Application of aminopyridine substances in inhibition of alpha-synuclein aggregation and Lewy body formation

Abstract

The invention provides application of an aminopyridine potassium channel inhibitor in inhibiting or reducing abnormal aggregation of alpha-synuclein or inhibiting or reducing formation of Lewy bodies or Lewy protrusions, and application of aminopyridine substances in treating dementia related to the Lewy bodies, such as Lewy body dementia or Parkinson's disease dementia.

Description

Technical Field

[0001] The present invention provides the use of aminopyridine potassium channel inhibitors in inhibiting or reducing the abnormal aggregation of α-synuclein or inhibiting or reducing the formation of Lewy bodies or Lewy processes, as well as the use of aminopyridine substances in treating Lewy body-related dementia, such as Lewy body dementia or Parkinson's disease dementia. Background Art

[0002] Dementia is a chronic, comprehensive, and often irreversible decline in cognitive function. Dementia is primarily characterized by memory impairment, decreased thinking ability, impaired language skills, and disorientation. Dementia often causes patients to have difficulty with short-term memory, severely impacting their daily functioning. As the disease progresses, patients with dementia may experience a decline in their thinking, judgment, and problem-solving abilities, and their ability to express and understand language may also be affected. Furthermore, patients with dementia may experience confusion about time, place, and people, leading to disorientation.

[0003] In synucleinopathies such as dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and multiple system atrophy (MSA), patients harbor misfolded aggregates of α-synuclein, which are closely associated with disease progression. Aggregates located in neuronal cell bodies are called "Lewy bodies," while aggregates located in neuronal dendrites and axons are called "Lewy processes." Lewy bodies and Lewy processes, formed by aggregates of misfolded α-synuclein, lead to impaired neuronal function and death, resulting in cognitive and motor impairments. Lewy bodies and Lewy processes are also found in the brains of patients with neurodegenerative diseases such as Alzheimer's disease (AD) and Huntington's disease, further demonstrating that abnormal α-synuclein aggregation plays a crucial role in the pathogenesis of various neurodegenerative diseases.

[0004] Lewy body dementia is considered the third leading cause of dementia. It is a group of neurodegenerative diseases characterized clinically by fluctuating cognitive impairment, vivid visual hallucinations, and spontaneous parkinsonism, and pathologically by Lewy bodies in neuronal cells. The formation of Lewy bodies (also known as Lewy bodies) plays a vital role in the development of Lewy body dementia. The characteristics of Lewy body dementia include fluctuations in cognitive ability. The patient's cognitive level may change significantly in a short period of time, and is often accompanied by visual hallucinations, which seriously affect the patient's perception and daily life. In addition, although this type of dementia may also show bradykinesia and muscle rigidity, hallucinations and psychiatric symptoms are usually more prominent. Lewy bodies in Lewy body dementia are widely present in the cerebral cortex and brainstem, leading to early cognitive symptoms.

[0005] Compared to dementia with Lewy bodies, Parkinson's disease dementia typically develops several years after Parkinson's disease diagnosis (usually 10 to 15 years), and approximately 40% of Parkinson's disease patients will develop Parkinson's disease dementia (see https: / / www.msdmanuals.cn / professional / neurologic-disorders / delirium-and-dementia / dementia-with-lewy-bodies-and-parkinson-disease-dementia). In Parkinson's disease dementia, hallucinations and other psychiatric symptoms are relatively rare, with the primary focus on decreased executive function and attention. Lewy bodies are primarily localized in the substantia nigra, and cognitive decline typically appears later in the disease progression.

[0006] In patients with multiple system atrophy, it is mainly found in glial cells of neural tissue, especially in oligodendrocytes.

