WO2011157059A1 - 异类叶升麻苷或其药学上可接受的盐的用途 - Google Patents

异类叶升麻苷或其药学上可接受的盐的用途 Download PDF

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WO2011157059A1
WO2011157059A1 PCT/CN2011/000998 CN2011000998W WO2011157059A1 WO 2011157059 A1 WO2011157059 A1 WO 2011157059A1 CN 2011000998 W CN2011000998 W CN 2011000998W WO 2011157059 A1 WO2011157059 A1 WO 2011157059A1
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disease
use according
amyloid
pharmaceutically acceptable
peptide
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PCT/CN2011/000998
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English (en)
French (fr)
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林汉钦
苏慕寰
黄永名
唐静静
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杏辉天力（杭州）药业有限公司
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Priority to AU2011267724A priority Critical patent/AU2011267724B2/en
Priority to CN2011800298829A priority patent/CN103037868A/zh
Priority to KR1020137000895A priority patent/KR101847501B1/ko
Priority to CA2802441A priority patent/CA2802441C/en
Priority to JP2013514533A priority patent/JP5968878B2/ja
Priority to SG2012091914A priority patent/SG186717A1/en
Publication of WO2011157059A1 publication Critical patent/WO2011157059A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/64—Orobanchaceae (Broom-rape family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/602—Glycosides, e.g. rutin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the present invention relates to a novel use of an isoform of flavonoids for inhibiting the production, accumulation or aggregation of amyloid beta peptides, and more particularly to the novel use of isoforms for the prevention or treatment of diseases or conditions associated with amyloid beta peptides. . Background technique
  • Alzheimer's disease is thought to be associated with the accumulation of a peptide with 39-43 amino acids called amyloid ⁇ peptides (tube ⁇ ) It is a hydrolysate of the amyloid precursor protein.
  • ⁇ 1-40 is the most abundant and low in toxicity, while ⁇ 1-42 is highly toxic to neurons and highly fibrillogenic, and is considered to be the most relevant ⁇ in the pathogenesis of Alzheimer's disease. form.
  • the ⁇ monomer can be oligomerized to form a soluble ⁇ oligomer (oligomer), which is further aggregated outside the cell to form insoluble fibrils or senile plaques.
  • the disease or condition associated with A ⁇ includes Down syndrome, Dutch-type Hereditary cerebral hemorrhage with amyl oid (HCHWA) Dutch, and Guam Parkinson's disease-missing Parkinsonism-deme ntia complex on Guam (Clinical Neurology and Neurosurgery (1990) 92:
  • cerebral amyloid angiopathy J. Neuropath. Exp. Neuro. (2002) 61: 282-293
  • inclusion body myositis Neurology (2006) 66: 65-68
  • frontotemporal loss Neurology (2002) 13-5: 719-723
  • Age-related macular degeneration Experimental Eye Rese arch (2004) 78: 243-256
  • Pick's disease Neuroscience Letters (1 994) 171: 63-66) and others.
  • the A ⁇ -related disease or condition is generally associated with the production, accumulation or accumulation of A ⁇ , including the presence of abnormal A ⁇ or ⁇ aggregates in the organism due to factors such as congenital such as heredity, or acquired factors such as aging or the environment. .
  • amyloid beta peptide and aggregates thereof it is easy to elicit various diseases or conditions in an organism, and therefore one of the objects of the present invention is to provide an active ingredient which inhibits the production, accumulation or aggregation of amyloid beta peptide, which can be used as a food. , drinks, chews, patches, skin care products or other additives.
  • Another object of the present invention is to provide a medicament and method for preventing or treating an amyloid beta peptide-related disease or condition.
  • the present invention discloses a use of inhibiting the production, accumulation or aggregation of amyloid beta peptide by a heterologous flavonoid or a pharmaceutically acceptable salt thereof, and preparing a disease preventing or treating amyloid beta peptide or The use of the condition of the drug.
  • the above-mentioned heterophylloside or a pharmaceutically acceptable salt thereof is used for inhibiting the damage or apoptosis of the neuron by the amyloid ⁇ -peptide, thereby retaining, improving or restoring learning and memory.
  • the effective dose of the above-mentioned drug to humans is equivalent to 0.2 mg to 4.0 mg of isoforms of ricin or a pharmaceutically acceptable salt per kilogram of body weight per day.
  • Fig. 1 shows the percentage of extracellular ⁇ 1-40 content of each well, and the results show that the heterophylloside (D) of the present invention has an excellent activity for significantly reducing the extracellular accumulation of ⁇ 1 -40;
  • Figure 2 shows the percentage of ⁇ 1-40 content in the cells of each well
  • Figure 3 shows the effect of each test sample on the amount of enthalpy exhibited
  • Figure 4 shows the effect of each test sample on the degradation of ⁇ 1-40
  • Figure 5 shows the effect of each test sample on the oligomerization of A ⁇ 1-42
  • Figure 6 shows schematically the generation, removal and aggregation of ⁇
  • Figure 7 shows a schedule of animal tests
  • Figure 8 shows the effect of each test sample on the exploratory ability of experimental rats
  • Figure 9 shows the effect of each test sample on the passive avoidance response of experimental rats
  • Figure 10 shows the effect of each test sample on the spatial representation of water maze in experimental rats
  • Figure 11 shows the effect of each test sample on the water maze reference memory test of experimental rats
  • Figures 12A-12E show the large experimental Brain tissue staining results of rats
  • Figure 13A shows the detection of acetylcholine content in the cortex and hippocampus of experimental rats. fruit
  • Fig. 13B shows the results of detection of choline content in the cortex and hippocampus regions of experimental rats;
  • Fig. 14A shows the results of acetylcholinesterase activity measured in the cortex of experimental rat brain;
  • Fig. 14B shows the experiment Results of acetylcholinesterase activity measured in the hippocampus of rat brain.
  • amyloid beta peptides have a common feature, namely the formation of amyloid beta peptide aggregates. These amyloid beta peptide aggregates may appear in the form of fibers or plaques and precipitate in the system, organ, tissue or body fluid of the organism, thereby causing various diseases or conditions. If it can effectively inhibit the production, accumulation or aggregation of amyloid ⁇ -peptide, it should avoid various diseases or conditions caused by the formation of aggregates of amyloid ⁇ -peptide, which should be used as an effective prevention or treatment of amyloid ⁇ -peptide related diseases or conditions. One of the ways.
  • the present invention uses an isoform of the following formula, or a pharmaceutically acceptable salt thereof, as an active ingredient for inhibiting (for example, reducing or avoiding) the production, accumulation or aggregation of amyloid ⁇ -peptide, particularly starch inhibition.
  • Sample ⁇ isoform of the following formula, or a pharmaceutically acceptable salt thereof, as an active ingredient for inhibiting (for example, reducing or avoiding) the production, accumulation or aggregation of amyloid ⁇ -peptide, particularly starch inhibition.
  • U.S. Patent No. 7,087,252, ⁇ 2 discloses a 25-50 wt% echinacoside and 5-15 wt% leaf amygdalin prepared from the fleshy stem of Cistanche tubulosa (Schenk Wight). (acteoside) preparations which are useful for anti-senile dementia heterophylloside and various other phenylethanoid glycosides are known to be included in the preparation.
