CN102666836A - Cell or culture extract of cladonia macilenta purple and/or biruloquinone as acetylcholinesterase inhibitors - Google Patents
Cell or culture extract of cladonia macilenta purple and/or biruloquinone as acetylcholinesterase inhibitors Download PDFInfo
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Abstract
The present invention relates to cell or culture extract of Cladonia macilenta purple, biruloquinone and pharmaceutically acceptable salts thereof which have acetylcholinesterase (AChE) inhibitory activity, and pharmaceutical composition and functional food for preventing, treating, or alleviating neurodegenerative disease, myasthenia of smooth muscle of gastrointestinal tract or urinary bladder, or glaucoma, comprising the same.
Description
Technical field
The present invention relates to be used for E.C. 3.1.1.7 (acetylcholinesterase; AChE) quinone (Biruloquinone) and pharmaceutical salts thereof in the thalline of the thin rhabdolith stamen of the purple of suppressor factor (Cladonia macilenta purple) or cultivation extract, the cloth, and the pharmaceutical composition and the functional foodstuff that comprise above-mentioned substance.
Background technology
E.C. 3.1.1.7 also is known as AChE, be a kind of can make to have regulate the active neurotransmission vagusstoff of parasympathetic neuron (acetycholine, ACh) degraded (through its hydrolytic activity) generate the enzyme of choline and acetate.It forms and moves to its function of cytolemma performance on endoplasmic reticulum.It is a kind of important enzyme, is found in cholinergic neuron and on every side more, especially at neuromuscular junction, also is found in blood plasma, liver and other tissue.
Usually, vagusstoff is to secrete the neurotransmitter of transmitting action potential to synaptic cleft (synaptic cleft) and through the acceptor that combines postsynaptic neuron by aixs cylinder terminal film.After the stimulation of transmission unit, this material is decomposed into choline and acetate under the E.C. 3.1.1.7 effect, is transported back to nerve ending and is used for synthetic new vagusstoff molecule there through absorbing again then.
Vagusstoff is carried out finding after the active research, with regard to the synthetic of vagusstoff with decompose with regard to the mechanism, on a lot of healths with spiritual disease/imbalance all with the improper minimizing significant correlation of vagusstoff concentration.
Alzheimer (Alzheimer ' s disease (AD)), be also referred to as senile dementia, be that most typical vagusstoff is diseases related.The cardinal symptom of Alzheimer is hypomnesis, language and spatial perception ability and judgment imbalance.About the pathogenic factor or the morbidity process of this disease, delivered a lot of hypothesis, but also indeterminate at present.Yet Alzheimer patient's cns is impaired usually, and especially the damage of cholinergic neuron is the most serious.And, it is reported that there is very big dependency in this damage and Alzheimer patient's the decline of study, memory and cognitive power of cholinergic neuron.The effort that improves the cholinergic neuron relevant with AD is main with choline hypothesis (Cholinergic Hypothesis) mainly.On the basis of this assumption, along the direction active development therapeutical agent that improves impaired cholinergic neuron.In order to improve impaired cholinergic neuron; Can adopt following method: using vagusstoff precursor (ACh precursor) is cholinergic neurotransmitter; Use cholinergic agonist (receptor agonist), perhaps keep the concentration of ACh in the cynapse with respect to the AChE suppressor factor.But cholinergic agonist has in vivo the shortcoming of degraded easily, therefore, adopts the AChE suppressor factor usually.
In fact; Through example U.S. food Drug Administration (FDA) authentication and that be used as the AChE suppressor factor of treatment of alzheimer's disease agent tacrine (tacrine) (THA is arranged;
E2020 (donepezil)
and rivastigmine (rivastigmine)
are wherein; Extraction has Galanthamine (galanthamine from the compound of natural product; Galanthus nivalis), selagine A (huperzine A, Huperzia serrata) etc.
Degraded through prevention ACh keeps these AChE suppressor factor of ACh concentration to have the effect of improving cognitive function.Yet known these AChE suppressor factor have problems such as liver toxicity, short, low bioavailability of transformation period.Therefore, need more study to develop new AChE suppressor factor.
Simultaneously, other pathological research report relevant with the choline neural system, the stomach motion is regulated by nerve stimulation, and vagusstoff can improve the stomach motion.Therefore, use a kind of AChE suppressor factor that is called as prostigmin(e) (neostigmine) sometimes, be used to treat the abdominal distension that causes by the postoperative ileus increase or by the unable dysuria that causes of detrusor urinae of bladder.