[0007] Despite the increasing understanding of synucleinopathies, existing research models have limitations in simulating Lewy body formation in the human brain. Traditional animal models, such as neurotoxic agents such as MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), rotenone, and 6-hydroxydopa, primarily cause dopaminergic neuron death by attacking the activity of mitochondrial respiratory chain complexes and are unable to effectively simulate the formation and aggregation of Lewy bodies in the brains of human Parkinson's disease patients. Using molecular cloning technology to synthesize human α-synuclein and prepare preformed fibrils (α-Syn PFFs), we have successfully induced the formation of Lewy bodies and Lewy processes in cell and mouse models. This method is considered an effective means of studying Lewy body pathology.

[0008] Therefore, it is necessary to find drugs that can effectively inhibit α-Syn aggregation or the formation of Lewy bodies or Lewy processes, so as to treat and improve Lewy body-related diseases or dementia. Summary of the Invention

[0009] The inventors of the present invention have found that potassium channel antagonists such as 4-aminopyridine (4-AP) can effectively reduce α-Syn aggregation or Lewy body formation in vivo, indicating that the molecule can be used to prevent or treat Lewy body-related diseases.

[0010] 4-AP is a potassium channel inhibitor. Its extended-release form, dalfampridine, has been approved by the US FDA for improving walking impairment in patients with multiple sclerosis (MS). 4-AP works by blocking the outflow of potassium ions from nerve cells, causing cell membrane depolarization and thereby enhancing the conduction of nerve impulses. This mechanism is particularly suitable for patients with MS, as the nerve fibers of MS patients often suffer from impaired signal transmission due to myelin damage. 4-AP can act within the spinal cord to increase the release of neurotransmitters from sensory neurons, thereby increasing the excitability of the motor network, thereby alleviating the symptoms of spinal muscular atrophy.

[0011] In some embodiments, the present invention relates to a method for inhibiting or reducing α-synuclein aggregation in a subject, comprising administering to the subject an effective amount of a potassium ion channel antagonist or a pharmaceutically acceptable salt thereof; a potassium ion channel antagonist or a pharmaceutically acceptable salt thereof for inhibiting or reducing α-synuclein aggregation in a subject; or use of a potassium ion channel antagonist or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting or reducing α-synuclein aggregation in a subject.

[0012] In some embodiments, the present invention relates to a method for inhibiting or reducing the formation of Lewy bodies or Lewy processes in a subject, the method comprising administering to the subject an effective amount of a potassium ion channel antagonist or a pharmaceutically acceptable salt thereof; a potassium ion channel antagonist or a pharmaceutically acceptable salt thereof for inhibiting or reducing the formation of Lewy bodies or Lewy processes in a subject; or use of a potassium ion channel antagonist or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting or reducing the formation of Lewy bodies or Lewy processes in a subject.

[0013] In some embodiments, the potassium channel antagonist is 4-aminopyridine, 4-(dimethylamino)pyridine, 4-(methylamino)pyridine, and 4-(aminomethyl)pyridine.

[0014] In some embodiments, the potassium channel antagonist is 4-aminopyridine.

[0015] In some embodiments, the α-synuclein is phosphorylated at Ser129.

[0016] In some embodiments, the therapeutically effective amount is an amount in the range of about 0.5 mg to 100 mg per administration and the potassium channel antagonist is administered one to three times per day. In some embodiments, the therapeutically effective amount is about 0.5 mg to 10 mg per administration, and the therapeutically effective amount is about 10 mg per administration.

[0017] In some embodiments, the potassium channel antagonist is formulated for oral administration.

[0018] In some embodiments, the subject has Lewy body disease.

[0019] In some embodiments, the Lewy body disease is Lewy body dementia, Parkinson's disease dementia, Parkinson's disease, multiple system atrophy, Alzheimer's disease, or Huntington's disease.

[0020] In some embodiments, the Lewy body disease is Lewy body dementia, wherein Lewy bodies are widespread in the cerebral cortex and brainstem of a subject with Lewy body dementia.

[0021] In some embodiments, the Lewy body disease is Parkinson's disease dementia, wherein the Lewy bodies are localized in the substantia nigra.