  • hydrates or other solvent solvates, prodrugs and metabolites of the isoforms are considered to be functional equivalents of the isoforms.
  • the "prodrug” means that a precursor compound can be hydrolyzed, oxidized or otherwise reacted under biological conditions (in vivo or in vitro) to produce a heterophylloside.
  • the "metabolite” refers to a compound formed by metabolism of a heterologous leaf asparagine in a cell or organism.
  • a “pharmaceutically acceptable salt” of a heterologous leaf gonadoside When a “pharmaceutically acceptable salt" of a heterologous leaf gonadoside is administered to an organism, it usually has the same or similar medical effect as the isoform of the genus sylvestre, which is physiologically tolerable and does not occur. Sensitive or similar reaction.
  • the pharmaceutically acceptable salt of the heterophylloside can include, but is not limited to, an iron salt, a calcium salt or a magnesium salt, and the like.
  • preventing is meant avoiding or delaying the appearance of a disease or condition in an organism, and said “treating” means slowing or preventing the progression of the disease or condition, or returning the condition of the organism to a better or normal state. .
  • amyloid beta peptide-associated disease or condition means that the occurrence of the disease or condition is usually associated with the formation, accumulation or aggregation of amyloid-like ⁇ -peptide, and in particular, the occurrence of the disease or condition is caused by amyloid ⁇ -peptide.
  • amyloid ⁇ -peptide When an abnormal production, accumulation or aggregation of amyloid ⁇ -peptide is found in a certain proportion of organisms having a certain disease or condition, the disease or condition is also considered to be related to the amyloid ⁇ -peptide.
  • the aggregation of the amyloid ⁇ peptide is similar to the pathological characteristic of the disease or condition, the disease or condition may be considered to be amyloid ⁇ -peptide.
  • the active ingredient for inhibiting amyloid ⁇ -peptide provided by the present invention can also be used as an additive for foods, drinks and the like to achieve convenient use for inhibiting the formation, accumulation or aggregation of amyloid ⁇ -peptide.
  • a medical composition comprising aspartic acid, or a pharmaceutically acceptable salt thereof, as an active ingredient, and may comprise a suitable carrier, diluent or excipient, etc., to present, for example, a powder, a granule Agent
  • drugs or pharmaceutical compositions can be administered orally, topically, parenterally, dermally, nasally, ocularly, intraocularly or by other routes.
  • Alzheimer's disease is a chronic neurodegenerative disorder characterized by a gradual loss of cognitive ability and severe behavioral abnormalities, followed by loss of language and motor skills, and to the patient and his family. The quality of life is easily affected.
  • the present invention specifically selects ⁇ which is more related to Alzheimer's disease.
  • Echinacoside, Acteoside and Isoacteoside have the following structural formulas:
  • Cinoptera
  • the medium of the native human neuroblastoma SH-SY5Y in Example 1 was replaced with a chemical medium (EMEM/F12 medium (Cat. No. 12500-062), Hepes 5 mM, glucose 0.6%, NaHC03 3 mM, glutamine 2.5 mM, insulin 25 g/ml, Transferin 100 g/ml, Progestrone 20 nM, Putrescine 60 ⁇ , sartite (Sodium selenite) 30 nM, Heparin 2 g/ml). Each well has 1 x 105 SH-SY5Y cells and a medium volume of 300 ⁇ l. After 30 minutes, the test samples A-D shown in Table 1 were added to different wells at a concentration of 50 g/ml for 24 hours, followed by Human ⁇ 1-40.
  • EMEM/F12 medium Cat. No. 12500-062
  • Hepes 5 mM glucose 0.6%
  • NaHC03 3 mM glutamine 2.5 mM
  • insulin 25 g/ml
  • Immunoassay kits (Catalog # KHB3482 Invitrogen) were used to analyze the ⁇ 1-40 content in the culture medium of each well.
  • the human neuroblastoma SH-SY5Y accumulates ⁇ in the extracellular medium, and Figure 1 shows the percentage of ⁇ 1-40 in the medium after the SH-SY5Y well was treated with each test sample AD.
  • the control group that was not treated with any test sample was used as a baseline. The results are shown as the mean standard error, while the statistical difference between the control and test sample groups indicates * indicates ⁇ ⁇ 0.05, ** indicates ⁇ ⁇ 0 ⁇ 01, and *** indicates ⁇ ⁇ 0 ⁇ 001.
  • test sample ⁇ (the phenylethanoid-containing preparation) and the test sample C (the phylloside) reduced the ⁇ 1-40 content in the medium by about 20%
  • test sample D heterologous leaf sesame Glycoside
  • the results in Figure 1 show that isoforms (D) have an excellent activity for significantly reducing the extracellular accumulation of A ⁇ 1-40.
  • Example 3 Accumulation of ⁇ -40 in cells in each test sample
  • Each well has 1 x 105 SH-SY5Y cells and a medium volume of 300 ⁇ l.
  • the SH-SY5Y cells in each well were treated with the test sample A-D at a concentration of 50 g/ml for 24 hours, and then the cells in each well were made into cell homogenization solution, and human ⁇ 1-40 was utilized.
  • Immunoassay kits (Catalog # KHB3482 Invitrogen) analyzed their ⁇ 1-40 content.
  • Figure 2 shows the percentage of ⁇ 1-40 content in the cells of the SH-SY5Y well, based on the control group not treated with any test sample. As shown in Fig. 2, none of the test samples AD caused significant accumulation of A ⁇ in the cells.
  • Example 4 Effect of each test sample on the performance of APP in cells
  • Each well had 1 x 105 SH-SY5Y cells and the medium volume was 300 ⁇ l.
  • the SH-SY5Y cells in each well were treated with the test sample AD at a concentration of 50 g/ml for 24 hours, and then the cells were partially homogenized (50 mM Hepes pH 7.5, 1 mM EDTA, 150 mM NaCl, 1% NP- 40, 1 mM PMSF, 5 g/ml aprotinin, lO g/ml leupeptin) was homogenized, and insoluble matter was removed by ultracentrifugation.
  • the protein was separated by SDS-polyacrylamide gel electrophoresis and transferred to PVDF, and then detected by immunoblot (antiA i-17, 6E10 or antiAPP-c antibody). holoAPP content.
  • Figure 3 shows the effect of test samples A-D on the performance of APP in cells, expressed as a percentage, and based on a control group (Vehicle) not treated with any test sample. As shown in Figure 3, test samples A-D did not reduce the activity of APP performance.
  • Example 5 Degradation experiment of ⁇ -40 on extracellular samples of each test sample
  • the mouse neuroblastoma neuro-2a releases an enzyme that decomposes ⁇ in the chemical medium, but does not accumulate enough ⁇ in the medium.
  • the neuro-2a was cultured in the medium for 24 hours, after which the cell-free medium was taken out and treated with the test sample AD at a concentration of 50 g/ml and 10 ng of the synthetic ⁇ 1-40 for 24 hours, respectively, after which the tests were examined. Whether the sample has an activity that promotes degradation of ⁇ by an enzyme in the medium.
  • test sample D did not promote extracellular degradation of ⁇ .
  • Example 6 Experiment of ⁇ -42 oligomerization of each test sample
  • HFIP l,l,l,3,3,3-Hexa-fluro-2-propanol
  • FIG. 5 shows the effect of test sample AD on ⁇ 1-42 oligomerization, respectively, and the results are shown as a percentage and based on a control group not treated with any test sample.
