阅读说明：本技术 人参皂苷m1用于治疗亨丁顿舞蹈症的用途 (Use of ginsenoside M1 for treating Huntington's chorea ) 是由 理筱龙 花国峰 理昱杰 于 2019-04-23 设计创作，主要内容包括：本发明公开人参皂苷M1用于制造供治疗亨丁顿舞蹈症(HD)的药物的用途；以及用于治疗HD的医药组合物,包括人参皂苷M1及医药上可接受的载体。(The invention discloses the use of ginsenoside M1 in the manufacture of a medicament for the treatment of Huntington's Disease (HD); and a pharmaceutical composition for treating HD, comprising ginsenoside M1 and a pharmaceutically acceptable carrier.)

1. A method of treating Huntington's Disease (HD) in a subject in need thereof, comprising administering to the subject an effective amount of ginsenoside M1.

2. The method of claim 1, wherein the individual exhibits a mutant HTT protein.

3. The method according to claim 2, wherein the mutant HTT protein accumulates in neurons of the individual.

4. The method of claim 1, wherein the ginsenoside M1 is administered in an amount effective to (i) reduce the formation of Reactive Oxygen Species (ROS) and/or (ii) reduce cytotoxicity in neurons of the subject, and/or (iii) improve motor coordination, (iv) prolong lifespan, and/or (v) reduce the formation of mHtt aggregates in the striatum of the subject.

5. Use of ginsenoside M1 in the manufacture of a medicament for treating Huntington's Disease (HD) in an individual in need thereof.

6. The use according to claim 5, wherein the individual exhibits a mutant HTT protein.

7. The use according to claim 6, wherein the mutant HTT protein accumulates in neurons of the individual.

8. The use of claim 5, wherein the medicament is effective to (i) reduce the formation of Reactive Oxygen Species (ROS) and/or (ii) reduce cytotoxicity in neurons of the subject, and/or (iii) improve motor coordination, (iv) prolong lifespan, and/or (v) reduce the formation of mHtt aggregates in the striatum of the subject.

9. A pharmaceutical composition for treating Huntington's Disease (HD) comprises ginsenoside M1 and pharmaceutically acceptable carrier.

Technical Field

The invention relates to a new application of ginsenoside M1 in treating Huntington's Disease (HD).

Background

Dington's disease (HD) is a somatomicro-dominant, inherited neurodegenerative disease caused by aberrant CAG trinucleotide repeat amplifications in the Huntington gene. The disease manifests clinically as progressive involuntary dyskinesia, dementia and ultimately death. To date, there is no effective treatment for HD.

Ginsenoside, which is a main active ingredient of ginseng, is known to have various pharmacological activities, such as anti-tumor, anti-fatigue, anti-allergic and anti-oxidative activities. Ginsenosides have a basic structure consisting of a sex-lipid-alkane (gonane) steroid nucleus with 17 carbon atoms arranged in a tetracyclic ring. Ginsenosides are metalated in vivo, and recent studies have shown that metabolites of ginsenosides, rather than naturally occurring ginsenosides, are readily absorbed by the body and serve as active ingredients. Some ginsenosides have been reported to have beneficial effects on certain neurodegenerative and aging diseases. Among them, ginsenoside M1, also called compound k (ck), is known as a metabolite of protopanaxadiol-type (protoxadiol-type) ginsenoside through the gypenoside pathway of human intestinal bacteria. To date, no prior art reference has reported the utility of ginsenoside M1 in the treatment of HD

Disclosure of Invention

In the present invention, ginsenoside M1 was unexpectedly found to be effective in alleviating one or more symptoms of Huntington's Disease (HD). Accordingly, the present invention provides a novel method of treating HD in an individual.

Accordingly, the present invention provides a method of treating Huntington's Disease (HD) in a subject in need thereof, comprising administering to the subject an effective amount of ginsenoside M1.

In some embodiments, the individual exhibits accumulation of a mutant HTT protein, particularly a mutant HTT protein, in a neuron in the individual.