In addition; Myasthenia gravis (myasthenia gravis) is a kind of autoimmunity neuromuscular disease; Its occurrence cause is that the acetylcholine receptor that is positioned at the postsynaptic neuromuscular junction is damaged, thereby has suppressed the hormesis of neurotransmitter acetylcholine.To this illness, medically adopt acetylcholinesterase depressant such as pyridostigmine bromide (mestinon) or prostigmin(e) to treat.Pyridostigmine bromide is the medicine of the most frequently used treatment myasthenia gravis, the hydrolytic activity that it can acetylcholine esterase inhibition, thus the concentration that increases vagusstoff makes vagusstoff be retained on the acceptor in the muscle cell.Although this medicine has the advantage that reaches result of treatment in the short period of time, the spinoff of suffering from abdominal pain or suffering from diarrhoea often appears according to its dosage.And acetylcholinesterase depressant is used in the myasthenia gravis treatment of present exploitation, and is not enough for the selectivity of Nicotine type and mAChR, and therefore the stimulation owing to M-ChR causes having side effects.In addition, its specific absorption is very low, because only can the implementation part effect, so its therapeutic domain is narrow.
In addition, glaucoma is a kind of eye disease, causes optic nerve injury because intraocular pressure raises, and causes progressivity, non-reversibility to be lost one's sight.In this case, it is reported that acetylcholinesterase depressant can promote the absorption again of waterborne liquid, thereby reduce intraocular pressure.But what pay particular attention to is when the acetylcholinesterase depressant treatment glaucoma of using exploitation at present is more than 6 months, may have cataractous risk.
For effectively prevention and treatment and the relevant various diseases/imbalance of vagusstoff concentration minimizing, once proposed through using the vagusstoff precursor to promote vagusstoff synthetic replacement scheme.Yet, because its short term effect can not get into hemato encephalic barrier (BBB), the therefore main drug treatment that adopts the hydrolytic action of acetylcholinesterase depressant such as tacrine containment vagusstoff.
Yet, as stated, it is reported and present exploitation can cause a series of spinoffs, for example hepatopathy, gastrointestinal dysfunction (stomachache or diarrhoea), myalgia etc. with commercially available acetylcholinesterase depressant.
Simultaneously, lichens (lichens) is divided into about 14000 kinds as the symbiosis complex body of Mycophyta (fungi), algae (algae) and/or cyanobacteria (cyanobacteria).Once proposed the secondary metabolite (secondary metabolites) of lichens is used as antiseptic-germicide (antimicrobial agent) or anti-herbivore agent (antiherbivore agent).And; Some extracts of lichens among the people once as various therapeutical agents; And the multiple metabolite that discloses lichens has various biological activitys; As antitumor, antibiotic (antibacterial), antimycotic (antifungal), antiviral (antiviral), analgesic (antipyretic), anti-inflammatory (antiinflammatory) and anti-oxidant activity (Oksanen, the I.2006. problem of the ecology of lichens and biotechnology aspect (Ecological and biotechnological aspects of lichens). applied microbiology and biotechnology (Applied Microbiology and Biotechnology) .73 (4): 723-734.).Therefore, the lichens metabolite receives great concern as potential pharmaceutical formulations (pharmacological agents) source.
To this, the inventor strives to find the material that can treat the various diseases/imbalance relevant with the improper minimizing of vagusstoff concentration; Therefore find that lichens forms effectively acetylcholine esterase inhibition of fungi (lichens forming fungi (LFF)).
Summary of the invention
Technical scheme
Therefore, an object of the present invention is to provide the thalline extract (cell extract) or the cultivation extract (culrute extract) that can suppress the thin rhabdolith stamen of the active purple of AChE (Cladonia macilenta purple).
Another object of the present invention provides quinone (Biruloquinone) or its pharmaceutical salts in the cloth with the Formula I that suppresses the active ability of AChE and derive from the thin rhabdolith stamen of purple.
Another object of the present invention provide the thalline of the thin rhabdolith stamen of purple cultivate quinone in extract, the cloth or cloth in the pharmaceutical salts of quinone as the application of AChE suppressor factor.
Another object of the present invention provides the gravis that is used to prevent or treat nerve degenerative diseases, gi tract or smooth muscle of bladder, or glaucomatous pharmaceutical composition, and it comprises at least a material that is selected from down group: the pharmaceutical salts of quinone and Bu Li quinone in the thalline of the thin rhabdolith stamen of purple or cultivation extract, the cloth.
Another object of the present invention provide the thalline of the thin rhabdolith stamen of purple cultivate quinone in extract, the cloth or cloth in the pharmaceutical salts of quinone in prevention or the gravis of treatment nerve degenerative diseases, gi tract or smooth muscle of bladder or the application in the glaucoma.
Another object of the present invention provides the gravis that is used to prevent or treat nerve degenerative diseases, gi tract or smooth muscle of bladder, or glaucomatous method, and it comprises uses at least a material that is selected from down group to individuality: the pharmaceutical salts of quinone and Bu Li quinone in the thalline of the thin rhabdolith stamen of purple or cultivation extract, the cloth.
Another object of the present invention provides the gravis that is used to prevent or alleviate nerve degenerative diseases, gi tract or smooth muscle of bladder, or glaucomatous food, and it comprises at least a material that is selected from down group that individuality is used: the pharmaceutical salts of quinone and Bu Li quinone in the thalline of the thin rhabdolith stamen of purple or cultivation extract, the cloth.