  • test sample A forms containing phenylethanoid
  • B echinacoside
  • C asparagine
  • D heterophyllin
  • heterologous leaf aspirin (D) can inhibit the degree of oligomerization of A ⁇ 1-42 to 98.93 ⁇ 1.70, which means that the heterophylloside (D) can effectively reduce the oligomerization of A ⁇ 1-42, and then Inhibition of ⁇ formation of filaments or senile plaques.
  • Figure 6 shows schematically the generation, removal and aggregation of ⁇ (reference source:
  • Figure 6 shows that extracellular ⁇ accumulation in the medium (1) is affected by ⁇ intracellular accumulation (2), ⁇ expression (3), ⁇ degradation (4), ⁇ oligomerization (5), and ⁇ production (6) And so on.
  • the heterologous leaf cohoposide (D) has the effect of lowering the extracellular ⁇ accumulation (1) and reducing the oligomerization of ⁇ compared to the other test samples AC.
  • Degree (5) has excellent utility and should be further used to inhibit the aggregation of ⁇ .
  • heterologous leaf asparagine (D) on the extracellular accumulation of ⁇ (1) is not due to the increase in the accumulation of ⁇ in cells (2) and the decrease in sputum expression in cells (3) Or, it promotes the degradation of ⁇ extracellularly (4), so it is speculated that heterophylloside (D) can directly reduce the production of ⁇ (6).
  • isoforms (D) or a pharmaceutically acceptable salt thereof can be used as an active ingredient for inhibiting the production, accumulation or aggregation of ⁇ , and it is expected that the isoflavone (D) can effectively inhibit ⁇ -induced neurons. Injury or apoptosis to further preserve, improve or restore learning and memory. Further, based on the above results, the isophylloside (D) or a pharmaceutically acceptable salt thereof should be used for the prevention or treatment of A ⁇ -related diseases or conditions, and for inhibiting the production, accumulation or aggregation of A ⁇ .
  • the ⁇ -related disease or condition may include, but is not limited to, Alzheimer's disease, mild cognitive impairment, Louis's dementia, Down's syndrome, Dutch-type amyloidosis, Guam Parkinson's disease - loss Syndrome complex, cerebral amyloid angiopathy, inclusion body myositis, frontotemporal dementia, age-related macular degeneration, Pico disease, and others.
  • the ⁇ is exemplified by the largest amount of ⁇ 1-40 in ⁇ or ⁇ 1-42 having high fiber formation, other amino acid fragments may be contained.
  • the isoform of the flavonoid (D) has the best effect of reducing the production, accumulation and aggregation of ⁇ .
  • the sputum ⁇ 1-42 was first infused into the lateral ventricle of 250-300 g male SD rats (purchased from Lesco Co., Ltd.) to cause nerve damage in rats, affecting The memory and learning ability of the rats can induce the formation of plaque-like deposits in the rat brain as an animal model resembling Alzheimer's disease.
  • the animal model of Alzheimer's disease induced by ⁇ can be found in the literature data of Nabeshima et al.
  • FIG. 7 shows the experimental schedule of the animal test, evaluation of the exploration behavior on the 7th day after the start of infusion of ⁇ 1-42, and passive avoidance learning evaluation on the 8th to 9th day, A water maze was evaluated 10 to 13 days, and a probe test was performed on the 14th day.
  • the experimental group design is shown in Table 2.
  • the sham operation group (Sham) was treated with TFA solution (64.9% sterile ddH20, 35% acetonitrile, 0.1% trifluoroacetic acid), while the other experimental groups were dissolved at 0.5 ⁇ l per hour.
  • the ⁇ 1-42 treatment of the TFA solution is equivalent to the administration of 300 ⁇ 1/12 ⁇ l of ⁇ 1-42 (Tocris 1428; MW: 4514.08) per day.
  • test samples were orally administered to experimental rats prior to training in tests such as exploration ability, passive avoidance response, and water maze.
  • Table 2 shows the conditions of each experimental group, wherein test sample D is the heterophylloside in Table 1, and Aricept is a commercially available drug for treating dementia such as Alzheimer's disease. All test samples were prepared daily in double distilled water and administered by gastric tube orally.
  • Example 7 Equipment and measurement of exploration capabilities
  • the exploration capability measuring device consists of a length, width, height of 40 cm and a stainless steel floor. There are 16 holes of 3 cm in diameter on the bottom plate, 7 cm from both sides, and the spacing between the holes is 4 cm.
  • the measurement time of each rat was 10 minutes, and the number of times the rat was pierced was tested.
  • Figure 8 shows the experimental results of the animal exploration behavior according to Table 2. As shown in Figure 8, ⁇ 1-42 was infused into the experimental rats via the ventricle, which caused the exploration ability of the experimental rats to be low, while the test samples D (heterologin) and Aricept could effectively enhance the experimental rats. Exploring ability, and test sample D (heterophyllin) was superior to Aricept 0.75 mg/kg at a dose of 5 mg/kg.
  • the passive avoidance device consists of a bright room, a dark room and a gate between the two rooms. The rats were placed in the bright room while the gate was opened, and the rats were allowed to enter the dark room within 90 seconds for the experiment.
  • Training period The screened rats were placed in the bright room, and the gate was opened. After the rats entered the dark room, the gate was closed, and the bottom plate was stimulated with current for 5 seconds. Then, the rats were taken out from the dark room and returned to the cage.
  • the rats were placed in the bright room, and the gate was opened, and the step-through latency (STL) of the rats in the bright room was recorded.
  • STL step-through latency
  • Figure 9 shows the results of an experiment in which the passive avoidance reaction was carried out according to the animals shown in Table 2.
  • the experimental rats were given ⁇ 1-42 by intraventricular infusion, which significantly caused the obstacles of passive avoidance learning reaction in experimental rats, and the treatment of test sample D (heterologous aspirin) and Aricept could be improved.
  • Experimental rats were induced to passive avoidance of learning rats due to infusion of ⁇ 1-42 into the ventricles.
  • test sample D heterophyllin
  • test sample D heterologin
  • the dose is superior to Aricept 0.75 mg/kg.
  • Example 9 Water maze experiment
  • the swimming pool was divided into four quadrants, and the hidden platform was fixed in the fourth quadrant and placed 1 cm below the water surface.
  • Each rat was given two trainings per day, with two training sessions of 4 hours and 2 minutes of each training to find a hidden platform.
  • the first training was a spatial performance test.
  • Each rat was given a maximum of 120 seconds to swim to find a hidden platform. If the rat successfully found a hidden platform within 120 seconds, let the rat rest on the platform for 30 seconds. Clock; if the rat has not found a hidden platform before the end of time, the score of the rat is counted as 120 Seconds, and grab it to the hidden platform for 30 seconds.
  • This spatial performance test was conducted for a total of 4 days.
  • the hidden platform was taken from the water labyrinth pool, the rats were placed in the first quadrant, and 60 seconds of swimming was given. The time taken by the rats in the quadrant of the original hidden platform in the pool was recorded. Reference memory test (probe test).
  • Figure 10 shows the results of the spatial performance test performed on the animals shown in Table 2
  • Figure 11 shows the results of the experimental memory test according to the animals shown in Table 2, and the sham operation group.
