a pathological section of the cortex. The blue arrows indicate white matter edema, and the green arrows indicate an increase in microglia.

[0177] Figure 5 shows the detection results of acetylcholine and choline acetyltransferase.

[0178] Figure 6 shows the results of RNA expression profiling analysis.

[0179] Figure 7 shows the RBANS total index results.

[0180] Figure 8 shows the RBANS changes in the completer and in ITT (MAR) (ITT: Intent to Treat, MAR: Missing-at-Random).

[0181] Figure 9 shows the mean variation of the RBANS subscales.

[0182] Figure 10 shows the response rate.

[0183] Figure 11 shows the SLEDAI-2K score comparison.

[0184] Figure 12 shows the changes in mental confusion.

[0185] Figure 13 shows the overall patient change impression (PGIC) at 12 weeks. Detailed Implementation

[0186] Example 1 Animal Experiment Protocol

[0187] This study aimed to evaluate the efficacy of memantine in a lipopolysaccharide (LPS)-induced cognitive impairment model in C57 mice. This model simulates inflammation-induced cognitive dysfunction, providing a basis for exploring potential treatment strategies.

[0188] The experimental design is shown in Figure 1. C57BL / 6 mice were randomly divided into five groups, with 40 mice in each group:

[0189] Blank control group: Mice that did not receive any treatment were used to provide baseline behavioral and biological parameters.

[0190] Model group: Cognitive impairment was induced by intraperitoneal injection of LPS to simulate inflammation-related cognitive impairment.

[0191] Positive control group: treated with donepezil at a dose of 0.83 mg / kg in the first week and 1.66 mg / kg in the second week, as a reference for known cognitive-improving drugs.

[0192] Treatment group 1: Memantine (5 mg / kg) was administered to observe the efficacy of low-dose treatment.

[0193] Treatment group 2: Memantine (15 mg / kg) was administered to observe the efficacy of high-dose treatment.

[0194] All mice were administered the drug for 14 consecutive days, during which time multiple behavioral experiments (new object recognition experiment, three-box social experiment, five-hole attention experiment, and water maze experiment) were conducted in batches. At the end of the experiment, brain tissue samples were collected for pathological and molecular biological analysis.

[0195] Example 2: Pathological Analysis of Brain Tissue

[0196] Pathological sections of the hippocampus and cortex: morphological and numerical changes of neurons were observed through H&E staining.

[0197] H&E staining: Hematoxylin and eosin staining was used to observe the overall structural changes in the hippocampus and cortical tissues, including the arrangement of neurons, the morphology of cell nuclei, and the extent of inflammatory infiltration.

[0198] Quantitative analysis: The number of surviving neurons and pathological change scores per unit area were quantitatively calculated using image analysis software to further clarify the protective effect of treatment on brain tissue.

[0199] In normal hippocampal tissue sections, neurons appear light gray, with regular, centrally located nuclei and evenly distributed cytoplasm, exhibiting clear overall structure and displaying typical characteristics of healthy neurons. However, in the LPS-induced C57 mouse model, clearly pathological neurons were observed in the dentate gyrus (DG region) of the hippocampus. These neurons appeared deep purple, with significantly shrunken cell bodies, absent or blurred cytoplasm, and were stained more deeply than surrounding normal neurons, exhibiting disordered morphology. These features indicate severe pathological degeneration of the neurons (neurons marked with blue arrows in Figure 2 appear deep purple, with poorly discernible cytoplasm, significantly shrunken cell bodies, and significantly deeper staining than surrounding tissue, displaying typical pathological features; red arrows in Figure 3 indicate neuronal degeneration).

[0200] Pathological sections of the memantine treatment group showed a significant protective effect against LPS-induced neuronal damage. Low-dose memantine (5 mg / kg) was able to partially prevent neuronal degeneration in the DG area, and the nucleus and cytoplasm structure of many neurons recovered relatively clearly. High-dose memantine (15 mg / kg) showed even more significant therapeutic effects, with neuronal morphology approaching normal, a significant reduction in the number of diseased neurons stained with deep purple, and good overall neuronal structural recovery.

[0201] Furthermore, pathological sections showed that the degree of inflammatory cell infiltration in the hippocampus of the memantine treatment group was significantly lower than that of the model group, indicating that it also has a certain effect in inhibiting local inflammation. High-dose memantine showed a superior protective effect in reducing neuronal damage and lesions compared to low-dose memantine. In summary, memantine can effectively protect the neuronal structure of the DG region of the hippocampus in LPS-induced mice, and reduce pathological degeneration and inflammatory infiltration.

[0202] Table 2. Statistical table of the number of degenerated neurons in the DG region of the hippocampus of animals. Note: Compared with the model group, ※P<0.05; ※※P<0.01.

[0203] Table 3. Statistics on the number of animals with increased microglia in the DG region of the seahorse.

[0204] Table 2 shows that, compared with the model group, the high-dose memantine group (15 mg / kg) significantly reduced neuronal degeneration in the dentate gyrus (DG region) of the hippocampus in mice. Pathological section analysis indicated that the number of diseased neurons in the DG region was significantly reduced in the high-dose group, and the structure and morphology of the neuronal cell bodies were closer to the normal state. Further staining results showed that the nuclei of neurons in the high-dose group were clearly visible, the cytoplasm was evenly distributed, and the overall survival of neurons was significantly protected.

[0205] Furthermore, LPS exposure leads to an increase in the number of microglia and neuronal loss in the cortex and hippocampus. Microglia play a crucial role in LPS-induced neuronal loss, and removing microglia can effectively prevent neuronal loss. In an LPS-induced mouse model, studies have shown that LPS leads to neuronal loss and an increase in microglia in the cortex and hippocampus. As shown in Table 3, the high-dose group effectively inhibited LPS-induced microglia infiltration and significantly reduced the number of microglia in the hippocampus. This indicates that the high-dose memantine group has a strong effect in alleviating neuroinflammatory responses. Specifically, it manifests as a reduction in the infiltration of inflammatory markers in the hippocampus, a significant reduction in tissue inflammation, and a more favorable microenvironment for neuronal survival. In conclusion, the high-dose memantine group not only demonstrates excellent performance in inhibiting neuronal degeneration but also plays an important role in alleviating neuroinflammatory responses and protecting the structural integrity of the hippocampus.

[0206] In the LPS-induced C57 mouse model, significant pathological changes were observed in the white matter region of the cortex. Pathological sections showed obvious edema in the white matter region of the model group, significantly widened interneuronal gaps, sparse cell distribution, and a density significantly lower than that of the normal control group. Further observation revealed a significant increase in the number of microglia in the model group, with enlarged cell bodies and retracted processes, exhibiting a typical activated state, suggesting a strong neuroinflammatory response in the cortical region, leading to tissue structure destruction and abnormal cell distribution (Figure 4: blue arrows indicate white matter edema, green arrows indicate increased microglia in the model group).