Beneficial effect
The pharmaceutical salts of quinone and Bu Li quinone is strong acetylcholinesterase depressant of imitating in the thalline of the thin rhabdolith stamen of purple or cultivation extract, the cloth, the activity of its ability acetylcholine esterase inhibition.Therefore; The improper minimizing diseases associated of vagusstoff concentration/imbalance that pharmaceutical composition or the food that contains them can be used for preventing or treats and caused by acetylcholine esterase active is like the gravis or the glaucoma of nerve degenerative diseases, gi tract or smooth muscle of bladder.
Especially, because the thalline of the thin rhabdolith stamen of purple or cultivate in extract, the cloth quinone and pharmaceutical salts is the active skull cap components that derives from the thin rhabdolith stamen of purple, so they have security to the body of living.Therefore, can they be applied to patient who suffers from said disease/imbalance or the patient who hopes prevention said disease/imbalance, can as traditional acetylcholinesterase depressant, not have side effects.
Description of drawings
Accompanying drawing be will combine and above-mentioned or other purpose and characteristic of the present invention presented through the following description of this invention, wherein:
Fig. 1: be illustrated in the histogram of inhibiting activity of acetylcholinesterase, that thallus (Thallus) extract of lichens is planted in 16 (16) that the South Pole, Hungary and China gathers;
Fig. 2: be illustrated in the histogram that the inhibiting activity of acetylcholinesterase, of isolating lichens formation fungi (lichens-forming fungus) extract in thallus (Thallus) extract of lichens is planted in the South Pole, Hungary and Chinese 16 (16) of gathering;
Fig. 3: quinone is to concentration-inhibition curve of AChE in the cloth;
Fig. 4: the cytotoxicity analysis result of quinone PC12 cell in the cloth;
Fig. 5: the histogram that the ability of quinone prevention oxidative stress in the cloth is shown; And
Fig. 6: quinone is shown in the cloth to the double reciprocal plot (Lineweaver-Burk plot) of the inhibition behavior of AChE.
Embodiment
Unless otherwise prescribed, technology used herein and scientific and technical terminology have the identical implication with one of ordinary skill in the art's common sense of the present invention.In addition, the mode that all documents of mentioning among this paper are all consulted in full is incorporated into this.
One side of the present invention provides the thalline extract or the cultivation extract of the thin rhabdolith stamen of purple of ability acetylcholine esterase inhibition activity.
Thin rhabdolith stamen (Cladonia macilent) is to comprise that worldwide the lichens that Denmark extensively distributes forms fungi (Lichen-forming fungi; LFF); It is on morphology and chemically have 2 (two) to plant dissimilar subcultures, i.e. purple (purple) type and white (white) type.The inventor finds that in above-mentioned two types, the purple type has the inhibiting activity of acetylcholinesterase, of strong effect, and white type shows low activity.Said in the present invention purple type is meant thin rhabdolith stamen of purple (Cladonia macilenta purple) or thin rhabdolith stamen (Cladonia macilent).
In the present invention, term " extract " is meant the material that adopts the known ordinary method of association area from the thin rhabdolith stamen of purple or its culturing filtrate (cultural filtration), to extract.In addition, " extract " not only comprises the said extracted composition, also comprises the dried powder of this extraction composition and utilizes them to carry out all forms of formulationization.
In the present invention, being used for from thin rhabdolith stamen of purple or the extraction of its culturing filtrate can be C with the solvent that obtains extract of the present invention
1-4Alcohol or its aqueous solution such as methyl alcohol, ethanol, propyl alcohol or butanols, normal hexane, ETHYLE ACETATE, acetone, methylene dichloride, or its mixture, preferred C
1-4Alcohol is like methyl alcohol or ethanol.During extraction, can use the former material of the thin rhabdolith stamen of purple or its pulverised form.The usage quantity scope of solvent is that the thin rhabdolith stamen of the dry purple of every 100g uses 0.1～5L, and the scope of the non-limiting temperature of said extraction is 4～120 ℃.In addition, extraction can be carried out 10 minutes～30 days, can use conventional extraction instrument, ultrasound to pulverize extractor and perhaps divide the gold-plating device.Solvent in the extract that is obtained can be removed through suction strainer and/or lyophilize.
In the present invention; " E.C. 3.1.1.7 (Acetylcholinesterase) "; Also being known as " AChE ", is a kind of enzyme that can make neurotransmission vagusstoff degraded (through its hydrolytic activity) generate choline and acetate, has very big cognation with the concentration change of vagusstoff.Therefore; Acetylcholinesterase depressant has been used to prevent the multiple disease/imbalance relevant with the improper minimizing of vagusstoff concentration with treatment; It is nerve degenerative diseases; For example Alzheimer (Alzheimer ' s disease), parkinson's disease (Parkinson ' s disease), ischemic encephalopathy (Ischemia brain disease), myasthenia gravis (myasthenia gravis), hypomnesis, alcohol addiction etc., the gravis of gi tract or smooth muscle of bladder or glaucoma.