In some embodiments, ginsenoside M1 is administered in an amount effective to (i) reduce the formation of Reactive Oxygen Species (ROS) and/or (ii) reduce cytotoxicity, particularly in neurons in a subject, and/or (iii) improve motor coordination, (iv) prolong lifespan, and/or (v) reduce the formation of mHtt aggregates in the striatum of a subject.

In some embodiments, ginsenoside M1 is administered by parenteral or enteral route.

The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the invention will be apparent from the following detailed description of several specific embodiments, and from the appended claims.

Drawings

For the purpose of illustrating the invention, there is shown in the drawings embodiments which are presently preferred. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described. In the drawings:

figures 1A-1B show that ginsenoside M1 significantly reduced cytotoxicity in mHtt expressing cells. (FIG. 1A) STHdhQ7 and STHdhQ109 cells were treated with 30. mu.M ginsenoside M1 or vehicle (0.1% DMSO) for 24 hours. The survival of STHdhQ7 and STHdhQ109 cells was quantified by MTT reduction assay. (FIG. 1B) STHdhQ109 cells were treated with 1-30. mu.M ginsenoside M1 or vehicle (0.1% DMSO) for 24 hours. The survival of STHdhQ109 cells was quantified by MTT reduction assay. Results are expressed as mean ± SEM of triplicate samples. Multiple groups will be analyzed using single factor variance analysis (ANOVA) followed by a Student-Newman-couls assay (Student-Newman-Keuls test) afterwards. p value<0.05 will be considered significant.^ap<0.05: STHdhQ7 between STHdhQ109 cells (fig. 1A), or compared to untreated (carrier-treated) sthdq 7 cells (fig. 1B).^bp<0.05: compared to untreated (carrier treated) STHdhQ109 cells.

Fig. 2 shows that ginsenoside M1 significantly reduced ROS production in STHdhQ109 cells. ROS indicator H in 10. mu.M cells₂Treating STHdh with 1-30 μ M ginsenoside M1 or vehicle (0.1% DMSO) in the presence of DCFDA^Q109Cells were incubated for 1 hour. Cellular ROS content was measured by detecting the fluorescence intensity using a fluorescence plate reader. Results are expressed as mean ± SEM of triplicate samples. Multiple groups will be analyzed using single factor variance analysis (ANOVA) followed by a student-newmann-kols assay afterwards. p value<0.05 will be considered significant.^ap<0.05: with untreated (carrier-treated) STHdh^Q109And (4) comparing cells.

FIG. 3 showsIt was shown that ginsenoside M1 significantly reduced the degree of phosphorylation of AMPK in STHdhQ109 cells. Treating STHdh with 10 or 30 μ M ginsenoside M1 or vehicle (0.1% DMSO)^Q7And STHdh^Q109Cells were cultured for 24 hours. The extent of phosphorylation of AMPK was measured by western blot method. Western blot results represent three different experiments and the histogram shows the quantification as mean ± SEM of the three experiments. Multiple groups will be analyzed using single factor variance analysis (ANOVA) followed by a student-newmann-kols assay afterwards. p value<0.05 will be considered significant.^ap<0.05：STHdh^Q7And STHdh^Q109Between cells.^bp<0.05: with untreated (carrier-treated) STHdh^Q109And (4) comparing cells.

Fig. 4 shows that ginsenoside M1 significantly reduced the degree of phosphorylation of ATM in STHdhQ109 cells. Treating STHdh with 10 or 30 μ M ginsenoside M1 or vehicle (0.1% DMSO)^Q7And STHdh^Q109Cells were cultured for 24 hours. The degree of phosphorylation of ATM was measured by western blotting. Western blot results represent three different experiments and the histogram shows the quantification as mean ± SEM of the three experiments. Multiple groups will be analyzed using single factor variance analysis (ANOVA) followed by a student-newmann-kols assay afterwards. p value<0.05 will be considered significant.^ap<0.05：STHdh^Q7And STHdh^Q109Between cells.^bp<0.05: with untreated (carrier-treated) STHdh^Q109And (4) comparing cells.