[0022] In some embodiments, the Lewy body disease is multiple system atrophy, wherein Lewy bodies are primarily present in glial cells of neural tissue.

[0023] In some embodiments, the method improves the subject's motor coordination and learning and memory abilities. In some embodiments, the method improves the subject's hallucinations and psychotic symptoms. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The following drawings illustrate embodiments of the present invention by way of example only, but are not intended to limit the present invention in any way:

[0025] Figure 1 Immunocytochemistry experiments showed that 4-aminopyridine, 4-(dimethylamino)pyridine and 4-(aminomethyl)pyridine could reduce the level of p-α-Syn. Figure 1 A shows the molecular structures of the four compounds used in the experiment; Figure 1 B shows the staining results after administration of 20 μM 4-aminopyridine, where the green fluorescence is the p-α-Syn staining result and the red fluorescence is the MAP2 staining result (neuronal marker); Figure 1C shows the results of five independent replicate experiments for 4-aminopyridine, 4-(dimethylamino)pyridine, 4-(aminomethyl)pyridine, and 4-amino-2-chloropyridine, analyzed by Image J. P = 3.05899E-4, n = 5, Student's t test. C1 (4-aminopyridine) vs. Ctrl, P = 3.05899E-4; C2 (4-(dimethylamino)pyridine) vs. Ctrl, P = 2.61958E-4; C3 (4-(aminomethyl)pyridine) vs. Ctrl, P = 0.00163; C4 (4-amino-2-chloropyridine) vs. Ctrl, P = 0.66265. All four molecules were used in cell culture at a concentration of 20 μM.

[0026] Figure 2 4-Aminopyridine administration in drinking water reduced the formation of Lewy bodies induced by α-Syn PFFs. Figure 2 A is a schematic diagram of the injection of α-Syn PFFs into the dorsal striatum (DS) of mice; Figure 2 B is a schematic diagram of 4-aminopyridine drinking water administration in mice; Figure 2 C is an immunohistochemical image showing that 4-aminopyridine administration in drinking water reduces the formation of Lewy bodies in the substantia nigra pars compacta (SNc) induced by α-Syn PFFs, where green is p-α-Syn staining and red fluorescence is TH (dopaminergic neuron marker) staining; Figure 2 D shows the statistical results of the effect of 4-aminopyridine, 4-(dimethylamino)pyridine, or 4-(aminomethyl)pyridine on the formation of Lewy bodies in the substantia nigra pars compacta (SNc) induced by α-Syn PFFs (P < 0.0327, n = 6, Student's t test). C1 (4-aminopyridine) vs. Ctrl, P = 2.43038E-4; C2 (4-(dimethylamino)pyridine) vs. Ctrl, P = 6.84875E-5; C3 (4-(aminomethyl)pyridine) vs. Ctrl, P = 5.64131E-4. The drinking water concentration of all three molecules was 40 μg / ml.

[0027] Figure 3 The results showed that 4-aminopyridine administration in drinking water reduced the formation of Lewy bodies in the DMV brain region of mice induced by α-Syn PFF. Figure 3 A is the immunohistochemical result, showing that 4-aminopyridine drinking water reduces the formation of Lewy bodies in the DMV brain region, where the green is P-α-Syn staining and the red fluorescence is ChAT (cholinergic neuron marker) staining; Figure 3B shows the statistical results of the effect of 4-aminopyridine, 4-(dimethylamino)pyridine, or 4-(aminomethyl)pyridine on the formation of Lewy bodies in the DMV brain region of mice induced by α-Syn PFFs. P < 0.05. Control group, n = 6; 4-AP group, n = 7, Student's t test. C1 (4-aminopyridine) vs. Ctrl, P = 1.02725E-6; C2 (4-(dimethylamino)pyridine) vs. Ctrl, P = 1.2048E-5; C3 (4-(aminomethyl)pyridine) vs. Ctrl, P = 3.0462E-6. The drinking water concentration of all three molecules was 40 μg / ml. Specific implementation plan