The inhibiting activity of acetylcholinesterase, (about 60%) that the thalline of the thin rhabdolith stamen of purple of the present invention or cultivation extract have strong effect is compared other lichens thallus extract or lichens and is formed fungi (LFF) extract, has excellent inhibition activity.Therefore; The thin rhabdolith stamen of purple of the present invention extract can be used in prevention and treats the relevant disease/imbalance of the improper minimizing of vagusstoff concentration that is caused by acetylcholine esterase active, the i.e. gravis of nerve degenerative diseases, gi tract or smooth muscle of bladder or glaucoma.The example of above-mentioned nerve degenerative diseases has Alzheimer, parkinson's disease, ischemic encephalopathy, myasthenia gravis, hypomnesis, alcohol addiction etc.
Another aspect of the present invention provides the activity to E.C. 3.1.1.7 to have the inhibition ability and derives from quinone (Biruloquinone) in the cloth of Formula I of the thin rhabdolith stamen of purple (Cladonia macilenta purple),
< Formula I >
Quinone is from the isolating main compound of the thin rhabdolith stamen of purple in the cloth of Formula I.In the present invention, quinone also comprises its pharmaceutical salts according to different situations in the cloth.
Unless otherwise prescribed, the pharmaceutical salts of quinone can comprise the acid or basic salt based on quinone in the cloth in the cloth.The sodium that is exemplified as hydroxyl, calcium and the sylvite of these acidity or basic salt; And hydrobromate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, dihydrogen phosphate, acetate, SUMATRIPTAN SUCCINATE, Citrate trianion, tartrate, lactic acid salt, Uromaline salt (madelate), methane sulfonates (mesylate) and tosilate (tosylate), it can prepare through methods known in the art or technology.
In addition, the acid salt with free acid (free acid) formation also can be used as pharmaceutical salts of the present invention.Acid salt can obtain through ordinary method, for example with compound dissolution in excessive acid solution, use water-miscible organic solvent such as methyl alcohol, ethanol, acetone or acetonitrile that above-mentioned acid salt is precipitated then.The compound of equimolar amount and the acid in water or the alcohol (for example ethylene glycol monomethyl ether) are heated, and the mixture that obtains through evaporation drying then is perhaps through the sedimentary salt of suction filtration.
Available organic acid or mineral acid are as free acid.Mineral acid be exemplified as hydrochloric acid, phosphoric acid, nitric acid or tartrate, organic acid is exemplified as methanesulfonic (Methane sulfonic acid), tosic acid (p-toluene sulfonic acid), acetate, trifluoroacetic acid, Citric Acid, toxilic acid (maleic acid), succsinic acid, oxalic acid, phenylformic acid, fumaric acid, Uromaline (mandelic acid), propionic acid (propionic acid), lactic acid (lactic acid), oxyacetic acid (glycolic acid), glucono-(gluconic acid), galacturonic acid (galacturonic acid), L-glutamic acid, pentanedioic acid (glutaric acid), glucuronic acid (glucuronic acid), aspartic acid (aspartic acid), xitix, carbon acid (carbonic acid), vanillic acid (vanillic acid), hydroiodic acid HI (hydroiodic acid).
In addition, the present invention also can use the medicinal metal salt that forms with alkali.An alkali metal salt or alkaline earth salt can obtain through ordinary method, for example: compound dissolution in excessive alkali metal hydroxide or alkaline earth metal hydroxides solution, is filtered insoluble compound salt, evaporation and the dry filtrating that stays.
Preferred sodium, potassium or calcium salt, also preferred corresponding therewith silver salt, it passes through sodium, potassium or calcium salt and suitable silver salt (for example Silver Nitrate) prepared in reaction.
In a specific embodiment of the present invention, from the thalline extract of the thin rhabdolith stamen of purple or the method for cultivating quinone in the cloth of separation chemistry formula I the extract, it comprises: utilize lower alcohol such as C
1-4Alcohol or ETHYLE ACETATE (ethyl acetate) prepare extract from the thin rhabdolith stamen of purple, the said extracted thing is passed through toluene on post: ETHYLE ACETATE: (90: 20: 20, mixed solvent v/v) carried out wash-out to formic acid.
The thalline of the thin rhabdolith stamen of purple of the present invention is the IC of 27.1 μ g/ml with cultivating extract and inhibiting activity of acetylcholinesterase, that therefrom quinone shows in the cloth of isolating Formula I
50, and it is as mixed-type inhibitor.In addition, they can significantly reduce oxidative stress, find that through toxicity test they do not have toxicity.Therefore; The thalline of the thin rhabdolith stamen of purple of the present invention with cultivate extract and cloth in quinone can be used in prevention and treatment and the relevant disease/imbalance of the improper minimizing of vagusstoff concentration that causes by acetylcholine esterase active, the i.e. gravis of nerve degenerative diseases, gi tract or smooth muscle of bladder or glaucoma.The example of above-mentioned nerve degenerative diseases has such as Alzheimer, parkinson's disease, ischemic encephalopathy, myasthenia gravis, hypomnesis and alcohol addiction etc.