Fig. 5 shows that ginsenoside M1 significantly reduced the expression amount of γ H2AX in STHdhQ109 cells. Treating STHdh with 10 or 30 μ M ginsenoside M1 or vehicle (0.1% DMSO)^Q7And STHdh^Q109Cells were cultured for 24 hours. The expression amount of γ H2AX was measured by the western blot method. Western blot results represent three different experiments and the histogram shows the quantification as mean ± SEM of the three experiments. Multiple groups will be analyzed using single factor variance analysis (ANOVA) followed by a student-newmann-kols assay afterwards. p value<0.05 will be considered significant.^ap<0.05：STHdh^Q7And STHdh^Q109Between cells.^bp<0.05: with untreated (carrier-treated))STHdh^Q109And (4) comparing cells.

Fig. 6 shows that ginsenoside M1 significantly reduced the degree of phosphorylation of p53 in STHdhQ109 cells. Treating STHdh with 10 or 30 μ M ginsenoside M1 or vehicle (0.1% DMSO)^Q7And STHdh^Q109Cells were cultured for 24 hours. The degree of phosphorylation of p53 was measured by western blot. Western blot results represent three different experiments and the histogram shows the quantification as mean ± SEM of the three experiments. Multiple groups will be analyzed using single factor variance analysis (ANOVA) followed by a student-newmann-kols assay afterwards. p value<0.05 will be considered significant.^ap<0.05：STHdh^Q7And STHdh^Q109Between cells.^bp<0.05: with untreated (carrier-treated) STHdh^Q109And (4) comparing cells.

Figure 7 shows that oral administration of ginsenoside M1 significantly increased motor coordination in mice with HD disease. R6/2HD disease mice were orally administered ginsenoside M1 (30 mg/kg by weight) or vehicle daily for 4 weeks starting at 7 weeks of age. Wild type healthy control mice were orally administered vehicle daily. The motor coordination was assessed using a rotarod device assay. Results are expressed as mean ± SEM. Multiple groups were analyzed by single factor variational analysis (ANOVA) followed by a student-newmann-kols assay afterwards.^ap<0.05: between WT and R6/2-vector mice.^bp<0.05: compared with R6/2-carrier mice.

Figure 8 shows that oral administration of ginsenoside M1 significantly prolonged the lifespan of mice with HD disease. R6/2HD disease mice were orally administered ginsenoside M1 (30 mg/kg by weight) or vehicle daily for 4 weeks starting at 7 weeks of age. Wild type healthy control mice were orally administered vehicle daily. The longevity of the mice was determined. Results are expressed as mean ± SEM. Multiple groups were analyzed by single factor variational analysis (ANOVA) followed by a student-newmann-kols assay afterwards.^ap<0.05: between WT and R6/2-vector mice.^bp<0.05: compared with R6/2-carrier mice.

Figure 9 shows that oral administration of ginsenoside M1 reduced the formation of mHtt aggregates in the striatum of mice with HD disease. Wild type healthy control mice and R6/2HD disease mice were orally administered ginsenoside M1 (30 mg/kg by weight) or vehicle daily for 4 weeks starting at 7 weeks of age. The amount of mHtt aggregates in striatal lysates was analyzed by filter delay assay.

Detailed Description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the following terms have the meanings ascribed to them unless otherwise indicated.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

The terms "comprising" or "comprising" are generally used in an inclusive/inclusive sense, meaning that one or more features, components, or elements are permitted. The term "comprising" or "comprises" includes the words "consisting of or" consisting of.