[0028] 1. Definition

[0029] The active ingredient potassium channel antagonist of the present invention can be used in various salt forms, including but not limited to pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts. Pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates, and phosphates; and organic acid salts such as acetates, oxalates, maleates, fumarates, citrates, benzoates, and methanesulfonates. Pharmaceutically acceptable metal salts include alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as magnesium and calcium salts; and aluminum and zinc salts. Pharmaceutically acceptable ammonium salts include ammonium and tetramethylammonium salts. Pharmaceutically acceptable organic amine addition salts include morpholinium and piperidine salts. Pharmaceutically acceptable amino acid addition salts include lysine, glycine, phenylalanine, aspartate, and glutamate.

[0030] The active ingredient potassium channel antagonist of the present invention can be used as a single active ingredient or used in combination with other drugs for treating dementia. The other drugs for treating dementia include but are not limited to drugs for treating Parkinson's-like movement symptoms, drugs for treating dementia, drugs for treating mental symptoms, drugs for treating autonomic dysfunction, such as dopamine drugs, cholinesterase inhibitors, quetiapine, clozapine, aripiprazole, donepezil, rivastigmine, galantamine, rivastigmine, memantine, serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, etc.

[0031] The potassium channel antagonist, an active ingredient of the present invention, can be administered orally, by injection, topically or in vitro, preferably orally or by injection.

[0032] "Subject" and "patient" are used interchangeably herein and refer to any mammalian subject, particularly a human, for whom diagnosis, treatment, or therapy is desired. Subjects as used herein include, but are not limited to, animals (e.g., cows, pigs, horses, sheep, dogs, and cats) and plants, including humanoids, such as humans, chimpanzees, and monkeys.

[0033] "Administration" refers to the delivery of a drug by any of a variety of methods and delivery systems known to those skilled in the art. Administration can be, for example, orally, or intravenously, by implant, transmucosally, transdermally, intradermally, intramuscularly, subcutaneously, or intraperitoneally. Administration can also be, for example, performed once, multiple times, and / or over one or more sustained periods.

[0034] A "therapeutically effective amount" refers to a dose of a drug that produces a therapeutic effect. Typically, this effect is achieved by inducing or enhancing physiological processes, or by blocking or inhibiting physiological processes, thereby assisting or promoting the alleviation or elimination of a disease or condition. Specifically, this includes objective or subjective improvement of a disease or symptom, such as a reduction in the severity of one or more symptoms. It is worth noting that full therapeutic effect does not necessarily require a single administration and may require the cumulative effect of multiple administrations. Therefore, a therapeutically effective amount can be achieved through multiple administrations.

[0035] "Treating" a disease means taking a course of action to achieve a desired benefit or outcome, including clinical effects such as alleviating, alleviating, or ameliorating one or more symptoms; reducing the severity of the disease; delaying or slowing the progression of the disease; and improving and stabilizing statistical indicators of the disease. Therefore, "treatment" can be understood as the specific steps taken to achieve these effects.

[0036] Alpha-synuclein is a phospholipid-binding protein abundant in presynaptic terminals and involved in the release and regulation of synaptic vesicles. Alpha-synuclein is the main component of Lewy bodies (aggregates of protein and lipids), and its spread and accumulation in dopaminergic cell bodies and other cell types is a hallmark of the disease.

[0037] Lewy bodies are abnormal protein aggregates found within nerve cells, primarily composed of alpha-synuclein. These aggregates are often associated with various neurodegenerative diseases, particularly Parkinson's disease dementia and dementia with Lewy bodies. The formation of Lewy bodies is closely associated with neuronal dysfunction, leading to motor and cognitive symptoms.