Therefore; The present invention is provided for preventing or treats with the relevant disease/imbalance of the improper minimizing of vagusstoff concentration that is caused by acetylcholine esterase active is the gravis or the glaucomatous pharmaceutical composition of nerve degenerative diseases, gi tract or smooth muscle of bladder, and it comprises at least a material that is selected from down group: the pharmaceutical salts of quinone in quinone and the cloth in the thalline of the thin rhabdolith stamen of purple or cultivation extract, the cloth.The example of nerve degenerative diseases as above.
Pharmaceutical composition of the present invention can be processed various preparations with pharmaceutical carrier and/or vehicle.Appropriate carriers and examples of excipients have: lactose, glucose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, Xylitol, maltose alcohol, starch, gum arabic, sodium-alginate, gelatin, calcium phosphate, Calucium Silicate powder, Mierocrystalline cellulose, methylcellulose gum, Microcrystalline Cellulose, Vinylpyrrolidone polymer, water, methyl hydroxybenzoate, nipasol, talcum powder, Magnesium Stearate and MO.Randomly, compsn of the present invention can also comprise weighting agent, antithrombotics, lubricant, wetting agent, spices, emulsifying agent, sanitas etc.
Pharmaceutical composition of the present invention can be through any conventional route administration; Like oral, local application (comprising oral cavity (buccal), hypogloeeis, skin and intraocular approach), non-oral (in subcutaneous, intracutaneous, intraperitoneal, the myelencephalon chamber, in the intramuscular, blood vessel and intraarticular approach); Perhaps transdermal route, but the invention is not restricted to these exemplary administering modes.
In addition, compsn of the present invention can be used as independent therapy application.But it can be with other acetylcholinesterase depressant known in the art perhaps administration successively simultaneously.The example of these acetylcholinesterase depressant has: E2020 (Aricept) (Japan defends E2020 hydrochloride (donepezil hydrochloride) capsule that material (Eisai) is sold), A Milin (Amirine) (day development medicine company (Nikken)), SM-10888 (SUMITOMO CHEMICAL pharmacy (Sumitomo)), MF-217 (Mediolanum Pharmaceutici-Angelini), Ro 46-5934 and HP-290 (Hirst-Russell (Hoesht-Russel)), ENA 713 (Shandeshi (Sandoz)), Itameline (Itameline) (Hirst-Russell), Metrifonate (Metrifonate) (Baeyer-Wales (Bayer-Wiles)), TAK 147 (Japanese military field (Takeda)), CP 118.954 (Pfizer (Pfizer)), Galanthamine (Galanthamine) (interior moral glycolylurea (Naedheim) drugmaker), ONO 1603 (Japan's little wild medicine (Ono)), Zifrosilone (Zifrosilone) (Ma Ruien (Marion Merrel Dow)).These acetylcholinesterase depressant are disclosed in (Alzheimers: treat (Alzheimer Disease:From Molecular Biology to Therapy), eds.Becker etc., pp.171-177 (1996) from molecular biology) such as Brufani; Schmidt etc. (Alzheimer :) from molecular biology treatment (Alzheimer Disease:From Molecular Biology to Therapy), eds.Becker etc., pp.217-221 (1996); Vargas etc. (Alzheimer :) from molecular biology treatment (Alzheimer Disease:From Molecular Biology to Therapy), eds.Becker etc., pp.251-255 (1996); Greig etc. (Alzheimer :) from molecular biology treatment (Alzheimer Disease:From Molecular Biology to Therapy), eds.Becker etc., pp.231-237 (1996); And Giacobini (Alzheimer :) from molecular biology treatment (Alzheimer Disease:From Molecular Biology to Therapy), eds.Becker etc., pp.187-204 (1996).
Compsn of the present invention can be in the gravis of nerve degenerative diseases, gi tract or smooth muscle of bladder or the administration of glaucomatous outbreak initial stage, perhaps also can administration behind above-mentioned PD.For example, can be in nerve degenerative diseases administration after postictal 1,2,3,4,5,6,7,8,9 or 10 hour, but be not limited to this.And administration compsn of the present invention can be used in the gravis or the glaucoma of prevention nerve degenerative diseases, gi tract or smooth muscle of bladder.Compsn of the present invention is repetitively administered as required.For example, under the situation of clinical needs, but administration every day is perhaps every at a distance from one section reasonable time, like 1～12 week, and preferred 3～8 all administrations, but be not limited thereto.
Compsn of the present invention can carry out formulationization so that promptly releasing or slowly-releasing of activeconstituents to be provided.This type formulation can be tablet, powder, pill, sachets (sachet), elixir (elixir), suspensoid, emulsion, solution, syrup, aerosol, soft or hard capsules, aseptic parenteral solution, sterilized powder etc.Compsn of the present invention can preferably provide with single dose form.