Huntington's Disease (HD) is a somatomomal dominant hereditary neurodegenerative disease with clinical manifestations of progressive involuntary movement disorder, dementia and eventual death [1 ]. It is caused by CAG trinucleotide amplification in exon 1 of the huntington (Htt) gene, which is located on the short arm of human chromosome 4 (4p 63). When CAG repeats exceed 36, translational polyglutamic acid (polyQ) containing Htt proteins [ mutant Htt (mhtt) ] interferes with the normal function of many cellular proteins, thereby compromising important cellular mechanisms [2 ]. Abnormal accumulation of polyQ-amplified mutant Htt also leads to accumulation in nuclei of neurons, astrocytes, cochlear neurons and many different types of peripheral cells [3 ]. Mutant Htt is known to promote protein misfolding, inhibiting the activity of proteasome activity, deregulating transcription, impairing synaptic function, increasing oxidative stress, degrading axons, and ultimately leading to neurodegeneration and neuronal loss [3 ]. Extensive release of glutamate from the cortico-striatal ends and impairment of neuronal survival are believed to be responsible for striatal neurodegeneration, which causes the initial symptoms of HD. Dysfunction of the nigrostriatal (nigro-striatal) pathway also contributes to the neuroexcitotoxicity of the striatum. Meanwhile, neuronal degeneration induced by the mutant Htt occurs mainly in non-striatal brain areas (e.g., cortex and substantia nigra) [4,5] and causes dyskinesias, dementia and eventual death [1,6 ]. In addition to neuronal disorders, metabolic abnormalities are another important marker of HD [7 ]. Hyperglycemia and abnormal glucose metabolism were observed in several mouse models of HD and in HD patients [8 ]. Deficiencies in several other metabolic pathways, such as cholesterol biosynthesis and urea cycle metabolism, are well documented [9,10 ]. Insufficient energy metabolism has been suggested to be an important causative factor in many neurological disorders. Recently, energy deficiency has become an important causative factor of HD [7 ]. Hyperglycemia and reduced insulin have been reported in several transgenic mouse models [8 ]. Abnormal expression of proteins associated with glucose metabolism has also been observed in several HD mouse models as well as in HD patients [8 ].

AMP-activated protease (AMPK) is the major energy sensor that regulates the array of downstream target genes and maintains cellular energy homeostasis by activating energy production and suppressing energy expenditure in many different tissues [11]AMPK is a heterotrimeric complex consisting of α, β and gamma subunits α and β subunits are each encoded by two different genes (α 1 and α 2 or β 1 and β 2) while gamma subunits are encoded by 3 genes (gamma 1, gamma 2 and gamma 3) [12 ]]. And AMPK can be expressed by several upstream enzymes [ calmodulin-dependent protease (CaMKK) and LKB1]Activation, via phosphorylation of threonine residue 172 within the catalytic domain of α subunits [13]. Other enzymes [ including cAMP dependent enzyme (PKA) and Ca²⁺Calponin-dependent protease II (CaMKII)]Also shown to modulate AMPK activity [14,15 ]]. Activation of AMPK by LKB1 is primarily triggered by an increase in AMP/ATP cell ratio [16]. In contrast, CaMKK and CaMK II activate AMPK during stimulation, thereby increasing intracellular calcium levels [17]The α subunits of AMPK are catalytic subunits and have at least two different isoforms (isoforms) (α 1 and α 2). AMPK- α 1 is widely expressed throughout the body, with α 2 subunits being predominantly expressed in the liver, heart and skeletal muscle [18 [ ]]. Of AMPKThe matrix includes many proteins in energy metabolism and proteins involved in many different machines [19]. For example, AMPK activation was found to increase ROS formation and subsequently cause mitochondrial damage and apoptosis [20,21]. AMPK also phosphorylates a number of proteins involved in other cellular functions, such as transcription and secretion [19,22 ]]. AMPK activation has a pro-apoptotic effect in a variety of cells including induction of stress signalling (stress signalling) (including p53, JNK, apoptotic protease-3, p38 and mTOR) and inhibition of fatty acid synthase and protein synthesis [23-26 ]]. In addition, AMPK has been found to inhibit axonal initiation and neuronal polarization via the PI3K (phosphatidic acid inositol 3-enzyme) pathway. Phosphorylation of motor protein (Kif5) by AMPK disrupts binding of Kif5 to PI3K, preventing PI3 from targeting to axons, and thereby inhibiting axon growth and neuronal polarization [27 ]]。