[0207] Following treatment with memantine, these pathological changes were significantly improved. The low-dose group (5 mg / kg) showed some relief, with reduced white matter edema in the cortical region, partial restoration of interneuronal gaps to near-normal levels, and a decrease in the number and activation of microglia. The high-dose group (15 mg / kg) showed even more significant therapeutic effects, with more complete restoration of white matter structure, denser neuronal arrangement, near-normal microglia numbers, and stable cell body and process morphology. These results indicate that memantine treatment can effectively inhibit the inflammatory response in the cortical region, reduce tissue damage, and, to some extent, restore the normal distribution and functional state of cortical neurons.

[0208] Table 4. Statistical table of the number of degenerated neurons in the prefrontal cortex of animal brains. Note: Compared with the model group, ※P<0.05; ※※P<0.01.

[0209] Table 5. Statistics on the number of animals with increased microglia in the prefrontal cortex of the brain.

[0210] Table 6. Statistics on the number of morphological changes in neurons in the prefrontal lobe of animal brains.

[0211] In the LPS-induced prefrontal cortex model of C57 mice, the positive control group (donepezil) and the low- and high-dose groups of the test substance (memantine) both showed significant improvement in prefrontal cortex neurological function, specifically in the following three aspects:

[0212] The number of degenerated neurons decreased significantly:

[0213] Pathological section analysis showed a significant reduction in the number of degenerated neurons in the treatment group. In the model group, a higher proportion of diseased neurons exhibited shrunken cell bodies, uneven cytoplasm, and blurred nuclei, while in the positive drug group and the test substance treatment group, the structure and morphology of the neuronal cell bodies were closer to normal. Particularly in the high-dose test substance group, the incidence of neuronal degeneration was significantly reduced, and neuronal survival was well protected.

[0214] Reduces white matter edema and improves local microcirculation:

[0215] The white matter edema observed in the model group, including the pathological features of widened interneuronal spaces and tissue thinning, was significantly alleviated in the treatment group. The low-dose imimantazone group showed some improvement, while the high-dose group showed even more significant improvement. The white matter structure in the treatment group was more compact, and the nerve fiber arrangement tended to be normal, indicating that the local microcirculation was effectively improved, providing support for tissue repair. It also reduced microglial infiltration and alleviated neuroinflammatory responses.

[0216] Sections of the model group showed a large aggregation of microglia, indicating an activated state, with a significantly higher number than in the normal control group. In the treatment group, the number of microglia was significantly reduced, and the degree of activation was decreased, especially in the high-dose memantine group, where microglia infiltration was essentially controlled. Further analysis showed that the expression levels of inflammatory markers decreased synchronously, and the local neuroinflammatory response was significantly alleviated.

[0217] The positive control group and the low- and high-dose memantine groups showed multiple effects in protecting the neuronal function of the prefrontal cortex, especially in reducing neuronal degeneration, alleviating white matter edema, and reducing microglial infiltration (Tables 4-6). Among them, the high-dose memantine group showed significant performance in protecting neuronal structure and function.

[0218] Pathological study conclusions:

[0219] (1) Compared with the blank control group, neurons in the hippocampus of the model group mice showed significant degeneration, especially in the dentate gyrus (DG area). Statistical results showed a significant increase in the number of degenerated neurons in the DG area, verifying the success of the LPS-induced mouse brain cell injury model. Similarly, compared with the blank control group, neurons in the prefrontal cortex of the model group mice also showed significant degeneration. The number of degenerated neurons was counted to further confirm the successful establishment of the animal model of brain injury.

[0220] (2) The high-dose group of the test substance EG501 showed significant protective effects across various evaluation indicators. Specifically, the high-dose group effectively protected the survival of neurons in the hippocampus and prefrontal cortex, and significantly reduced neuroinflammatory responses in these areas. Pathological analysis showed that the high-dose group of EG501 significantly improved the morphology and structure of surviving neurons, reduced cerebral edema, and significantly decreased the infiltration of neuroimmune cells, thereby effectively alleviating local neuroinflammatory responses. These results indicate that the high-dose group of EG501 has a strong effect in reducing neuroinflammatory responses and protecting the integrity of brain tissue.

[0221] Example 3 Biochemical Analysis

[0222] In the nervous system, acetylcholine (ACh) is an important excitatory neurotransmitter involved in the regulation of cognitive functions such as learning, memory, and attention. Cholinergic neurons in the hippocampus play a crucial role in the formation of spatial memory, short-term memory, and long-term memory by releasing ACh. However, neuroinflammation (such as LPS-induced inflammation) can inhibit the function of cholinergic neurons, leading to a decrease in ACh levels and thus significantly affecting cognitive function. Measuring serum ACh levels is a key indicator for evaluating the functional status of the cholinergic system.

[0223] In this experiment, serum ACh levels were measured using ELISA to reflect the state of the cholinergic neurotransmitter system. In the LPS-induced model, decreased ACh levels are considered a key mechanism by which neuroinflammation leads to cognitive impairment. Therefore, this experiment aimed to analyze the changes in ACh levels after treatment to understand the neuroprotective effects, target sites, and impacts on the cholinergic pathway of the drug.

[0224] Acetylcholine level detection: The serum acetylcholine content is measured by ELISA to evaluate the recovery of the neurotransmitter system.

[0225] The results showed that, compared with the normal control group, the ACh level in the model group (LPS-induced) mice was significantly decreased, indicating that cholinergic function was severely inhibited. This phenomenon was further supported by the ChAT activity assay: ChAT activity in the hippocampus of the model group mice was significantly reduced, suggesting that the ability to synthesize ACh was significantly impaired. After treatment with memantine, both ACh levels and ChAT activity recovered to varying degrees. The high-dose group (15 mg / kg) showed significant improvement compared with the model group, with its ACh levels and ChAT activity approaching or recovering to the levels of the normal control group (Figure 5).

[0226] The above results indicate that LPS-induced cholinergic neuronal function in mice is significantly impaired, while memantine can effectively improve LPS-induced cholinergic dysfunction by restoring ACh levels and enhancing ChAT activity. This provides strong experimental support for its potential application in the treatment of cognitive impairment.

[0227] Example 4 Molecular Biological Analysis

[0228] This study systematically detected LPS-induced gene expression changes using RNA sequencing (RNA-seq) through whole-mRNA expression profiling and explored the regulatory role of Memantine on key genes. The analysis covered mRNA, lncRNA, and mitochondrial RNA (mtRNA), with significant changes in mitochondrial gene expression revealing their important role in LPS-induced cognitive impairment and Memantine treatment.