  • FIG. 12A to 12E show brain tissue staining results.
  • Fig. 12B a large number of plaques were found in the rat brain in which ⁇ 1-42 was continuously infused
  • Fig. 12C and Fig. 12D the test sample D (heterologin) was treated at 2.5 mg/kg. Only a very small amount of plaque was found in the rat brain, and almost no plaque was produced in the rat brain after the test sample D (heterologin) 5 mg/kg. Comparing Fig. 12C to Fig.
  • Example 11 Neurotransmitter content in the cerebral cortex and hippocampus of rats
  • the rats after the water maze test were sacrificed, and the brain was quickly removed from the skull.
  • the cerebral cortex and hippocampus were removed by Glowinski & Iversen, weighed separately, and 50 mM Na-phosphate was added.
  • Buffer pH 7.8 is homogenized for determination of neurotransmitter concentration and enzyme content.
  • Tables 3 and 4 show the results of the determination of the neurotransmitter dopamine (DA) and its metabolites DOPAC and HVA in the cortex and hippocampus of the experimental rats according to Table 2.
  • DA neurotransmitter dopamine
  • Table 2 The neurotransmitter dopamine in the cortex of the brain of the experimental rats according to Table 2
  • Figure 13A shows the results of the detection of the content of the neurotransmitter acetylcholine (Acetylcholine) in the cortex and hippocampus of the experimental rats according to Table 2, and Figure 13B shows the experimental rats in the brain according to Table 2.
  • Choline content in the cortical and hippocampus Referring to the results shown in Fig. 13A and Fig. 13B, ⁇ 1-42 caused a decrease in acetylcholine content in the cortex and hippocampus of experimental rats, while test samples D and Aricept improved the cortical and hippocampus of experimental rats caused by ⁇ 1-42.
  • the region has a reduced acetylcholine content, and among them, the test sample D (heterophyllin) 5 mg/kg is the best.
  • Fig. 14A and Fig. 14B show the results of acetylcholinesterase activity measured by the experimental rats in the cortex and hippocampus regions of the brain, respectively, according to Table 2.
  • ⁇ 1-42 caused an increase in acetylcholinesterase activity in the cortex and hippocampus of the experimental rats
  • test samples D and Aricept improved the experimental rats caused by ⁇ 1-42.
  • the heterophylloin can effectively inhibit the formation, accumulation or aggregation of A ⁇ , thereby avoiding the formation of aggregates of A ⁇ , which can be used for preventing or treating Alzheimer's disease and other A ⁇ correlation. Disease or condition.
  • the heterologous leaf asparagine has an effect of significantly improving the memory or learning ability deterioration caused by ⁇ .
  • the isoforms can effectively inhibit the formation of plaque by aggregation of ⁇ or eliminate plaque.
  • the isoflavone can effectively improve the phenomenon that the neurotransmitter is reduced by ⁇ , so that it can have an effect of improving memory or learning ability decline.
  • the isoforms of scutellarin or a pharmaceutically acceptable salt thereof is in an effective therapeutic amount, for example, equivalent to about 0.2 mg/kg to 4 mg/kg (i.e., for 60 kg of adults).
  • the recommended daily dose of about 12 mg to 240 mg of isoforms is administered to a human individual, which should be