In the brain, AMPK is present in the hypothalamic neurons and plays a key role in the regulation of food intake [28]. Interestingly, AMPK function and regulation and its role in neurodegenerative diseases have attracted much attention. For example, higher AMPK activity is found in neurons with ischemia, HD and Alzheimer's Disease (AD). In the brain of stroke patients, AMPK is activated in the cortex and hippocampal neurons. Inhibition of AMPK reduces existing damage [29-31 ]]Lack of AMPK- α 2 has neuroprotective effects in the brain during ischemia [32]A recent study report by chen et al demonstrates that metformin (metformin), an activator of AMPK, enhances the biosynthesis of amyloidogenic peptides via upregulation of β -secretase (BACE1) in the AMPK-dependent pathway, which potentially may exacerbate the progression of AD [33]Inhibition of AMPK significantly suppresses the effect of metformin on a β production and BACE1 transcription santon et al have demonstrated that AMPK is a tau kinase, which induces tau phosphorylation in microtubule binding domains, furthermore, AMPK-induced tau phosphorylation inhibits tau binding to microtubules [34]These authors also found that AMPK- α 1, but not AMPK- α 2, was significantly activated corresponding to a β 1-42 [34]. Vingtteux et al demonstrated co-localization of phosphorylated AMPK with tau, which is Ser in AD brain²⁰²Or Ser³⁹⁶Phosphorylation [35 ]]In addition, exposure to amyloidogenic β peptide (A β s, of senile plaques in ADKey ingredient) leads to activation of AMPK, which is at Thr²³¹And Ser^396/404Phosphorylated tau and possibly contribute to AD tauopathy [34,35]These observations suggest a pathological role for AMPK activation in AD, since hyperphosphorylation of tau is a hallmark of AD, consistently, inhibition of AMPK suppresses the production of a β and tau phosphorylation [33,36]. These studies suggest that activation of AMPK in AD may contribute to neurodegeneration in AD.

We have previously reported that activation of the α 1 isoform of AMPK (AMPK- α 1) occurs in striatal neurons in humans and mice with HD [31,37 ]]. Overactivation of AMPK in the striatum leads to brain atrophy, promotes neuronal loss, and increases Htt aggregate formation in a transgenic mouse model of HD (R6/2) [37 ]]The prevention of nuclear translocation or inactivation of AMPK- α 1 ameliorates cell death caused by mutant Htt, aberrant activation of AMPK- α 1 in the striatal cell nucleus represents a novel toxic pathway induced by mutant Htt, use of the adenosine 2A receptor (A. sup. T. A. sup. 2A. sup. beta_2AR) blocking of AMPK- α 1 activation and nuclear enrichment by Selective agonists (CGS21680) via the cAMP/PKA-dependent pathway is associated with the rescue of brain atrophy [31,37]Further strengthen the participation of AMPK- α 1 in the pathogenesis of striatal HD.

ATM is a large (. about.370-kDa) serine/threonine protease. ATM is activated by DNA damage in an MRN (Mre11-Rad50-Nbs1) dependent manner. Although the function of these proteins has been well documented, the function of controlling cellular energy homeostasis and detailed molecular mechanisms is largely undescribed, which greatly hinders the development of therapies directed to brain energy deficiency. In the past years, the correlation of oxidative stress and DNA damage has been demonstrated. ATM is induced by oxidative stress via oxidation of cysteine residues [38 ]. Furthermore, oxidative stress induces DNA repair dysfunction through damage of DNA-PK complexes in HD. Over-expression of the 43Q-GFP fusion protein was found to increase ROS production and ATM activity and subsequently cause ATM-dependent DNA damage in PC12 cells [39 ]. ATM has been found to be involved in phosphorylation of AMPK, suggesting that AMPK may play a key role in DNA damage or DNA repair. IGF-1 induces AMPK phosphorylation in human and mouse embryonic fibroblasts via ATM-dependent and LKB 1-independent means [40 ]. AICAR or IR induces activation of AMPK via ATM-dependent pathways in HeLa and cancer cells [41,42 ]. Fouet al further reported that activation of ATM by etoposide induces ROS production and mitochondrial biosynthesis via phosphorylation/activation of AMPK. ROS may promote mitochondrial biosynthesis via the DNA damage/ATM/AMPK pathway [43 ].

In the present invention, ginsenoside M1 was unexpectedly found to be effective in alleviating one or more symptoms of HD. In particular, ginsenoside M1 was shown to reduce cytotoxicity, STHdh, in mHtt expressing cells^Q109Formation of Reactive Oxygen Species (ROS), STHdh in cells^Q109Extent of phosphorylation of AMPK, STHdh, in cells^Q109Degree of phosphorylation of ATM in cells, STHdh^Q109Expression amount of gamma H2AX in cells, and STHdh^Q109Degree of phosphorylation of p53 in cells. It was also demonstrated that oral administration of ginsenoside M1 reduced disease progression, improved motor coordination, increased longevity and reduced mHtt aggregate formation in the striatum of affected animals in a transgenic mouse model of HD (R6/2 mice).