[0229] The study included a control group, a model group, and a high-dose Memantine treatment group (15 mg / kg). It focused on analyzing gene expression changes in the hippocampus and cortical tissues, aiming to reveal the mechanism of mitochondrial dysfunction in cognitive impairment and the potential therapeutic effects of Memantine.

[0230] RNA-seq analysis revealed significant changes in the expression of five mitochondrial genes in the hippocampus and cortex across different groups, involving mitochondrial protein-coding genes, tRNAs, and key metabolic factors. These gene expression changes reflect the core regulatory role of mitochondria in LPS-induced neurological dysfunction and Memantine treatment (Figure 6, Table 7, Table 8).

[0231] Table 7 Differentially expressed mitochondrial genes

[0232] Table 8. Changes in mitochondrial mRNA in different groups

[0233] Cerebral cortex:

[0234] mt-Nd4: The LPS-induced group showed a significant decrease (from 242.3 to 70.9), which recovered after treatment (226.3).

[0235] mt-Atp6: The LPS-induced group showed a moderate decrease (from 177.6 to 97.9), which improved after treatment (184.4).

[0236] mt-Tr: No change among groups, indicating that mitochondrial tRNA expression is stable in this tissue.

[0237] Seahorse:

[0238] mt-Tm: significantly increased in the LPS-induced group (from 1.96 to 12.2), and partially decreased after treatment (7.1).

[0239] mt-C01: LPS-induced group showed sharp upregulation (468.7 to 1560.8), with partial remission after treatment (1091.1).

[0240] In the cerebral cortex, mitochondrial mRNAs (mt-Nd4 and mt-Atp6) are downregulated by LPS, but can be restored with treatment. The reduction of mt-Nd4 and mt-Atp6 indicates impaired mitochondrial function, as these genes encode key components of the electron transport chain (ETC). This may lead to neuronal vulnerability in this region.

[0241] In the hippocampus, mitochondrial mRNAs (mt-Tm and mt-CO1) are upregulated in response to LPS. Treatment reduces their expression but does not normalize them. The upregulation of mt-Tm and mt-CO1 may reflect compensatory biosynthesis or stress response in hippocampal mitochondria due to LPS-induced damage.

[0242] A comparison of mitochondrial mRNA changes in the cortex and hippocampus suggests that different brain regions may respond differently to LPS-induced neuroinflammation. This may reflect changes in neuronal vulnerability, microglia activation patterns, or mitochondrial dynamics in these regions.

[0243] Mitochondria, as the energy center of cells, play a crucial role in maintaining neuronal metabolic homeostasis, regulating oxidative stress, and signal transduction. In the LPS-induced inflammatory cognitive impairment model, mitochondrial dysfunction is one of the important mechanisms leading to neuronal damage and cognitive decline. This study, by analyzing the expression changes of key mitochondrial genes (such as mt-Nd4, mt-Atp6, mt-Tr, mt-Tm, and mt-C01), revealed the mechanism by which memantine improves mitochondrial dysfunction.

[0244] Regulatory role of memantine in cortical mitochondrial function

[0245] mt-Nd4:

[0246] Memantine treatment significantly upregulated the expression of the mt-Nd4 gene, indicating its crucial role in promoting mitochondrial electron transport chain (ETC) activity. mt-Nd4 encodes a core protein of ETC, and its increased expression directly promoted the restoration of ATP synthesis. ATP, as the primary energy source for neurons, is essential for synaptic plasticity and signal transduction. By enhancing ETC function, Memantine alleviated LPS-induced energy metabolism disorders and restored the functional state of cortical neurons. This effect may significantly improve the neuronal adaptability under high energy demands, enhance synaptic connection efficiency, and thus improve cognitive performance.

[0247] mt-Atp6:

[0248] Following Memantine treatment, the expression of the mt-Atp6 gene significantly increased, further supporting the enhancement of mitochondrial ATP production and improved metabolic function. As a higher control center for cognitive function, the cortex's neuronal activity is highly dependent on mitochondrial energy supply. Enhanced mt-Atp6 expression not only meets the energy needs of neurons but may also alleviate metabolic stress induced by neuroinflammation by stabilizing mitochondrial membrane potential (Δψm) and reducing cellular energy crisis. Enhanced metabolic homeostasis may provide support for complex cognitive tasks and improve LPS-induced cortical dysfunction.

[0249] Regulatory role of memantine in hippocampal mitochondrial function

[0250] mt-Tr (tRNA gene):

[0251] In the model group, the significant downregulation of mt-Tr reflects LPS-induced adaptive regulation of mitochondrial stress, which may reduce mitochondrial burden by decreasing protein synthesis requirements. However, this adaptation may impair mitochondrial biosynthesis and neuronal function in the long term.

[0252] Memantine treatment can optimize this regulatory process, helping to balance mitochondrial biosynthesis and repair functions, and protecting neurons from further damage. This effect is particularly important for the cortical and hippocampal regions, which have high energy demands and high metabolic activity.

[0253] mt-Tm (tRNA gene):

[0254] Memantine treatment significantly downregulated mt-Ty expression, which may protect hippocampal neurons by reducing the burden of mitochondrial protein synthesis and alleviating oxidative stress. The hippocampus is a core brain region for memory formation and is highly dependent on metabolic homeostasis. Excessive protein synthesis and unfolded protein stress (UPRmt) can lead to mitochondrial dysfunction, and Memantine may avoid this metabolic burden by reducing mt-Ty expression, thereby enhancing the hippocampus's tolerance to excitotoxicity and inflammation.

[0255] mt-C01:

[0256] In the model group, the expression level of mt-CO1 was significantly increased, suggesting that LPS-induced oxidative stress may exacerbate neuronal damage through excessive ROS production. However, Memantine treatment significantly downregulated the expression level of mt-CO1, which may reduce neuroinflammatory damage to the hippocampus by regulating oxidative metabolism and reducing ROS production. Studies have shown that hippocampal neuronal survival is closely related to the level of oxidative stress, and this antioxidant regulation by Memantine may directly protect neurons and improve hippocampus-dependent learning and memory functions.

[0257] Significant changes in mitochondrial gene expression further reveal the molecular mechanisms of LPS-induced neurological dysfunction and the potential role of Memantine treatment:

[0258] The key role of metabolic regulation:

[0259] Upregulation of mt-Nd4 and mt-Atp6 expression in the cortical region suggests that Memantine may restore energy balance by promoting electron transport chain activity, providing ATP support to damaged neurons. This metabolic improvement may help enhance neuronal functional homeostasis and mitigate the negative effects of neuroinflammation.

[0260] Stress adaptation and antioxidant protection:

[0261] The regulation of mt-Tr and mt-Tm expression in the hippocampus reflects the adaptive response of mitochondria to LPS-induced damage, and Memantine further alleviates protein synthesis and oxidative stress by optimizing this adaptive process. Furthermore, the downregulation of mt-CO1 suggests that Memantine may protect neurons and improve cognitive function by regulating ROS levels.