[0038] Lewy neurites are long, thin projections found within nerve cells, often associated with Lewy bodies. These projections are formed by abnormal aggregation of alpha-synuclein and are commonly seen in various neurodegenerative diseases.

[0039] "About" refers to a range of values that falls within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater or less) of the stated reference value.

[0040] The following examples are merely illustrative of the present invention and do not limit the present invention. Those skilled in the art may make non-essential improvements and adjustments to the embodiments, which are still within the scope of protection of the present invention.

[0041] 2. Materials and Methods

[0042] 2.1 Experimental animals and materials

[0043] The experimental animals used in this invention were 8-week-old male SPF C57 BL6J mice purchased from Vital River. The mice were housed under the following conditions: an ambient temperature of 22 ± 0.5°C, a 12-hour light / dark cycle, and free access to food and water. In addition, commercially available 4-aminopyridine was used in this invention.

[0044] 2.2 α-Synuclein Purification and α-Synuclein Fibril (PFF) Preparation

[0045] Alpha-synuclein purification and alpha-synuclein fibrils (PFFs) were performed using methods known in the art, such as inducing expression of human alpha-synuclein using molecular cloning techniques and purifying the protein using molecular sieves and anion exchange columns. Protein concentration was then determined, and alpha-synuclein was further induced to form fibrillar aggregates in vitro, which were verified using thioflavin-T and electron microscopy. For specific procedures, see Luk, KC, et al., (2012), Science 338, 949-953.

[0046] 2.3 Primary neuronal cell culture

[0047] Primary neuronal cell culture was performed using methods known in the art: the hippocampus of newborn rats was isolated and minced, and then digested with papain for primary hippocampal neuron culture. For specific steps, see Cramer, T. M. Letal., (2024), STAR Protoc 5, 102991.

[0048] 2.4 Immunocytochemistry

[0049] Immunocytochemistry was performed using methods known in the art: primary hippocampal neurons were fixed with 4% paraformaldehyde, then serum-blocked, incubated with a primary antibody (e.g., P-α-Syn) and a secondary antibody (GAR488), and then mounted for fluorescence imaging. For experimental procedures, refer to Cramer, T.M. Let al., (2024), STAR Protoc 5, 102991.

[0050] 2.5 Stereotaxic injection into mouse brain

[0051] Pre-prepared α-synuclein was stereotaxically injected into the specific brain region at a concentration of 5 mg / mL in a volume of 0.5 μL to 1 μL. For detailed experimental procedures, please refer to Luk, KC, et al., (2012), Science 338, 949-953 and Xie et al., (2022), Cell 185, 4298-4316e4221.

[0052] 2.6 Brain extraction by cardiac perfusion, frozen sectioning, and immunohistochemistry

[0053] After the experiment, mice were anesthetized with urethane. Once unconscious, a perfusion pump was used to perfuse physiological saline and then 4% paraformaldehyde into the left ventricle. The brains were then removed intact. The brains were post-fixed in 4% paraformaldehyde for 8 hours and then transferred to a 30% sucrose solution for dehydration.

[0054] After dehydration, the brain was mounted on a microtome and the target brain region was sliced at 40 μm for further immunohistochemical staining. For detailed experimental procedures, please refer to Luk, KC, et al., (2012), Science 338, 949-953 and Xie et al., (2022), Cell 185, 4298-4316e4221.

[0055] 2.7 Imaging

[0056] After immunohistochemistry was completed, images were taken using an Olympus VS120 fluorescence microscope (10x objective) and a Zeiss LSM800 fluorescence microscope (20x and 63x objectives). The images were saved for subsequent graphical analysis. The imaging results were statistically analyzed and plotted using Imaris and GraphPad.

[0057] 2.8 Data Statistical Methods

[0058] All experimental data are expressed as mean ± standard error, *P < 0.05, **P < 0.01, ***P < 0.001.

[0059] 3. Examples

[0060] Example 1: Reduction of abnormal aggregation of α-synuclein in primary mouse hippocampal neurons induced by α-Syn PFF.