Accordingly, the present invention provides a method of treating or preventing Huntington's Disease (HD) in a subject in need thereof, comprising administering to the subject an effective amount of ginsenoside M1.

Ginsenoside M1, also known as compound k (ck), 20-O- β -D-glucopyranosyl-20 (S) -protopanaxadiol, is one of the saponin metabolites known in the art. The chemical structure of ginsenoside M1 is as follows:

ginsenoside M1 is known as a metabolite of protopanaxadiol-type ginsenoside through the gypenoside pathway of human intestinal bacteria. Ginsenoside M1 can be found in blood or urine after ingestion. Ginsenoside M1 can be prepared from ginseng plants by fungal fermentation by methods known in the art, such as taiwan patent application No. 094116005(I280982) and U.S. patent No. 7,932,057, which are incorporated herein by reference in their entirety. In certain embodiments, the ginseng plant used to prepare ginsenoside M1 includes Araliaceae (Araliaceae), ginseng (Panax) genus, e.g., ginseng genus (p.ginseng) and pseudoginseng genus (p.pseudo-ginseng) (also known as Panax notoginseng). Generally, the method for preparing ginsenoside M1 comprises the following steps: (a) providing a powder of ginseng plant material (e.g., leaves or stems); (b) providing fungi for fermenting ginseng plant material, wherein the fermentation temperature range is 20-50 ℃, the fermentation humidity range is 70-100%, the pH value range is 4.0-6.0, and the fermentation period range is 5-15 days; (c) extracting and collecting fermentation products; and (D) isolating 20-O-beta-D-glucopyranosyl-20 (S) -protopanoxadiol from the fermentation product.

When the ginsenoside M1 is described as "isolated" or "purified" in the present invention, it is understood that it is not absolutely isolated or purified, but relatively isolated or purified. For example, purified ginsenoside M1 refers to a more purified ginsenoside than its naturally occurring form. In a particular embodiment, a formulation comprising purified ginsenoside M1 may comprise ginsenoside M1 in an amount greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, or 100% (w/w) of the total formulation. It is understood that when an amount is used herein to indicate a ratio or dose, the amount generally includes a range of plus or minus 10%, or more specifically, a range of plus or minus 5% of the amount.

As used herein, the terms "huntingtin protein", "huntingtin protein" or "HTT" refer to a huntingtin protein encoded by a huntingtin gene, also referred to as the HTT gene or HD gene. This gene is polymorphic due to the variable amount of CAG codon repeats in the first exon encoding glutaminic acid. In its wild type, this protein contains 6 to 35 glutaminic acid residues and does not cause huntington's disease. In individuals affected by HD, this protein contains more than 35 glutamic acid residues and is named polyQ-htt, a mutated form that causes Huntington's disease. The wild type htt has a mass of about 350kD and a size of about 3144 amino acids. As used herein, unless otherwise indicated, the term "htt" refers to the wild-type form of htt protein, i.e., htt which is a polyglutamic acid bundle containing less than 36 glutaminic acid residues. Mutant HTT proteins have aberrant function and/or activity or additional activity or function (e.g., aggregation with transcription factors, etc.) as compared to non-mutant wild-type HTT proteins.

As used herein, the terms "individual" or "subject" and the like include humans and non-human animals, such as pets (e.g., dogs, cats, and the like), farm animals (e.g., cattle, sheep, pigs, horses, and the like), or experimental animals (e.g., rats, mice, guinea pigs, and the like).

The term "treating" as used herein refers to administering or administering a composition comprising one or more active agents to an individual having a disorder, a symptom or condition of a disorder, or a progression of a disorder, with the purpose of treating, curing, alleviating, altering, remediating, ameliorating, augmenting, or affecting the disorder, a symptom or condition of the disorder, a disability resulting from the disorder, or a progression of the disorder or a symptom or condition thereof. As used herein, the terms "prevent" or "preventing" and the like refer to the administration or administration of a composition comprising one or more active agents to an individual susceptible to or susceptible to a disorder or a symptom or condition thereof, and thus relates to the prevention of the occurrence of the disorder or symptom or condition thereof or the underlying cause thereof.