[0262] Changes in mitochondrial gene expression indicate that LPS-induced inflammatory neurological damage affects mitochondrial function in multiple ways, including decreased electron transport chain activity, dysregulation of tRNA production, and oxidative metabolic disorders. Memantine treatment, by upregulating or downregulating the expression of these genes, significantly restored mitochondrial energy metabolism function, reduced oxidative stress and metabolic pressure, and protected the survival and function of cortical and hippocampal neurons. These effects may constitute a key mechanism by which it improves cognitive dysfunction.

[0263] RNA-seq analysis revealed the crucial role of mitochondrial genes in LPS-induced cognitive impairment and clarified the molecular basis of memantine therapy. Memantine restores metabolic homeostasis and reduces oxidative stress and inflammatory damage by regulating mitochondrial gene expression, providing a new direction for the treatment of cognitive impairment. These findings not only deepen our understanding of the role of mitochondrial function in cognitive impairment but also provide important experimental evidence for developing mitochondrial-targeted therapeutic strategies.

[0264] Example 5 Clinical Trial

[0265] The development of EG-501 began with an in-depth exploration of the molecular mechanisms of cognitive impairment. Previous studies have shown that neuroinflammation, mitochondrial dysfunction, and impaired synaptic plasticity are core pathological features of cognitive impairment. Basic experiments (such as the LPS-induced C57 mouse model) revealed that EG-501 can significantly improve mitochondrial function, reduce oxidative stress, and restore neuronal metabolism and synaptic function by regulating key genes (such as mt-Nxx and mt-Cxx). These findings lay the foundation for the potential expansion of EG-501's indications and provide sufficient theoretical support for conducting Phase II clinical trials. With the support of basic research and animal experiments, this Phase II clinical trial of EG-501 focuses on cognitive impairment in patients with systemic lupus erythematosus (SLE). This trial design aims to verify the efficacy of EG-501 in real patients and provide a scientific basis for expanding its indications to other neuroinflammatory diseases.

[0266] Selection criteria:

[0267] The current Phase II clinical trial of EG-501 primarily targets patients with systemic lupus erythematosus (SLE), aiming to evaluate its efficacy in improving cognitive impairment. Inclusion criteria include the following:

[0268] (1) Diagnosed with SLE by a doctor.

[0269] (2) Report NPSLE symptoms on the screening questionnaire recommended by the EULAR guidelines, but only on a subset of the questions on psychotic symptoms, and use a cutoff score of at least 5, with a score of ≥2.5 in Part 1.

[0270] (3) Objective cognitive impairment (based on RBANS total index score ≤85, i.e. more than one standard deviation below the standard mean of 100).

[0271] The trial plans to recruit a total of 80 participants. Currently, 34 participants have been randomly assigned to treatment, and 27 participants have completed treatment.

[0272] Medication regimen:

[0273] Randomized patients begin titration upwards, reaching the maximum dose within 4 weeks. The starting dose is EG-501 5 mg twice daily (BID) (10 mg daily) or a placebo of the same appearance, increasing by 10 mg / day weekly until a maximum dose of 40 mg daily (i.e., 20 mg twice daily) is reached. For patients unable to tolerate the full 40 mg daily dose, individualized dose adjustments are permitted, with the adjustment window extending to the end of week 6. A clinic safety check is performed at the third visit (week 6). From week 6 to week 12, maintain the dose of 20 mg twice daily or the individualized maximum tolerated dose.

[0274] Primary endpoint:

[0275] Changes in the RBANS (Repetitive Neuropsychological Status Assessment) total index score after 12 weeks of treatment.

[0276] Secondary endpoint:

[0277] (1) RBANS subscales: immediate memory, visuospatial / constructive ability, language, attention, and delayed memory.

[0278] (2) Polysymptomatic Distress Scale (PDS).

[0279] (3) Beck Depression Inventory (BDI).

[0280] (4) Hospital Anxiety and Depression Scale (HADS).

[0281] (5) Systemic lupus erythematosus disease activity index (SLEDAI-2K).

[0282] (6) Patient Global Impression of Change (assessed only at the study endpoint).

[0283] The Repetitive Neuropsychological Status Assessment (RBAS) is a standardized cognitive function assessment tool that encompasses five core subscales (immediate memory, visuospatial / constructive ability, language, attention, and delayed memory) and a total index to comprehensively assess a patient's cognitive function. Changes in the subscales reflect improvements in specific areas of cognitive function, while changes in the total index reflect changes in overall cognitive ability.

[0284] Table 9 Interim Analysis Results: Changes in RBANS

[0285] Data Analysis:

[0286] Table 9 shows the changes in the RBANS subscale and total index of subjects in Group A (high-dose EG-501 group) and Group B (low-dose EG-501 group) at baseline and treatment endpoint (12 weeks) in the clinical trial.

[0287] Immediate memory index:

[0288] Group A: The baseline score was 81.53, which rose to 100.67 after treatment, a change of +19.14 points.

[0289] Group B: The baseline score was 86.88, which rose to 97.33 after treatment, a change of +10.45 points.

[0290] Explanation: The significant improvement in immediate memory indicates that EG-501 has a significant therapeutic effect in enhancing the ability to acquire and process short-term information, and the improvement in the high-dose group is significantly better than that in the low-dose group.

[0291] Apparent space / tectonic index:

[0292] Group A: The baseline score was 69.24, which increased to 71.92 after treatment, a change of +2.68 points.

[0293] Group B: The baseline score was 68.76, and the score after treatment was 71.2, a change of +2.44 points.

[0294] Explanation: The improvement in visuospatial ability was relatively small in both groups, which may be related to the lower degree of impairment or greater difficulty in improving this function in SLE patients.

[0295] Language Index:

[0296] Group A: The baseline score was 92.29, and the score after treatment was 91.5, a change of -0.79 points.

[0297] Group B: The baseline score was 97.41, and the score after treatment was 96.38, a change of -1.03 points.

[0298] Explanation: The language index showed no significant improvement or only a slight decline in both groups. This may be related to the fact that language function is relatively less affected by cognitive impairment, and may also suggest that EG-501 has a limited effect on improving language function.

[0299] Attention Index:

[0300] Group A: The baseline score was 88.71, which improved to 99.08 after treatment, a change of +10.37 points.

[0301] Group B: The baseline score was 88.47, and the score after treatment was 89.67, a change of +1.2 points.

[0302] Explanation: The significant improvement in the attention index, especially in the high-dose group, indicates that EG-501 plays an important role in attention regulation, which may be related to its mechanism in regulating the cholinergic system and reducing inflammatory response.

[0303] Delayed Memory Index:

[0304] Group A: The baseline score was 73.47, which increased to 82.17 after treatment, a change of +8.7 points.