In addition, compsn of the present invention can be with " treatment significant quantity " administration." treatment significant quantity " used herein is meant the amount that is enough to treat disease/imbalance.
Be to be understood that; The treatment significant quantity of compsn should be confirmed according to various correlative factors; These factors comprise individual patient situation to be treated, age, body weight, health, reaction sensibility and sex; During diet, administration time, route of administration, excretion rate, the treatment, the seriousness of patient's symptom and with the medicine of compsn administation of combination of the present invention or administration simultaneously, and the known factor of pharmaceutical field; Therefore, above-mentioned dosage should not be construed as and limits scope of the present invention by any way.For example; Be used under the situation of the animal except that the mankind; The dosage of present composition single dose can be Unit 200～10000 (IU)/body weight (kg); Preferably Unit 200～5000 (IU)/body weight (kg), more preferably Unit 200～2000 (IU)/body weight (kg), most preferably 500～1000IU.In addition, be used for casting aside the body weight factor under the human situation, the dosage of present composition single dose can be 25000～45000IU, preferably 25000～40000IU, more preferably 30000～40000IU.
In another embodiment; The present invention relates to be used to prevent or treat gravis or the glaucomatous method of the disease/imbalance relevant with the improper minimizing of vagusstoff concentration that is caused by acetylcholine esterase active like nerve degenerative diseases, gi tract or smooth muscle of bladder, it comprises uses at least a material that is selected from down group to individuality: the pharmaceutical salts of quinone and Bu Li quinone in the thalline of the thin rhabdolith stamen of purple or cultivation extract, the cloth.
Term used herein " is used for treatment (treating) " and " treatment (treatment) " is meant disposal and prevention or guard method on the therapeutics.Therefore, need the patient of treatment to hope gravis or the glaucomatous individuality of prevention nerve degenerative diseases, gi tract or smooth muscle of bladder and the individuality of suffering from above-mentioned disease among the present invention.Term used herein " individuality " is meant the mankind, primates and some Mammals for example dog, horse, cat, sheep, pig, the ox etc. that need treatment.
In another embodiment; The present invention relates to be used to prevent or alleviate gravis or the glaucomatous heath food of the disease/imbalance relevant with the improper minimizing of vagusstoff concentration that is caused by acetylcholine esterase active like nerve degenerative diseases, gi tract or smooth muscle of bladder, it comprises at least a material that is selected from down group: the pharmaceutical salts of quinone and Bu Li quinone in the thalline of the thin rhabdolith stamen of purple or cultivation extract, the cloth.
The pharmaceutical salts that heath food of the present invention can comprise at least a thalline that is selected from the thin rhabdolith stamen of purple or cultivate quinone and Bu Li quinone in extract, the cloth separately or the material of forming with other food or food ingredient.In addition, heath food of the present invention can be used according to conventional methods.The components in proportions that contains in the food answers diaphram application target (prevention, health care or therapeutic are disposed) to confirm.Usually, when making food or beverage, the addition of quinone or its pharmaceutical salts can be 10 weight % or following, preferably 5 weight % or following in the extract of the thin rhabdolith stamen of purple, the cloth.But be adjusted to the food that purpose takes for a long time with health and can comprise the said activeconstituents that is less than above-mentioned amount.And, because there is not the problem of secure context in above-mentioned activeconstituents, therefore can use activeconstituents in the food of the present invention more than above-mentioned amount.
Above-mentioned heath food type does not have particular restriction.The example that can comprise the heath food of quinone in the thin rhabdolith stamen of purple extract, the cloth or its pharmaceutical salts has meat, sausage, bread, chocolate, carbohydrate, snack, Biscuits, Piza, hand-pulled noodles or other noodles, chewing gum class, contains ice-cream milk-product, various soup class, beverage, tea, potus, beverage and compound vitamin.Food of the present invention comprises all heath food on the ordinary meaning.
Food of the present invention is under the situation of healthy beverage, and is the same with conventional beverage, and said healthy beverage can contain various flavouring agents, natural carbohydrate etc. as added ingredients.Above-mentioned natural carbohydrate can be monose such as glucose or fructose, disaccharide such as SANMALT-S or sucrose, natural sweeteners such as dextrin, Schardinger dextrins or synthetic sweetener such as asccharin or aspartame etc.The ratio of above-mentioned natural carbohydrate is generally every 100ml healthy beverage and contains the 0.01～0.4g that has an appointment, preferably 0.02～0.03g.
Except that mentioned component, food of the present invention can further contain various nutritional supplements, VITAMINs, ionogen, seasonings, tinting material, pectic acid and salt thereof, Lalgine and salt thereof, organic acid, colloid viscosity protective material (protective colloid viscosity agent), pH regulator agent, stablizer, sanitas, glycerine, alcohols and be used for the carbonating agent of soda pop.In addition, food of the present invention can contain use pulp (pulp, fruit flesh) when making straight juice, nectar and vegetable drink.The ratio of these additives is unimportant, common per 100 weight parts food of the present invention, and the range of choice of additive is 0.01～0.1 weight part.