The term "effective amount" as used herein refers to an amount of active ingredient that imparts a desired therapeutic effect to the subject being treated. For example, an effective amount for treating or preventing HD can be an amount that is capable of prohibiting, ameliorating, alleviating, or preventing one or more symptoms or disorders or the progression thereof. In some embodiments, an effective amount, as used herein, can be an amount effective to reduce Reactive Oxygen Species (ROS) formation and cytotoxicity in neuronal cells, particularly mutated neurons, of an HD individual. In some embodiments, an effective amount as used herein may be an amount effective to improve motor coordination, prolong lifespan, and reduce mHtt aggregate formation in the striatum of an HD individual.

The therapeutically effective amount may vary depending on various reasons, such as route and frequency of administration, weight and kind of the individual receiving the drug, and purpose of administration. The person skilled in the art can determine the dosage in each case on the basis of the disclosure herein, established methods, and his own experience. For example, in certain embodiments, the oral dosage of ginsenoside M1 used in the present invention is 10 to 1000mg/kg per day. In some examples, the oral dosage of ginsenoside M1 used in the present invention is 100 to 300mg/kg daily, 50 to 150mg/kg daily, 25 to 100mg/kg daily, 10 to 50mg/kg daily, or 5 to 30mg/kg daily. Further, in some embodiments of the invention, ginsenoside M1 is administered periodically for a period of time, for example, daily for at least 15 days, one month, or two months or more.

According to the present invention, ginsenoside M1 can be used as an active ingredient for treating or preventing Huntington's Disease (HD). In one embodiment, a therapeutically effective amount of the active ingredient may be formulated with a pharmaceutically acceptable carrier into a pharmaceutical composition in a suitable form for delivery and absorption. Depending on the mode of administration, the pharmaceutical compositions of the invention preferably comprise from about 0.1% to about 100% by weight of active ingredient, wherein the weight percentages are calculated on the basis of the weight of the entire composition.

As used herein, "pharmaceutically acceptable" means that the carrier is compatible with the active ingredient in the composition, and preferably stabilizes the active ingredient and is safe for the subject to be treated. The carrier may be a diluent, carrier, excipient or matrix for the active ingredient. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbose, mannose, starch, acacia, calcium phosphate, alginate, tragacanth (tragacanth gum), gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The composition may additionally comprise lubricants, such as talc, magnesium stearate and mineral oil; a wetting agent; emulsifying and suspending agents; preservatives, such as methyl and propylhydroxybenzoates; a sweetener; and a flavoring agent. The compositions of the present invention may provide rapid, sustained or delayed release of the active ingredient upon administration to a patient.

According to the present invention, the composition may be in the form of tablets, pills, powders, lozenges, packets, troches, elixirs, suspensions, lotions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injectable solutions and packaged powders.

The compositions of the invention may be delivered via any physiologically acceptable route, such as oral, parenteral (e.g., intramuscular, intravenous, subcutaneous, and intraperitoneal), transdermal, suppository, and intranasal methods. For parenteral administration, it is preferably used in the form of a sterile aqueous solution, which may contain other substances sufficient to render the solution isotonic with blood, for example, salts or glucose. The aqueous solution may be suitably buffered (preferably at a pH of 3 to 9) as required. The preparation of suitable parenteral compositions under sterile conditions can be accomplished using standard pharmacological techniques well known to those skilled in the art and without the need for additional creative work.

According to the present invention, ginsenoside M1 or a composition comprising ginsenoside M1 as an active ingredient can be used to treat individuals suffering from, or at risk of, Huntington's Disease (HD). In particular, ginsenoside M1 or a composition comprising ginsenoside M1 as an active ingredient can be administered to a subject with or at risk of acquiring HD to prevent the occurrence of a disease or to ameliorate symptoms or delay the worsening of symptoms.

The invention is further illustrated by the following examples, which are provided for purposes of illustration and not limitation. Those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.