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Abstract

异类叶升麻苷或其医药学上可接受的盐被作为一种淀粉样β肽生成、累积或聚集的抑制剂，以预防或治疗与淀粉样β肽相关性疾病或状况。

Description

异类叶升麻苷或其药学上可接受的盐的用途
技术领域
本发明涉及异类叶升麻苷在抑制淀粉样 β肽生成、 积累或聚集的抑制 剂的新用途， 尤其涉及使用异类叶升麻苷预防或治疗与淀粉样 β肽相关的 疾病或状况的新用途。 背景技术
阿滋海默氏症 (Alzheimer's disease)被认为与一种具有 39-43个胺基酸 的肽的积累相关， 该肽被称为淀粉样 β肽 (amyloid β peptides) (筒称 Αβ) , 其为类淀粉前体蛋白 APP (amyloid precursor protein)的一种水解产物。其 中 Αβ1-40最为大量且毒性低， 而 Αβ1-42则对神经元有较高的毒性， 且具 高度纤维形成性 (fibrillogenic), 被认为是与阿滋海默氏症的发病最为相关 的 Αβ形式。 Αβ单体可经寡聚化而形成可溶性的 Αβ寡聚体 (oligomer) , 进 一步聚集于细胞外形成不可溶性的纤维丝或老年斑块 (senile plaque)。
一般认为与 Αβ相关的疾病或状况包含唐氏症 (Down syndrome)、荷兰 型遗传生^ ϊ出血伴淀粉样变病 (Hereditary cerebral hemorrhage with amyl oid (HCHWA) Dutch),关岛帕金森氏症-失智症复合症 (Parkinsonism-deme ntia complex on Guam) (Clinical Neurology and Neurosurgery (1990) 92:
305-310); 大脑淀粉样血管病 (J. Neuropath. Exp. Neuro. (2002) 61 : 282 -293); 包涵体肌炎 (Neurology (2006) 66: 65-68); 额颞叶型失智症 (Neuro report (2002) 13-5: 719-723); 年龄相关黄斑变性 (Experimental Eye Rese arch (2004) 78: 243-256); 皮克病（Pick's disease)(Neuroscience Letters (1 994) 171 : 63-66)及其它。
所述 Αβ相关的疾病或状况一般而言与 Αβ的生成、 积累或聚集有关， 包括因先天如遗传、 或后天如老化或环境等因素而导致生物体中存在不正 常的 Αβ或 Αβ聚集体数量。
一般认为如果能抑制 Αβ的生成、 积累或聚集， 应可作为有效预防或 发明内容
鉴于淀粉样 β肽和其聚集体， 容易在生物体内引发各种疾病或状况， 因此本发明的目的之一是提供一种抑制淀粉样 β肽生成、 积累或聚集的有 效成份， 其可作为食品、 饮品、 咀嚼物、 贴片、 皮肤保养品或其它添加剂。 本发明的另一目的则是提供一种预防或治疗淀粉样 β肽相关疾病或状况的 药物及方法。
为达到上述目的， 本发明揭示了以异类叶升麻苷或其医药学上可接受 的盐抑制淀粉样 β肽生成、 积累或聚集的用途， 以及制备预防或治疗淀粉 样 β肽相关的疾病或状况的药物的用途。
作为优选， 上述异类叶升麻苷或其医药学上可接受的盐用以抑制该淀 粉样 β肽导致神经元的损伤或凋亡， 进而保留、 改善或恢复学习与记忆能 力。
作为优选， 上述药物对人类的有效剂量相当于每日每公斤体重 0.2毫 克至 4.0毫克的异类叶升麻苷或其医药学上可接受的盐。
为使本发明的上述目的、 特征和优点能更明显易懂， 下文特举出实施 例， 并配合附图作详细说明。 附图的简要说明
图 1示出了各井 (well)的细胞外 Αβ1-40含量百分比， 结果显示本发明 的异类叶升麻苷 (D)具有显著降低 Αβ 1 -40在细胞外积累的极佳活性；
图 2示出了各井的细胞内的 Αβ1-40含量百分比；
图 3示出了各测试样品对 ΑΡΡ表现量的影响；
图 4示出了各测试样品对 Αβ1-40降解的影响；
图 5示出了各测试样品对 Αβ1-42寡聚化的影响；
图 6示意地示出了 Αβ的生成、 清除与聚集过程；
图 7示出了动物试验的时程表；
图 8示出了各测试样品对实验大鼠的探索能力影响；
图 9示出了各测试样品对实验大鼠的被动回避反应的影响；
图 10示出了各测试样品对实验大鼠进行水迷宫空间表现的影响； 图 11示出了各测试样品对实验大鼠进行水迷宫参考记忆试验的影响； 图 12A-12E示出了实验大鼠的脑部组织染色结果；
图 13A示出了实验大鼠脑部皮质区和海马区的乙酰胆碱含量检测结 果；
图 13B示出了实验大鼠脑部皮质区和海马区的胆碱含量检测结果； 图 14A示出了实验大鼠脑部皮质区所测得的乙酰胆碱酯酶活性结果； 图 14B示出了实验大鼠脑部海马区所测得的乙酰胆碱酯酶活性结果。 实施发明的最佳方式
许多由淀粉样 β肽引发的疾病均具有一种共通的特征， 即淀粉样 β肽 聚集体的形成。 这些淀粉样 β肽聚集体可以如纤维或斑块的形态出现， 并 且沉淀在生物体的系统、 器官、组织或体液中， 进而引发各种疾病或状况。 如能有效抑制淀粉样 β肽的生成、 积累或聚集， 应可避免淀粉样 β肽形成 聚集体而引发的各种疾病或状况， 其应可作为有效预防或治疗淀粉样 β肽 相关疾病或状况的方式之一。
有鉴于此， 本发明以具有下式的异类叶升麻苷或其医药学上可接受的 盐作为抑制（例如降低或避免)淀粉样 β肽生成、 积累或聚集的有效成份， 尤其是抑制淀粉样 β
Figure imgf000004_0001
美国专利 7,087,252 Β2揭示了一种从管花肉苁蓉 (Cistanche tubulosa (Schenk) Wight)的肉质茎所制备的含 25-50 wt%松果菊苷 (echinacoside)及 5-15 wt%类叶升麻苷 (acteoside)的制剂， 其可用于抗老年痴呆症 (senile dementia) 异类叶升麻苷及多种其它苯乙醇苷类（phenylethanoid glycosides) 已知被包含于该制剂中。
在本发明中， 异类叶升麻苷的水合物或其它溶剂溶合物、 前药及代谢 物均被视为异类叶升麻苷的功能上的等同物。 所述"前药"指某种前趋化合 物可于生物条件 (活体内或活体外）下水解、 氧化或进行其它反应而产生异 类叶升麻苷。 所述"代谢物 "指异类叶升麻苷于细胞或生物体内被代谢所形 成的化合物。
当异类叶升麻苷的"医药学上可接受盐"施予生物体时， 其通常可具有 与异类叶升麻苷相同或类似的医疗功效， 在生理上可忍受， 且不会产生过 敏或类似反应。 所述异类叶升麻苷的医药学上可接受盐可包含但不限于铁 盐、 钙盐或镁盐等。
所述"预防"指避免或延迟疾病或状况在生物体中出现， 而所述"治疗" 则指减緩或阻止疾病或状况的发展， 或使生物体的状况回复至较佳或正常 的状态。
所述"淀粉样 β肽相关性疾病或状况 "指此疾病或状况的发生通常与淀 粉样 β肽的生成、 积累或聚集相关， 尤其指此疾病或状况的发生为淀粉样 β肽所导致。 而当在具有某种疾病或状况的一定比例的生物体上发现有淀 粉样 β肽的不正常生成、 积累或聚集现象时， 也可认为此疾病或状况为淀 粉样 β肽相关。 另外， 当淀粉样 β肽的聚集处与疾病或状况所发生的病理 特征影响位置相近时， 亦可认为此疾病或状况为淀粉样 β肽相关。
本发明所提供的抑制淀粉样 β肽的有效成份， 亦可作为食品、 饮品等 添加剂使用， 以达到抑制淀粉样 β肽生成、 积累或聚集的方便性使用。
Figure imgf000005_0001
物或医 组合物， 包含异类叶升麻苷或其医药学上可接受的盐作为有效成份， 并可 包含适当的载剂、 稀释剂或赋形剂等， 以呈现如散剂（powder)、 颗粒剂