[0305] Group B: The baseline score was 80 points, and the score after treatment was 81.27 points, with a change of +1.27 points.

[0306] Explanation: Improved delayed memory indicates that EG-501 can enhance the long-term storage and retrieval of information, and the high-dose group is also more effective than the low-dose group.

[0307] RBANS Total Index (Figure 7):

[0308] Group A (possibly the treatment group): Baseline score was 75.29, rising to 85.25 after treatment, a change (ΔA) of +9.96 points. The RBANS total index in Group A increased by nearly 10 points, a significant improvement typically considered clinically significant (≥10 points). This suggests that patients receiving the intervention in Group A may have experienced a significant improvement in overall cognitive function.

[0309] Group B (possibly the control group): Baseline score was 77.35, post-treatment score was 80.93, a change (ΔB) of +3.58 points. The change in the RBANS total index in Group B was small, not reaching a clinically significant moderate difference (≥7 points). This suggests that the intervention in Group B may have limited effectiveness in improving cognitive function.

[0310] The interim analysis of the RBANS total index showed significant differences in changes at baseline and treatment endpoint between the two groups (Group A and Group B). The change in Group A (+9.96) was significantly greater than that in Group B (+3.58), suggesting that the intervention in Group A may have a stronger effect on improving cognitive function in SLE patients. However, since the trial has not yet been unblinded, group identification cannot be fully determined at this time, but the significant differences indicate that the trial intervention may have a positive impact on cognitive function.

[0311] Interim clinical trial conclusions:

[0312] Significant clinical improvement:

[0313] In Group A, the RBANS total index improved by nearly 10 points, meeting the criteria for clinical significance. This significant improvement may reflect the effectiveness of the intervention on the patients' overall cognitive function, especially in the short term (12 weeks), where patients may have experienced substantial improvements in areas such as memory and attention.

[0314] Possible dose effects:

[0315] Although the trial has not yet been unblinded, the significant changes in the index in group A suggest that this group may have received effective treatment (such as a high-dose intervention with EG-501). This potential dose-dependent effect is consistent with findings in previous basic research and further supports the role of EG-501 in improving cognitive impairment.

[0316] Baseline stability in the control group:

[0317] The slight increase in the total RBANS index in group B may reflect baseline stability in the control group during treatment, and some patients may have experienced slight improvement due to trial participation, improved care conditions, or spontaneous disease fluctuations. However, this change did not reach clinical significance, indicating that controlled interventions (such as placebo or standard treatment) have limited effect on improving cognitive function.

[0318] Mechanisms supported by basic research:

[0319] The potential improvement in Group A can be linked to the findings of EG-501 mechanism studies. In basic research, EG-501 promotes ATP production and improves neuronal metabolic function by regulating mitochondrial function (e.g., upregulating mt-Nxx and mt-Axxx). Simultaneously, its anti-inflammatory mechanisms (e.g., reducing ROS levels and inhibiting neuroinflammation) may further alleviate neurological damage in SLE patients. These mechanisms may directly translate into a significant improvement in the RBANS total index in trials.

[0320] Indicators of potential long-term efficacy:

[0321] During the short-term treatment of 12 weeks, Group A already showed significant improvement in cognitive function. If this trend continues over a longer period (such as 24 or 52 weeks), further improvement in the RBANS total index will validate the long-term efficacy of the intervention. This provides important evidence for future long-term trials and practical clinical applications.

[0322] Although this trial has not yet been unblinded, the interim analysis results of the RBANS total index have provided important support for the potential efficacy of EG-501 in cognitive impairment in SLE patients. The near 10-point improvement in the RBANS total index in Group A suggests that EG-501 may significantly improve cognitive impairment in patients through its mechanisms of regulating mitochondrial function and inhibiting neuroinflammation. This mechanism of action has broad applicability, providing a scientific basis for expanding its indications in other diseases.

[0323] The mechanism of action of EG-501 lies in its precise regulation of NMDA receptors. This regulation improves cognitive function in several ways:

[0324] Optimize signal transmission:

[0325] EG-501 prevents short-term neuronal overload and signal distortion by inhibiting the overactivation of NMDA receptors by glutamate, thereby achieving clearer and more efficient information processing. In clinical practice, the significant improvement in the immediate memory index and attention index in group A (an increase of 19.14 points and 10.37 points, respectively) is highly consistent with this mechanism.

[0326] Promoting Long-Term Enhancement (LTP):

[0327] LTP is a key process for converting short-term memories into long-term memories. EG-501 may indirectly activate the LTP mechanism by optimizing glutamate signaling, thereby enhancing the strength of specific neural connections. In group A, the improvement in the delayed memory index (+8.7 points) further validates the clinical significance of this mechanism.

[0328] Enhance synaptic plasticity:

[0329] The NMDA receptor regulation of EG-501 can rapidly modulate synaptic strength and promote the encoding and storage of new information, which is highly consistent with the improvement results of multiple indicators of the RBANS subscale in clinical practice.

[0330] EG-501 also holds potential value in cognitive impairment induced by immune-related diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). Neuroinflammation, often present in MS and RA patients, significantly affects attention, memory, and executive function. EG-501 alleviates neuroinflammatory responses by reducing the expression of inflammatory cytokines such as TNF-α and IL-6, and restores interneuronal information transmission by enhancing cholinergic neurotransmission, such as increasing acetylcholine levels and choline acetyltransferase activity. These mechanisms of action are highly consistent with the significant improvement in attention and memory observed in basic experiments using EG-501.

[0331] Meanwhile, the mechanism of action of EG-501 also holds significant potential application in post-stroke cognitive impairment and traumatic brain injury (TBI). Mitochondrial damage caused by stroke and TBI typically manifests as increased protein synthesis burden and impaired energy metabolism. EG-501 optimizes mitochondrial protein synthesis requirements, reduces mitochondrial stress, and improves the cellular metabolic environment by regulating the expression of mt-Tx and mt-Ty genes, thereby promoting neuronal survival and repair. Furthermore, EG-501's role in enhancing synaptic plasticity and restoring neural network function may accelerate cognitive recovery and provide better prognosis for patients.

[0332] In summary, EG-501 demonstrates its potential for expanding indications across multiple diseases by improving mitochondrial function, reducing oxidative stress, and inhibiting neuroinflammation. The interim results of this trial not only validated the significant role of EG-501 in SLE-related cognitive impairment but also revealed its broad applicability in cognitive impairment in systemic lupus erythematosus, Parkinson's disease, amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, attention deficit hyperactivity disorder (ADHD), sepsis-associated encephalopathy, or mild cognitive impairment. In the future, through further Phase III clinical trials and expanded indication validation, EG-501 will become a breakthrough drug for the treatment of cognitive impairment, bringing tangible clinical benefits to more patients.