To the present invention be described in further detail with reference to following examples.Yet, be to be understood that to the invention is not restricted to following specific embodiment.
Embodiment 1: phycoblastus extract and lichenoid form become the preparation of fungus extract
During 2007～2008 in the South Pole, Hungary and China gathers 16 kinds of phycoblastus.In addition; Adopt Yamamoto method (Yamamoto ' s method) (Yamamoto; Y.; Mizuguchi; R. and Yamada; Y.1985. the tissue culture of red skin sunglo and Ramalina yasudae and from its culture, prepare usninic acid (Tissue cultures of Usnea rubescens and Ramalina yasudae and production of usnic acid in their cultures). agricultural and biological chemistry (Agricultural and Biological Chemistry) .49 (11): 3347-3348.) from phycoblastus, separates lichens formation fungi (lichen forming fungi, LFF), in cultivation 60 days in the MY substratum under 15 ℃.Then it is carried out drying and collects 50g phycoblastus and LFF respectively.It was extracted 3 hours this operation repetition 3 times with 1L acetone or methyl alcohol.Then acetone or methanol extract are carried out vacuum-evaporation under 40 ℃,, be diluted to 1mg/ml then with the 10%DMSO dissolving.
Embodiment 2: phycoblastus extract and lichenoid form become the AChE of fungus extract to suppress active
Suppress active in order to study the AChE that the phycoblastus extract that obtains from embodiment 1 and lichenoid form become fungi (LFF) extract, adopt (Ellman, G.E. such as Elman; Courtnery, D., Andres; V., Featherstone, R.M.; The new rapid colorimetric determination method of acetylcholine esterase active (A new and rapid colorimetric determination of acetylcholinesterase activity.), Biochem.Pharmacol.1961,7; The colourimetry of describing 88-95), with acetyl cholinesterase iodide (acetylthiocholine iodide) as substrate.At first, (10mMTris-HCl (pH 7.2) contains 1M NaCl, 50mM MgCl with 5 volumes (5vol) homogeneous damping fluid with the PC12 cell culture
2And 1%Triton X-100) at Glass-
(Terre-Haute, Ind.'s homogenizer homogenize in USA), and then with 10,000g carried out centrifugal 30 minutes.The supernatant of gained is as the enzyme source.All extraction steps are all implemented under 4 ℃ of conditions.As protein standard, (Mo. USA) measures protein concentration for Sigma Co., St.Louis to adopt bicinchoninic acid (bicinchoninic acid) test kit with bovine serum albumin.Use 96 hole microtiter plates (microtiter plate) form to utilize the percent hydrolysis of spectrophotometry monitoring AChE.Cryodesiccated extract is dissolved in 5% DMSO 99.8MIN. earlier, with solution dilution to 1,000 μ g/ml.Each extract is mixed with enzyme solution, hatched 15 minutes under 37 ℃.After in above-mentioned reaction mixture, adding the 50mM sodium phosphate buffer (pH 8.0) of Elman (Ellman) reaction mixture (0.5mM acetyl thio choline, 1mM 5,5 ' dithio two (2-nitrobenzoic acid) are (DTNB)), read the absorbancy at 405nm place at once.In order to confirm whether reaction is linear, served as interval duplicate reading 10 minutes with 2 minutes.The AChE that calculates phycoblastus extract and LFF extract suppresses active percentage, as the inhibition percentage (negative control hole) of maximum activity, and measures IC
50Repeat above-mentioned experiment 3 times, confirm IC with MV
50It is active as shown in Figure 1 that the AChE of phycoblastus extract suppresses, and it is active as shown in Figure 2 that the AChE of LFF extract suppresses.
Can know that from Fig. 1 and Fig. 2 it is about 15～35% that the AChE of phycoblastus extract suppresses activity; Except that the thin rhabdolith stamen of purple (Cladonia macilenta purple), lichenoid form becomes the AChE inhibition activity of fungus extract to be lower than 30%.When handling with the thin rhabdolith stamen of 1mg/ml purple, it is about 60% that the AChE of the thin rhabdolith stamen of purple suppresses activity.It can be used as functional material in the LFF low-purity, to have high inhibition active surface.
Embodiment 3: derive from the separation and the discriminating of quinone in the cloth of the thin rhabdolith stamen of purple extract
Extract with 1L methanol extract or its fermented liquid of ETHYLE ACETATE the thin rhabdolith stamen of purple of embodiment 1, and vacuum concentration 3 hours.At room temperature spissated extract is opened column chromatography (open column chromatography) then, obtain 10 isolates.Through MS and NMR the purple crystal in its isolate is analyzed, identified that it is quinone in the cloth (compound of Formula I).