(granule) , I 剂（tablet) , 片剂（troche), 丸剂（pill)、 胶嚢（capsule) , 水性或 油性溶液 (solution) , 悬浮液 (suspension) , 孔膏 (cream)、 软膏 (ointment)、 凝 胶 (gel)、 气雾剂（aerosol) , 栓剂（suppository), 贴剂（patch)或其它所需形式。 上述药物或医药组合物可通过口腔、 局部、 非经肠、 皮肤、 鼻、 眼、 眼内 或其它途径给药。
在本文中， 所述"或"一般定义为"及 /或"， 除非另有特别说明。
随着世界人口老龄化的日益严重， 与衰老有关的许多疾病例如失智症 (dementia)已然成为现今老年疾病的重点医疗研究之一，而在各种失智症中 又以阿滋海默氏症最为普遍。 阿滋海默氏症是一种慢性的神经退化性疾 病， 其特征为病人逐渐失去认知能力且出现严重的行为异常， 后续也会造 成语言和运动能力的丧失， 对病患本身与其家人的生活质量容易造成极大 的影响。 有鉴于罹患阿滋海默氏症的患者人数有逐渐增加的趋势， 造成家 庭与社会的严重负担， 因此本发明特捡选与阿滋海默氏症较为相关的 Αβ 进行试验。
在下列实施例中， 利用表一所提供的测试样品进行 Αβ试验， 并且与 未加入任何测试样品处理的对照组 (Vehicle)进行比较。 表一： 进行试验的样品
Figure imgf000006_0004
松果菊苷 (Echinacoside)、 类叶升麻苷 (Acteoside)和异类叶升麻苷 (Isoacteoside)分别具有下列结构式：
松果菊苷：
Figure imgf000006_0001
类叶升麻苷:
Figure imgf000006_0002
异类叶升麻苷:
Figure imgf000006_0003
实施例一： 神经瘤母细胞株的培养
将原生型（wild type)人类神经瘤母细胞 SH-SY5Y培养于 Eagle's Minimum essential Medium (EMEM)/Ham's F12 medium (1 : 1混合物) (含 10% FBS, 10 units/ml penicillin, 10 g/ml Streptomycin)中， 而原生型小鼠神 经瘤母细胞 Neuro-2a则培养于 minimum essential medium (MEM)培养基 (含 10% FBS, 10 units/ml penicillin, lO g/ml Streptomycin)中。 实施例二： 各样品对 ΑβΙ-40于细胞外的积累测试
将实施例一中的原生型人类神经瘤母细胞 SH-SY5Y的培养基置换成 化学成份培养基 (EMEM/F12 medium (Cat.No.12500-062), Hepes 5 mM, 葡 萄糖 0.6%, NaHC03 3 mM, 麸酰胺 2.5 mM, 胰岛素 25 g/ml, Transferin 100 g/ml, Progestrone 20 nM, Putrescine 60 μΜ, 亚石西酸 ] (Sodium selenite) 30 nM, Heparin 2 g/ml)。 每个井 (well)具有 1x105个 SH-SY5Y细胞， 而培 养基体积为 300 μ1。 30分钟后， 将表一中所示的测试样品 A-D分别以 50 g/ml的浓度加入至不同井中处理 24小时， 接着以 Human Αβ1-40
Immunoassay kits(Catalog # KHB3482 Invitrogen)分析各井的培养基中的 Αβ1-40含量。
人类神经瘤母细胞 SH-SY5Y会积累 Αβ于细胞外的培养基中， 而图 1 示出了 SH-SY5Y井分别经各测试样品 A-D处理后， Αβ1-40于培养基中的 含量百分比， 其以未加入任何测试样品处理的对照组为比较基准。 结果显 示为平均值士标准误差， 而对照组和测试样品组间的统计差异标示 *表示 Ρ<0.05 , **表示 Ρ<0·01 , ***表示 Ρ<0·001。
参考图 1所示，测试样品 Α (含苯乙醇苷的制剂）和测试样品 C (类叶升 麻苷)减少培养基中的 Αβ1-40含量约 20%, 而测试样品 D (异类叶升麻苷) 则减少培养基中的 Αβ1-40含量达 47.44 ± 16.62%。图 1结果显示异类叶升 麻苷 (D)具有显著降低 Αβ 1 -40于细胞外积累的极佳活性。 实施例三： 各测试样品对 ΑβΙ-40于细胞内的积累实验
每个井均具有 1x105个 SH-SY5Y细胞， 而培养基体积为 300 μ1。 将 各井中的 SH-SY5Y细胞以浓度 50 g/ml的测试样品 A-D处理 24小时后， 分别将各井中的细胞部份制成细胞均质液， 并利用 Human Αβ1-40
Immunoassay kits(Catalog # KHB3482 Invitrogen)分析其 Αβ1-40含量。
图 2示出了 SH-SY5Y井的细胞内的 Αβ1-40含量百分比， 以未加入任 何测试样品处理的对照组为比较基准。如图 2所示， 测试样品 A-D均未明 显造成 Αβ于细胞中积累。 实施例四： 各测试样品对 APP在细胞中表现的影响实验
每个井具有 1x105个 SH-SY5Y细胞， 而培养基体积为 300 μ1。 将各 井中的 SH-SY5Y细胞以浓度 50 g/ml的测试样品 A-D处理 24小时后， 将细胞部分以均质緩沖液 (50 mM Hepes pH 7.5, 1 mM EDTA, 150 mM NaCl, 1% NP-40, 1 mM PMSF, 5 g/ml aprotinin, lO g/ml leupeptin)进行均 质， 利用超高速离心除去不溶物质。 将蛋白质以 SDS-聚丙烯酰胺胶电泳 (polyacrylamide gel electrophoresis)分离， 并转渍到 PVDF月莫后再利用免疫 转渍法（immunoblot) (antiA i-17, 6E10或 antiAPP-c端抗体）来检测 holoAPP含量。
图 3示出了测试样品 A-D对 APP在细胞中表现的影响， 其以百分比 表示， 并以未加入任何测试样品处理的对照组 (Vehicle)为基准。 如图 3所 示， 测试样品 A-D并未降低 APP表现的活性。 实施例五： 各测试样品对 ΑβΙ-40于细胞外的降解实验
小鼠神经瘤母细胞 neuro-2a会在化学成份培养基中释放出分解 Αβ的 酵素， 但不会在培养基中积累足以侦测的 Αβ量。 将 neuro-2a在培养基中 培养 24小时， 之后将不含细胞的培养基取出， 并分别以浓度 50 g/ml的 测试样品 A-D及 10ng人工合成的 Αβ1-40处理 24小时， 之后检视各测试 样品是否具有可促进培养基中的酵素降解 Αβ的活性。利用 Human Αβ1-40 Immunoassay kits(Catalog # KHB3482 Invitrogen)分别检验各井中的 Αβ1-40 之残留量， 其显示为百分比， 并以未加入任何测试样品处理的对照组 (Vehicle)为比较基准。 如图 4所示， 测试样品 D (异类叶升麻苷)并未促进 Αβ于细胞外的降解。 实施例六： 各测试样品对 ΑβΙ-42寡聚化的实验
将干燥的 Human Api-42 自从冰箱取出静置至室温， 加入
l,l, l,3,3,3-Hexa-fluro-2-propanol(HFIP)溶解 Αβ1-42至浓度为 ImM, 然后 在室温下静置 1小时。以 Hamilton注射器将上述 ΑβΙ-42/HFIP容易进行分 装，并且以氮气将 HFIP吹干，接着存放于 -20。C。将 HFIP处理后的 Αβ1-42 以 PBS溶解，并分别以浓度 50 g/ml的测试样品 A-D且于 4 °C下振荡处理 24小时， 以制备 Αβ1-42的寡聚物（oligomer), 并利用 thioflavine T结合荧 光 (Ex=450 nm, Em=482 nm)以分析 Αβ1-42的寡聚化程度。 图 5示出了测试样品 A-D分别对 Αβ1-42寡聚化 (oligomerization)的影 响， 结果以百分比显示， 并以未加入任何测试样品处理的对照组为基准。 参考图 5所示测试样品 A (含苯乙醇苷的制剂）、 B (松果菊苷)、 C (类叶升 麻苷)和 D (异类叶升麻苷)均具有抑制 Αβ1-42寡聚化的活性， 其中异类叶 升麻苷 (D)可抑制 Αβ1-42寡聚化程度达 98.93士 1.70,亦即异类叶升麻苷 (D) 可有效降低 Αβ1-42的寡聚化， 进而可抑制 Αβ形成纤维丝或老年斑块。