[0061] The mice and α-Syn PFFs prepared in section "2. Materials and Methods" were used for control and test group experiments. The control group consisted of α-Syn PFFs + sterile saline; and the test group consisted of α-Syn PFFs + 4-aminopyridine (C1) / 4-(dimethylamino)pyridine (C2) / 4-(aminomethyl)pyridine (C3) / 4-amino-2-chloropyridine (C4).

[0062] α-Syn PFF + sterile saline and α-Syn PFF + 4-aminopyridine (C1) / 4-(dimethylamino)pyridine (C2) / 4-(aminomethyl)pyridine (C3) / 4-amino-2-chloropyridine (C4) were administered to primary mouse hippocampal neurons, respectively. The amount of C1, C2, C3, and C4 was 20 μM. The cells were then fixed for immunocytochemistry experiments. Figure 1 As shown in B, in the result image taken under the same antibody and reagent ratio and the same exposure parameters, it can be clearly observed that the P-α-Syn fluorescence of cells in the 4-AP treatment group decreased; Figure 1 C shows the results of five independent experiments repeated for 4-aminopyridine, and the results of quantitative analysis by Image J. Similarly, five independent experiments repeated for 4-(dimethylamino)pyridine (C2), 4-(aminomethyl)pyridine (C3), and 4-amino-2-chloropyridine (C4) were also shown in the Image J quantitative analysis. Figure 1 C.

[0063] Example 1 demonstrated that 4-aminopyridine (C1), 4-(dimethylamino)pyridine (C2), and 4-(aminomethyl)pyridine (C3) all significantly reduced abnormal α-synuclein aggregation in primary mouse hippocampal neurons induced by α-Syn PFFs and inhibited the formation of Lewy bodies. However, 4-amino-2-chloropyridine (C4) did not exhibit these effects.

[0064] Example 2: Reduction of Lewy body formation in the mouse CPu-SNc system induced by α-Syn PFF

[0065] After anesthesia, C57BL6J male mice of appropriate age were injected with α-Syn PFF into the dorsal striatum DS brain region of the mice using stereotaxic injection surgery. The injection coordinates were (+0.86, ±2.0, -2.4 mm). Figure 2 As shown in A. Figure 2As shown in Figure B, mice recovered for one week after surgery. The control group received normal drinking water, while the experimental group received 4-aminopyridine (40 μg / mL) in the drinking water. Two months later, the mice underwent cardiac perfusion, and their brains were harvested. Immunohistochemistry was performed on all SNc brain slices after frozen sectioning. P-α-Syn staining was performed on the SNc brain slices of all mice in the control and experimental groups using an Olympus VS120. Lewy bodies were identified and counted using Imaris software.

[0066] The experimental results can be found in Figure 2 C and Figure 2 D. Figure 2 In Figure C, it can be observed that compared with the normal water-drinking mice in the control group, the number of Lewy bodies formed in the SNc of mice that had been orally administered 4-aminopyridine for a long time was significantly reduced, indicating that oral administration of 4-aminopyridine can significantly reduce the formation of Lewy bodies in the SNc of mice induced by α-Syn PFF. Figure 2 D shows the results of multiple repeated independent experiments, in which oral administration of 4-(dimethylamino)pyridine (C2) and 4-(aminomethyl)pyridine (C3) also significantly reduced the formation of Lewy bodies in the mouse SNc induced by α-Syn PFFs.