[0333] Example 6: Phase II clinical trial (ClearMEMory, NCT03527472)

[0334] 6-1 Research Overview:

[0335] Design: Randomized, double-blind, placebo-controlled, multicenter (Vanderbilt University Medical Center (VUMC), Cleveland Clinic, UTHealth Houston).

[0336] Objectives: To identify an NPSLE cohort using symptoms, EHR mining, cognitive testing, and NR2A antibody; to evaluate the efficacy of EG-501 on the RBANS total index; and to evaluate the efficacy of EG-501 in treating NPSLE in a specific patient subgroup.

[0337] Duration: 12 weeks.

[0338] Treatment: Randomized patients are titrated upwards to reach the maximum dose within 4 weeks. The starting dose is EG-501 5 mg twice daily (BID) (10 mg daily) or a placebo of the same appearance, increasing by 10 mg / day weekly until the maximum dose of 40 mg daily (i.e., 20 mg twice daily) is reached. Individualized dose adjustments are permitted for patients who cannot tolerate the full 40 mg daily dose, with the adjustment window extending to the end of week 6. A clinic safety check is performed at the third visit (week 6). From week 6 to week 12, maintain the dose of 20 mg twice daily or the individualized maximum tolerated dose. Background immunomodulators (e.g., HCQ) are permitted.

[0339] Population: Adults aged 18–69 years with a physician-diagnosed systemic lupus erythematosus (SLE). Cognitive impairment symptoms associated with neuropsychiatric SLE (NPSLE): NPSLE symptoms (based on an EULAR score ≥5, with a minimum score of 2.5 in Section 1), RBANS ≤85. Exclusion criteria included extreme age, recent medication changes, severe renal / psychiatric illness, and pregnancy. N=56, randomized (EG-501 N=26; placebo N=30); N=43 completers (EG-501 N=18; placebo N=25); Inclusion criteria: diagnosed NPSLE cognitive impairment (RBANS <90), ELISA+NR2A optional. See Tables 10-12 for details.

[0340] Primary endpoint: Change in RBANS total index (week 12 compared to baseline; MCID -5).

[0341] Secondary endpoints: RBANS subscales (e.g., immediate memory, visuospatial / constructive), systemic lupus erythematosus disease activity index (SLEDAI), BDI-II (depression), PSD (fatigue / thinking category), PGIC (overall impression at 4 / 12 weeks).

[0342] Safety: Treatment-induced adverse events (TEAEs), laboratory tests, discontinuation of treatment; descriptive analysis (Wilcoxon / x 2 No multiple adjustments; less than 30-40% when d=0.4).

[0343] [Amended according to Rule 26 22.12.2025] Subgroup: baseline RBANS <70, ELISA+NR2A, high SLEDAI (>8), age >50, population (32% Black).

[0344] Table 10 Overview of Participants

[0345] [Revised from Rule 26 to 22.12.2025] Table 11: Baseline and Demographic Information of Participants

[0346] Table 12 Reasons for Discontinuation of Treatment in Randomized Groups

[0347] 6-2 Primary endpoint: Change in RBANS total index

[0348] RBANS (Comprehensive Cognitive Screening) showed consistent EG-501 benefit in both completers and ITT (Missing Randomness, MAR), with a right-shifted plot (median +3.8 points) showing broad benefits. Areas of strength, demonstrating quantifiable cognitive improvements, primarily include: immediate memory improvement, attention improvement, and delayed memory improvement.

[0349] See Table 13, Table 14, Figure 8, and Figure 9 for details.

[0350] Table 13 Changes in RBANS

[0351] Table 14 RBANS Changes: Detecting Differences Between Two Completion Groups

[0352] Example of component representation: Immediate memory (domain-specific): EG-501 +5.3 to +2.1 (p = 0.023). Visual space / structure: EG-501 +4.1 (7.3) to +0.2 (10.1); difference +3.9 (p = 0.083; 56% of EG-501 ≥ 5 MCID vs. 44%).

[0353] Explanation: The adjusted difference of +4.7 points exceeded the MCID threshold for mild cognitive impairment; the high response end expansion (95th percentile +20 vs. +15) suggests a preventative potential in approximately 15-20% of “super-responders.” Subgroup analysis: ELISA-positive group +7.2 vs. +4.1 (interaction p = 0.08); baseline score <70 group +12.5 vs. +5.8 (p = 0.06). This effect translated into gains in daily abilities (e.g., improved spatial navigation, a symptom occurring in approximately 30-50% of NPSLE patients).

[0354] 6-3 Responder Analysis (RBANS Threshold)

[0355] A high response rate (NNT 3–4) confirmed clinical significance, comparable to central nervous system benchmarks (e.g., donepezil). See Table 15 and Figure 10 for details. The response rate in the EG-501 group was approximately twice that of the control group (≥8-point improvement threshold), with significance confirmed by both chi-square and Fisher's tests. Statistical robustness: The results from both response thresholds were consistent, and ITT analysis confirmed statistical significance. Clinical value: NNT ≈ 3–4 indicates significant efficacy in improving cognition in NPSLE patients, with an effect strength comparable to major central nervous system drugs.

[0356] Table 15 Respondent Analysis Results

[0357] Explanation: Robust across populations; a threshold of ≥8 (above MCID 5-8) supports the Breakthrough Therapy Designation (BTD) efficacy criteria. Subgroup amplification: High SLEDAI (>8, ~50%) 75% vs. 40% (p = 0.07).

[0358] 6-4 secondary endpoints

[0359] The directional trend favors EG501, particularly central nervous system selectivity (e.g., no peripheral deterioration) as shown in Table 16 and Figures 11-13.

[0360] [Revised from Rule 26, December 2025] Table 16 Summary of Secondary Results

[0361] Comprehensive interpretation: Inadequate secondary endpoints showed a consistent central nervous system (CNS) / patient-reported outcome (PRO) trend (e.g., +35% risk for mild / asymptomatic PSD; +24% risk for early PGIC), validating the effectiveness of the RBANS scale without over-involving emotional / systemic symptoms. No reverse causality was found; the bidirectional correlation axis (similarity to CKD-AD pathology) supports its preventative potential.

[0362] Changes in SLEDAI-2K (Disease Activity) Total Score

[0363] Placebo vs EG-501 (±SD, MCID line): Placebo: mean -1.0 (SD 6.1); EG-501: mean -4.2 (SD 6.7); difference -3.2; p = 0.17; achieving a decrease of ≥3 points is consistent with MCID ≥3–4 points; clinical significance: selective CNS benefit;

[0364] No new seizures; potential neuroimmune regulation.

[0365] PSD: Trouble Thinking Changes

[0366] This study presents the pre- and post-treatment distribution of patients in each group within the "trouble thinking" category. The pre-treatment proportion of mild / no category was calculated based on the complementary proportions of moderate and severe categories (before placebo: 24%; before EG501: 23%). The EG501 group showed a significant decrease in the proportions of moderate and severe categories and a substantial increase in mild / no category after treatment (from 23% to 83%), demonstrating a clear advantage over the placebo group (RD+35%).