图 6示意地示出了 Αβ的生成、 清除与聚集过程 (参考来源：
Pharmacology & Therapeutics (2005) 108: 131)。 图 6表明培养基中细胞外的 Αβ积累（1)会受到 Αβ细胞内积累量 (2)、 ΑΡΡ表现 (3)、 Αβ降解 (4)、 Αβ寡 聚化 (5)以及 Αβ生成 (6)等影响。 根据上述实施例二至六的细胞实验结果， 相较于其它测试样品 A-C而言，异类叶升麻苷 (D)具有降低细胞外 Αβ积累 (1)的作用， 并且对于降低 Αβ的寡聚化程度 (5)有极佳的效用， 应可进一步 用以抑制 Αβ的聚集。 此外， 异类叶升麻苷 (D)降低 Αβ于细胞外积累（1)的 作用并非源于异类叶升麻苷增进了 Αβ于细胞内的积累（2)、 降低了细胞的 ΑΡΡ表现 (3)、 或增进了 Αβ于细胞外进行降解 (4), 因此推测异类叶升麻苷 (D)可直接减少 Αβ的生成 (6)。
综合上述结果，异类叶升麻苷 (D)或其医药学上可接受的盐可作为抑制 Αβ生成、 积累或聚集的有效成份， 预计异类叶升麻苷 (D)可有效抑制 Αβ 导致神经元的损伤或凋亡， 以进而保留、 改善或恢复学习与记忆能力。 此 外，根据上述结果，异类叶升麻苷 (D)或其医药学上可接受盐应可用于预防 或治疗 Αβ相关疾病或状况， 以及用于抑制 Αβ的生成、 积累或聚集。
所述 Αβ相关疾病或状况可包含但不限于阿滋海默氏症、 轻度认知障 碍、 路易氏体失智症、 唐氏症、 荷兰型类淀粉变性症、 关岛帕金森氏症- 失智症复合症、 大脑淀粉样血管病、 包涵体肌炎、 额颞叶型失智症、 年龄 相关性黄斑变性、 皮克病以及其它。 另外， 所述 Αβ虽以 Αβ中最大量的 Αβ1-40或具有高度纤维形成性的 Αβ1-42为例， 但也可包含其它胺基酸片 段。
在上述测试样品中， 异类叶升麻苷 (D)具有降低 Αβ生成、 积累和聚集 的最佳效用。 下列实施例七至十一中， 首先于 250~300公克重的雄性 SD 大鼠 (购自乐斯科股份有限公司）的侧脑室内输注 Αβ1-42, 以造成大鼠的神 经损坏， 影响大鼠的记忆与学习操作能力， 并可诱导大鼠脑中形成似老年 斑块的沉积， 以作为拟似阿滋海默氏症的动物模式。 经 Αβ诱导的阿滋海 默氏症的动物模式可参考 Nabeshima等人的文献数据 (Neuroscience Letters (1994) 170: 63-66)(British Journal of Pharmacology (1999) 126: 235-244)。 将大鼠麻醉后， 在大鼠的左脑室设置输注管， 进行缝合后归回饲养笼 中照顾。 图 7示出了动物试验的实验排程， 在开始输注 Αβ1-42后的第 7 天进行探索能力（exploration behavior)评估， 第 8至 9天进行被动回避反应 (passive avoidance learning)评估, 第 10至 13天进行水迷宫 (water maze)评 估，第 14天则进行空间性探索实验 (probe test)。实验组别设计如表二所示， 其中假手术组 (Sham)以 TFA溶液 (64.9% sterile ddH20, 35% acetonitrile, 0.1% trifluoroacetic acid)进行处理， 而其它实验组则每小时以 0.5μ1溶解于 TFA溶液的 Αβ1-42处理，相当于每天给予 300ρηιο1/12μ1的 Αβ1-42 (Tocris 1428; MW: 4514.08)。 整个试验期间， 在进行探索能力、 被动回避反应 以及水迷宫等测试的训练前经口投予测试样品给实验大鼠。 表二显示各个 实验组别的条件， 其中测试样品 D为表一中的异类叶升麻苷， 而 Aricept 则为市售用以治疗失智症例如阿滋海默氏症的药物。 所有测试样品均以二 次蒸馏水每日制备， 并以胃管经口灌胃方式给予。
在实施例七至十一中， 结果显示为平均值 ±标准误差， 而 Αβ1-42对照 组和其它实险组间的统计差异标示 *表示 ΡΟ.05 , **表示 PO.01 , ***表示 Ρ<0·001。
最后牺牲所有实验大鼠， 取其脑部进行切片和染色， 并进行神经传递 物质的测定。 动物实验设计
Figure imgf000010_0001
实施例七： 探索能力的设备与测定 探索能力测定装置系由一长、 宽、 高均 40 cm及一个不锈钢底板所组 成， 底板上有 16 个直径 3 cm的洞， 距两侧 7 cm, 各洞的间距为 4 cm。 每只大鼠的测定时间为 10分钟， 测试大鼠穿洞的次数。
图 8示出了根据表二所示的动物探索行为（exploration behavior)的实验 结果。 如图 8所示， Αβ1-42经脑室输注予实验大鼠后， 会造成实验大鼠的 探索能力低下， 而测试样品 D (异类叶升麻苷)和 Aricept均可有效增进实验 大鼠的探索能力， 且测试样品 D (异类叶升麻苷)在 5 mg/kg的剂量下优于 Aricept 0.75 mg/kg的功效。 实施例八： 被动回避反应实验
被动回避装置由一明室、 一暗室以及一介于两室间的闸门所构成。 将大鼠置入明室， 同时开启闸门， 以大鼠在 90秒内进入暗室者， 供 做本实验。
训练期： 将筛选过的大鼠置入明室， 同时开启闸门， 待大鼠进入暗室 后， 关闭闸门， 同时将底板通以电流刺激 5秒， 之后自暗室取出大鼠， 归 回饲养笼。
于训练后 24小时， 再将大鼠置入明室， 同时开启闸门， 记录大鼠在 明室之滞留时间 （ step-through latency, STL ) 。
图 9示出了根据表二所示动物进行被动回避反应的实验结果。 参考图 9 , 实验大鼠经脑室输注给予 Αβ1-42后， 会显著造成实验大鼠的被动回避 学习反应的障碍， 而经测试样品 D (异类叶升麻苷)和 Aricept的治疗均可 改善实验大鼠因脑室输注 Αβ1-42导致实验大鼠被动回避的学习障碍现象。 如图 9所示， 测试样品 D (异类叶升麻苷)于 2.5 mg/kg的剂量下与 Aricept 0.75 mg/kg的效果相当， 而测试样品 D (异类叶升麻苷)于 5 mg/kg的剂量 下则优于 Aricept 0.75 mg/kg的功效。 实施例九： 水迷宫实验
本实验将泳池分成四个象限， 将隐藏平台固定置于第四象限上， 并且 置于水面下方 1公分处。 每一大鼠每天均给予两次训练， 两次训练间隔为 4小时， 每次训练均给予 2分钟以找寻隐藏平台。 第一次训练为空间表现 (spatial performance)试验， 每只大鼠最多给予 120秒的时间游泳找寻隐藏 平台， 若大鼠于 120秒内成功找到隐藏平台， 则让大鼠于平台上休息 30 秒钟；而若大鼠于时间终止前尚未找到隐藏平台，则将大鼠的分数计为 120 秒， 并将其抓至隐藏平台休息 30秒钟。 此空间表现试验一共进行 4天。 于第 5天将隐藏平台自水迷宫泳池取走， 再将大鼠置于第一象限， 并且给 予 60秒钟的时间游泳， 记录大鼠在泳池内原隐藏平台的象限所花的时间， 以进行参考记忆试验 (probe test)。
图 10示出了根据表二所示动物进行空间表现试验结果， 而图 11示出 了根据表二所示动物进行参考记忆试验的实验结果， 并与假手术组