[0067] Example 3: α-Syn PFF-induced reduction of Lewy body formation in cholinergic neurons in the DMV brain region of mice After anesthesia, C57BL6J male mice of appropriate age were anesthetized and injected with α-Syn PFF into the dorsal motor nucleus DMV brain region of the mice using brain stereotactic injection surgery. The injection coordinates were (-7.5, ±0.3, -3.3mm). The mice recovered for 1 week after surgery. The control group was given normal drinking water, and the experimental group was given 4-aminopyridine drinking water (concentration 40μg / mL). Two months later, the mice were perfused by heart, and the brains were removed. After frozen sections, immunohistochemistry experiments were performed on all DMV brain slices. P-α-Syn staining and imaging of P-α-Syn stained brain slices in the DMV brain region of all mice in the control and experimental groups were performed using Olympus VS120, and the number of Lewy bodies was identified and counted using Imaris software. Example 3 and Figure 3 A and 3B demonstrated that oral administration of 4-aminopyridine (C1), 4-(dimethylamino)pyridine (C2), and 4-(aminomethyl)pyridine (C3) could significantly reduce the formation of Lewy bodies in the DMV brain region of mice induced by α-Syn PFFs.

[0068] 4. Conclusion

[0069] This study demonstrates for the first time that 4-aminopyridine, 4-(dimethylamino)pyridine, and 4-(aminomethyl)pyridine can significantly inhibit endogenous α-Syn aggregation, Lewy body, and Lewy neurite formation induced by α-Syn PFFs. Subsequently, the inhibitory effects of 4-aminopyridine, 4-(dimethylamino)pyridine, and 4-(aminomethyl)pyridine on Lewy body formation were further confirmed in vivo in the mouse CPu-SNc and DMV, two brain regions closely associated with Parkinson's disease dementia. These results suggest that 4-aminopyridine, 4-(dimethylamino)pyridine, and 4-(aminomethyl)pyridine may be key compounds that effectively inhibit α-Syn aggregation, Lewy body, and Lewy neurite formation, providing new insights into the treatment of neurodegenerative diseases associated with Lewy body lesions, such as dementia with Lewy bodies and Parkinson's disease dementia.

Claims

1. A method for inhibiting or reducing α-synuclein aggregation in a subject, the method comprising administering to the subject an effective amount of a potassium channel antagonist or a pharmaceutically acceptable salt thereof.

2. A method for inhibiting or reducing the formation of Lewy bodies or Lewy processes in a subject, the method comprising administering to the subject an effective amount of a potassium ion channel antagonist or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or 2, wherein the potassium channel antagonist is 4-aminopyridine, 4-(dimethylamino)pyridine, 4-(methylamino)pyridine, and 4-(aminomethyl)pyridine.

4. The method of claim 1 or 2, wherein the potassium channel antagonist is 4-aminopyridine.

5. The method of claim 1 or 2, wherein the therapeutically effective amount is an amount in the range of about 0.5 mg to 100 mg per administration and the potassium channel antagonist is administered one to three times per day.

6. The method of claim 5, wherein the therapeutically effective amount is about 0.5 mg to 10 mg per administration, wherein the therapeutically effective amount is about 10 mg per administration.

7. The method of claim 1 or 2, wherein the potassium channel antagonist is formulated for oral administration.

8. The method of claim 1 or 2, wherein the subject has Lewy body disease.

9. The method of claim 1 or 2, wherein the Lewy body disease is dementia with Lewy bodies, Parkinson's disease dementia, Parkinson's disease, multiple system atrophy, Alzheimer's disease, or Huntington's disease.

10. The method of claim 1 or 2, wherein the Lewy body disease is Lewy body dementia, wherein Lewy bodies are widespread in the cerebral cortex and brainstem of a subject with Lewy body dementia.

11. The method of claim 1 or 2, wherein the Lewy body disease is Parkinson's disease dementia, wherein the Lewy bodies are localized in the substantia nigra.

12. The method of claim 1 or 2, wherein the Lewy body disease is multiple system atrophy, wherein Lewy bodies are primarily present in glial cells of neural tissue.

13. The method of claim 1 or 2, wherein the method improves the subject's motor coordination and learning and memory abilities.

14. The method of claim 1 or 2, wherein the method improves hallucinations and psychotic symptoms in the subject.

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