[0367] Overall Impression of Patient Changes (PGIC - Week 12)

[0368] The distribution of patient proportions in the two groups within the PGIC categories at week 12 is shown (randomized N = 43). The EG501 group had a higher proportion in the improvement / significant improvement category (56% vs 36%, difference +20%), a slightly lower proportion in the unchanged category (39% vs 48%, -9%), and a lower proportion in the deterioration category (0% vs 16%, difference -16%), demonstrating the potential advantage of EG501.

[0369] 6-5 Safety and Tolerability

[0370] EG-501 exhibits excellent characteristics, reflecting the established use of EG501 in the central nervous system (chronic use in AD >1 year). See Table 17 for details.

[0371] Table 17 Safety Summary

[0372] Summarize:

[0373] No emergency safety signals.

[0374] The long-term safety profile is consistent with that of memantine for the treatment of Alzheimer's disease (long-term use >1 year).

[0375] No mood deterioration (BDI-II neutral).

[0376] Selective effects on the central nervous system—without systemic immunosuppression.

[0377] 6-6 Summary

[0378] EG-501 (memantine hydrochloride) provides compelling proof of concept for the treatment of NPSLE cognitive impairment through its dual mechanism of action—immediate symptom relief and long-term neuroprotection. Phase II results confirmed statistically significant (p = 0.032), strong (d = 0.8), and clinically meaningful patient benefits with good tolerability. See Table 18.

[0379] Table 18 Mechanism Duality

[0380] In summary, these findings fully support the FDA's considerations for Fast Track and Breakthrough Therapy designation and reduce the risk of subsequent critical development.

[0381] Example 7: Introduction to the Closed-Loop Validation of the AI ​​Platform in this Application: EG-501 from Target to Phase II Clinical Trial

[0382] (1) Using whole genome data (>12,000 exons sequenced, 250,000 gene coding variants, target-related SNPs) and desensitized medical records (35,000 subjects, about 1,600 different disease phenotypes).

[0383] (2) Using machine learning methods such as LASSO and Random Forest, 12 of the most important NMDA-related phenotypes and 3 highly associated autoimmune diseases were screened from large-scale PheWAS phenotype data: neuropsychiatric systemic lupus erythematosus (NPSLE) cognitive impairment, connective tissue diffuse disease, and polymyositis rheumatism (based on the screened phenotypes, a classification / regression model was constructed to quantify the correlation between the target and the phenotype, and the model performance was evaluated through cross-validation).

[0384] (3) Determine the indications for SLE cognitive impairment based on commercial factors such as market size, patient base, and competitive landscape.

[0385] (4) Expand the sample through public databases, clean the data with AI and perform modeling analysis.

[0386] (5) Ultimately, NPSLE cognitive impairment was selected as the breakthrough indication.

[0387] (6) Target discovery: Target receptor antagonism → regulation of neuroinflammation and neuroprotection; Drug screening: EG-501 was identified as the core candidate drug; Patient screening: AI accurately identifies NPSLE phenotype population; Clinical trials: Randomized, double-blind, placebo-controlled phase II study.

[0388] Through the above steps, the end-to-end closed-loop validation from target discovery → drug screening → patient selection → Phase II clinical trial was successfully completed, making EG-501 the first case in China to complete the entire closed loop through an AI platform.

Claims

1. Use of 1-amino-3,5-dimethyladamantaneamine hydrochloride in the preparation of medicaments for the prevention or treatment of cognitive impairment.

2. The use according to claim 1, wherein the cognitive impairment is a cognitive impairment in systemic lupus erythematosus, Parkinson's disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, attention deficit hyperactivity disorder, sepsis-associated encephalopathy, or mild cognitive impairment. Use of 3,1-amino-3,5-dimethylammonium hydrochloride in the preparation of drugs that reduce microglia in the cortex and hippocampus. Use of 4,1-amino-3,5-dimethylammonium hydrochloride in the preparation of drugs that reduce neuronal loss in the cortex and hippocampus. Use of 5,1-amino-3,5-dimethylammonium hydrochloride in the preparation of drugs for regulating the expression of mitochondrial genes in brain tissue and / or improving mitochondrial dysfunction.

6. The use according to any one of claims 1-5, wherein the drug has one or more of the following effects (1)-(6): (1) Reduce, alleviate or restore neuronal lesions or degeneration in the hippocampus; (2) Reduce, alleviate or restore the infiltration of inflammatory cells in the hippocampus; (3) Reduce the number of microglia in the cortex and / or hippocampus; (4) Reduce, alleviate or restore neuronal loss in the cortex and / or hippocampus; (5) It relieves or restores edema in the white matter area of ​​the cortex, improves the local microcirculation, significantly widens the interneuronal gaps, and sparsely distributes cells. (6) Relieves or restores nerve inflammation; (7) Protects the integrity of brain tissue and improves the damage to the blood-brain barrier; (8) Improves oxidative stress in the nervous system; (9) Improves synaptic plasticity; (10) Inhibits excessive activation of NMDA receptors and improves short-term neuronal overload and signal distortion; (11) Increase acetylcholine and / or choline acetyltransferase levels.

7. The use according to any one of claims 1-5, wherein the drug has one or more of the following effects (1)-(5): (1) Enhance memory; (2) Enhance cognitive flexibility; (3) Improve social behavior; (4) Improves attention; (5) Improve spatial memory and / or learning ability; (6) Relieves symptoms of brain fog; (7) Reduce the disease activity index of systemic lupus erythematosus; (8) Improve symptoms of mental fatigue and / or mental confusion; (9) Improve the patient’s overall impression.

8. The use according to claim 1, wherein enhancing memory is enhancing delayed memory or delayed memory.

9. The use according to any one of claims 1-5, wherein the drug regulates the expression of mitochondrial genes in brain tissue and improves mitochondrial dysfunction.

10. The use according to any one of claims 1-5, wherein the drug improves mitochondrial metabolism.

11. The use according to any one of claims 1-10, wherein the drug improves the mitochondrial electron transport chain, mitochondrial respiratory function and / or ATP production.

12. The use according to any one of claims 1-11, wherein the drug increases the expression of mt-Nd4 and / or mt-Atp6 in mitochondria.

13. The use according to any one of claims 1-12, wherein the drug reduces the expression of mt-Tm, mt-Tr and / or mt-CO1 in mitochondria.

14. The use according to any one of claims 1-13, wherein the medicament further comprises other drugs; the other drugs are selected from cholinesterase inhibitors, excitatory amino acid receptor antagonists, vasodilators, anti-inflammatory drugs, antioxidant drugs, and mitochondrial regulators.