(Sham), Αβ1-42对照组和正对照组 Aricept的结果作比较。 参考图 10及图 11所示， 动物实验结果显示测试样品 D和药物 Aricept均可改善 Αβ 1 -42 诱发水迷宫空间表现和参考记忆缺失的现象， 而测试样品 D 5 mg/kg则优 于对照组 Aricept 0.75 mg/kg的效果。 实施例十： 大鼠脑部组织染色结果
将进行水迷宫实验后的大鼠断头， 并且快速将脑自头盖骨内移开， 进 行脑部海马区 Αβ1-42免疫组织染色。 图 12A至 12E示出了脑部组织染色 结果。 在图 12B中， 在连续输注 Αβ1-42的大鼠脑中发现大量的斑块， 而 在图 12C和图 12D中， 经测试样品 D (异类叶升麻苷) 2.5mg/kg处理后的大 鼠脑中仅发现极少量的斑块，而经测试样品 D (异类叶升麻苷） 5mg/kg处理 后的大鼠脑中则几乎没有斑块产生。 比较图 12C至图 12E, 经测试样品 D (异类叶升麻苷)处理后的大鼠脑中， 其斑块数量明显小于经药物 Aricept 处理过后的结果。 由此结果可知， 测试样品 D (异类叶升麻苷)可有效抑制 Αβ经聚集而形成斑块， 或者可消除斑块。 实施例十一： 大鼠大脑皮质区及海马区中的神经传导物质含量
将进行水迷宫实验后的大鼠牺牲掉， 并快速将脑自头盖骨内移开， 按 Glowinski & Iversen 的方法，将大脑皮质区及海马区分别取出，分别称重， 并加入 50 mM Na-phosphate buffer(pH 7.8) 进行均质， 以供进行神经传递 物质浓度及酶含量的测定。
表三和表四分别为根据表二所示实验大鼠于其脑部皮质区和海马区 的神经传导物质多巴胺 (DA)与其代谢物 DOPAC和 HVA的含量检测结果。 参考表三和表四所示的结果， Αβ1-42造成实验大鼠的皮质区和海马区的 DA含量降低， 而测试样品 D和 Aricept均可改善 Αβ 1 -42所造成的实验大 鼠皮质区和海马区的 DA含量降低的现象。 表三： 根据表二所示实验大鼠于其脑部皮质区的神经传导物质多巴胺
(DA)与其代谢物 DOPAC和 HVA的含量检测结果
DOPAC HVA DA
Sham 3.7l±0.58
Vehicle 2,33±8 2S
D 2.5 g/kg :12,53±3,.33 2,¾±0,5S
D 5 mg kg 2. 4±0.69 滅 4
Aricept 2. 2±0,7S
表 4: 根据表 2所示实验大鼠于其脑部海马区的神经传导物质多巴胺 (DA)与其代谢物 DOPAC和 HVA的含量检测结果
DOPAC DA
Sham 5.S7±0,92 3.6S±flil
Vehicle 5,13±O..S0: 3.39±0.36 1,Q ±0.21
D 2.5 mg kg i. S±I.15 3.68±0.46 5.41±l.f
D 5 mg kg 3-2¾^),25
Aricept 3,19±1.00 .2,45 3:S 2.33±0.37
图 13A为根据表二所示实验大鼠于其脑部皮质区和海马区的神经传 导物质乙酰胆碱 (Acetylcholine)的含量检测结果， 而图 13B则为根据表二 所示实验大鼠于其脑部皮质区和海马区的胆碱 (Choline)含量检测结果。 参 考图 13A和图 13B所示结果， Αβ1-42造成实验大鼠之皮质区和海马区的 乙酰胆碱含量降低，而测试样品 D和 Aricept均可改善 Αβ1-42所造成的实 验大鼠皮质区和海马区的乙酰胆碱含量降低的现象， 且其中以测试样品 D (异类叶升麻苷） 5 mg/kg的结果最佳。
图 14A和图 14B分别示出了根据表二所示实验大鼠于其脑部皮质区和 海马区所测得的乙酰胆碱酯酶 (acetylcholinesterase)活性结果。 参考图 14A 和图 14B所示结果， Αβ1-42造成实验大鼠皮质区和海马区的乙酰胆碱酯 酶活性增加，而测试样品 D和 Aricept均可改善 Αβ1-42所造成的实验大鼠 皮质区和海马区的乙酰胆碱酯酶活性增加的现象。
由于 Αβ的聚集体会损伤细胞， 进而引发各种疾病或状况。 根据实施 例二至六的细胞试验结果， 异类叶升麻苷可有效抑制 Αβ的生成、 积累或 聚集， 进而避免 Αβ形成聚集体， 其可用于预防或治疗阿滋海默氏症以及 其它 Αβ相关疾病或状况。
根据实施例七至九的动物试验结果， 异类叶升麻苷具有显著改善 Αβ 所致的记忆或学习能力衰退的效果。 而根据实施例十所示结果， 异类叶升 麻苷可有效抑制 Αβ经聚集而形成斑块， 或者消除斑块。 此外， 根据实施 例十一， 异类叶升麻苷可有效改善神经传导物质因 Αβ而减少的现象， 故 可具有改善记忆或学习能力衰退的效果。 根据上述细胞和动物试验结果， 如将异类叶升麻苷或其医药学上可接受的盐以某种有效治疗量， 如相当于 约 0.2毫克 /公斤至 4毫克 /公斤（即对 60公斤成人的建议剂量约为 12毫克 至 240毫克)的异类叶升麻苷的每日剂量投予至某一人类个体，其应可作为
、 、 i然本发明 以数个 佳 ϊ施例揭露如上: 但其 ;并非用以限定本发 明， 本领域技术人员在未脱离本发明所揭示的精神下所进行的等效替换或 修饰， 均应包含在本发明权利要求的范围内。

Claims

杈 利 要 求
1. 一种以异类叶升麻苷或其医药学上可接受的盐用于制备预防或治疗与 淀粉样 β肽相关的疾病或状况的药物的用途。
2. 根据权利要求 1所述的用途，其中所述疾病或状况与该淀粉样 β肽的生 成、 累积或聚集有关。
3. 根据权利要求 2所述的用途，其中所述疾病或状况与该淀粉样 β肽在细 胞外的生成、 累积或聚集有关。
4. 根据权利要求 1 至 3 中任一项所述的用途， 其中所述淀粉样 β 肽为 Αβ1-40或 Αβ1-42。
5. 根据权利要求 1所述的用途， 其中， 与淀粉样 β肽相关的所述疾病或状 况为阿滋海默氏症、 轻度认知障碍、 路易氏体失智症、 唐氏症、 荷兰型 类淀粉变性症、 关岛帕金森氏症-失智症复合症、 大脑淀粉样血管病、 包涵体几炎、 额颞叶型失智症、 年龄相关性黄斑变性或皮克病。
6. 根据权利要求 5所述的用途，其中所述药物用于预防或治疗阿滋海默氏 症。
7. 根据权利要求 1所述的用途，其中所述异类叶升麻苷或其医药学上可接 改善或恢复学习与记忆能力。 ' 、
8. 根据权利要求 1所述的用途， 其中， 所述药物对人类的一种有效剂量相 当于每日每公斤体重 0.2毫克至 4.0毫克的异类叶升麻苷或其医药学上 可接受的盐。
9. 一种以异类叶升麻苷或其医药学上可接受的盐抑制淀粉样 β肽生成、累 积或聚集的用途。 根据权利要求 9所述的用途，其中，所述异类叶升麻苷或其医药学上可 接受的盐用以抑制该淀粉样 β肽细胞外的生成、 累积或聚集。 根据权利要求 9或 10所述的用途， 其中， 所述淀粉样 β肽为 Αβ1-40 或 Αβ1-42。 根据权利要求 9所述的用途，其中，所述异类叶升麻苷或其医药学上可 接受的盐供以制备药品、 食品、 饮品、 咀嚼物、 贴片或皮肤保养品。
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EP2397144B1 (en) 2014-12-31
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CN106176778A (zh) 2016-12-07
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JP5968878B2 (ja) 2016-08-10
EP2397144A1 (en) 2011-12-21
MY160878A (en) 2017-03-31
AU2011267724A1 (en) 2013-01-24
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