15. A pharmaceutical composition for treating or preventing cognitive impairment, characterized in that, The drug contains anti-inflammatory agents, antioxidants, and mitochondrial modulators.

16. The pharmaceutical composition according to claim 15, wherein the mitochondrial regulator is 1-amino-3,5-dimethyladamantaneamine hydrochloride.

17. The pharmaceutical composition according to any one of claims 15 or 16, wherein the pharmaceutical composition regulates the expression of mitochondrial genes in brain tissue and improves mitochondrial dysfunction.

18. The pharmaceutical composition according to any one of claims 15-17, wherein the pharmaceutical composition improves mitochondrial metabolism.

19. The pharmaceutical composition according to any one of claims 15-18, wherein the pharmaceutical composition improves the mitochondrial electron transport chain, mitochondrial respiratory function and / or ATP production.

20. The pharmaceutical composition according to any one of claims 15-19, wherein the pharmaceutical composition increases the expression of mt-Nd4, mt-Atp6 and / or mt-Tr in mitochondria.

21. The pharmaceutical composition according to any one of claims 15-20, wherein the pharmaceutical composition reduces the expression of mt-Tm and / or mt-CO1 in mitochondria.

22. The use according to any one of claims 1-14 or the pharmaceutical composition according to any one of claims 15-21, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

23. The use or medicament according to claim 22, wherein the medicament is an injection, oral preparation, sustained-release preparation, transdermal patch, or nanoparticle medicament.

24. The use or medicine according to claim 22 or 23, wherein the daily dose of 1-amino-3,5-dimethyladamantane hydrochloride is 1-60 mg; and / or 1-amino-3,5-dimethyladamantane hydrochloride is taken once or twice daily; and / or 1-amino-3,5-dimethyladamantane hydrochloride is used for a prolonged period of time.

25. [Amended according to Rule 26, 22.12.2025] The use or medicine according to any one of claims 1-24, wherein the medicine is used for patients of the Black race.

26. A reagent kit, characterized in that, The kit contains reagents for detecting the expression of mitochondrial genes mt-Nd4, mt-Atp6, mt-Tr, mt-Tm, and mt-Co1.

27. The kit of claim 25 for use in the preparation of a kit for assessing mitochondrial dysfunction under inflammatory conditions, or in the preparation of a kit for identifying patients who may benefit from treatment with 1-amino-3,5-dimethylammonium hydrochloride.

28. A method for treating or preventing cognitive impairment in a subject, the method comprising administering 1-amino-3,5-dimethylammonium hydrochloride to a subject in need.

29. The method according to claim 28, wherein the cognitive impairment is a cognitive impairment arising from systemic lupus erythematosus, Parkinson's disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, attention deficit hyperactivity disorder, sepsis-associated encephalopathy, or mild cognitive impairment.

30. The method according to claim 28, wherein the treatment achieves one or more of the following effects (1)-(6): (1) Reduce, alleviate or restore neuronal lesions or degeneration in the hippocampus; (2) Reduce, alleviate or restore the infiltration of inflammatory cells in the hippocampus; (3) Reduce the number of microglia in the cortex and / or hippocampus; (4) Reduce, alleviate or restore neuronal loss in the cortex and / or hippocampus; (5) It relieves or restores edema in the white matter area of ​​the cortex, improves the local microcirculation, significantly widens the interneuronal gaps, and sparsely distributes cells. (6) Relieves or restores nerve inflammation; (7) Protects the integrity of brain tissue and improves the damage to the blood-brain barrier; (8) Improves oxidative stress in the nervous system; (9) Improves synaptic plasticity; (10) Inhibits excessive activation of NMDA receptors and improves short-term neuronal overload and signal distortion; (11) Increase acetylcholine and / or choline acetyltransferase levels.

31. The method according to claim 30, wherein the neuroinflammation is neuroinflammation of the cortex and / or hippocampus.

32. The method according to claim 28, wherein the treatment achieves one or more of the following effects (1)-(5): (1) Enhance memory; (2) Enhance cognitive flexibility; (3) Improve social behavior; (4) Improves attention; (5) Improve spatial memory and / or learning ability.

33. The method of claim 28, wherein the treatment increases acetylcholine and / or choline acetyltransferase levels.

34. The method of claim 28, wherein the treatment regulates the expression of mitochondrial genes in brain tissue and improves mitochondrial dysfunction.

35. The method of claim 28, wherein the treatment improves mitochondrial metabolism.

36. The method of claim 28, wherein the treatment improves the mitochondrial electron transport chain.

37. The method of claim 28, wherein the treatment improves mitochondrial ATP production.

38. The method of claim 28, wherein the treatment reduces, alleviates or restores the decrease in mt-Nd4 and / or mt-Atp6 expression in the cortex.

39. The method of claim 28, wherein the treatment reduces, alleviates or restores the increased expression of mt-Tm and / or mt-CO1 in the hippocampus.

40. The method of claim 28, wherein the treatment improves synaptic plasticity.

41. The method of claim 28, wherein the treatment inhibits excessive activation of NMDA receptors, improving short-term neuronal overload and signal distortion.

42. The method of claim 28, wherein the treatment improves neuropsychological states, depressive and / or anxiety states, and inflammatory states.

43. The method of claim 28, wherein the treatment further comprises administering other drugs to the subject, the other drugs being selected from cholinesterase inhibitors, excitatory amino acid receptor antagonists, vasodilators, anti-inflammatory drugs, antioxidant drugs, mitochondrial regulators, and traditional Chinese medicine for treating cognitive impairment.

44. The method according to claim 28, wherein the daily dose of 1-amino-3,5-dimethyladamantane hydrochloride is 1-60 mg.

45. The method according to claim 28, wherein the daily dose of 1-amino-3,5-dimethyladamantaneamine hydrochloride is 5-40 mg.

46. ​​The method according to claim 28, wherein the daily dose of 1-amino-3,5-dimethyladamantaneamine hydrochloride is 5-20 mg.

47. The method according to claim 28, wherein the 1-amino-3,5-dimethyladamantane hydrochloride is taken 1-3 times daily.

48. The method according to claim 28, wherein the 1-amino-3,5-dimethyladamantane hydrochloride is taken once or twice daily.

49. The method according to claim 28, wherein the 1-amino-3,5-dimethyladamantaneamine hydrochloride is continuously applied for more than 2 weeks.

50. The method according to claim 28, wherein the 1-amino-3,5-dimethyladamantaneamine hydrochloride is continuously applied for more than 4 weeks.

51. The method according to claim 28, wherein the 1-amino-3,5-dimethyladamantaneamine hydrochloride is continuously administered for more than 8 weeks.

52. The method according to claim 28, wherein the 1-amino-3,5-dimethyladamantaneamine hydrochloride is taken for a long period of time.

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