Method through the foregoing description 2 is measured the AChE inhibition activity of quinone in the cloth.As a result, suppress to be dosage-dependency (Fig. 3).The concentration of quinone increases to 100 μ g/ml from 0 in the cloth, follows to suppress percentage and increase fast.50% enzyme suppresses IC
50Required concentration is 27.1 μ g/ml (83.1 μ M).This result shows that quinone has AChE inhibition activity in the cloth that derives from the thin rhabdolith stamen of purple extract, and can increase the amount of vagusstoff.
Embodiment 4: quinone is to the toxicity test of impaired PC12 cell in the cloth
4.1 the purchase of cell and cultivation
The PC12 cell available from Korea S clone storehouse (Korean Cell Line Bank, KCLB).These cells are cultivated in containing left-handed Stimulina (l-glutamine), 5% foetal calf serum (FBS), 10% horse serum and antibiotic growth medium RPMI-1640.Cell is placed 37 ℃, 5%CO
2In the incubator.
4.2 cell toxicity test
Test preceding 24 hours with great-hearted PC12 cell (10
4/ hole) is inoculated in the collagenic coating plate of 96-hole.Experiment same day was with quinone culturing cell in the cloth of gradient concentration (6.25,12.5,25,50 and 100 μ g/ml) 3 hours.Adopt conventional 3-(4,5-dimethylthiazole-2-yl)-2,5-phenylbenzene tetrazolium bromide (MTT) reduction method (Shi; D.H., Wu, J.H.; Ge; H.M. and Tan, R.X.2009. new acetylcholinesterase depressant hopeahainol A is to provide protection (Protective effect of hopeahainol A, a novel acetylcholinesterase inhibitor of hydrogen peroxide-induced PC12 cell injury; On hydrogen peroxide-induced injury in PC12 cells). environmental toxicology and pharmacology (Environmental Toxicology and Pharmacology), 28 (1): 30-36.) measure cell viability.0.5mg/ml MTT solution added to hatch 4 hours in the substratum.Lysing cell in DMSO through measuring absorbancy at the 570nm place with ELIASA (microplate reader) (VERSAmax, molecule instrument, California, the U.S.), carries out quantitatively the amount of MTT Jia Za.Quinone is summarized among Fig. 4 PC12 cells in vitro toxicity in the cloth.
Experimental result shows, do not have significant difference with the cell viability of the PC12 cell of quinone in the cloth (6.25,12.5,25 and 50 μ g/ml) and 0.5%DMSO co-cultivation and cell without any processing, and this shows that quinone is low to PC12 cells in vitro toxicity in the cloth.But there were significant differences with cell without any processing with the cell viability of the PC12 cell of quinone co-cultivation in the cloth of 100 μ g/ml, and this shows that quinone has in vitro toxicity to the PC12 cell in the cloth.
Embodiment 5: the oxidative stress of quinone pair cell test in the cloth
Test preceding 24 hours with great-hearted cell (10
4/ hole) is inoculated in the collagenic coating plate of 96-hole, to detect the oxidative stress of quinone in the cloth.Experiment same day was with 100 μ M DCFH-DA culturing cells 30 minutes.After removing DCFH-DA, washed cell is also hatched with the RPMI substratum.Used in the cloth of different concns (25,12.5,6.25 and 1 μ g/ml) quinone pre-treatment PC12 cell then 30 minutes.Use then or need not 200 μ M H
2O
2Handled cell 30 minutes, with the final quantitative fluorescence property of fluorescence microplate reader (SpectraMax, molecule instrument, California, the U.S.).Quinone is summarized among Fig. 5 the prevention of external oxidative stress in the cloth.
The result shows, has obviously reduced H with the pretreated cell of quinone in 12.5 μ g/ml and the 25 μ g/ml cloth
2O
2The inductive oxidative stress.
Embodiment 6: quinone is to the inhibition dynamic test of AChE in the cloth
Use is carried out dynamics research from the E.C. 3.1.1.7 of electric eel (electric eel).Use in four concentration of substrate (250,500,1000 and 2000 μ M) and two cloth quinone concentration (61 and 122 μ M) to carry out enzyme assay.Detect in the cloth quinone to the inhibition type of enzyme through two inverses (Lineweaver-Burk) mappings.The corresponding inhibitor concentration of the slope of figure or intercept has provided the K that estimates
I(suppressor factor and enzyme bonded dissociation constant) and K
IS(suppressor factor and enzyme-substrate complex bonded dissociation constant).The result is summarized among Fig. 6.
The result shows, follows quinone in the cloth of higher concentration, and the inhibition behavior of quinone has increased slope and y y-intercept in the cloth, and this shows that quinone is a kind of mixing-II suppressor factor in the cloth.K
I(204 μ M) is greater than K
IS(12.5 μ M) shows suppressor factor strong to the avidity specific ionization enzyme of enzyme-substrate complex.
Embodiment 7: quinone is to the molecular docking of electric eel (Elecyrophorus electricus) AChE in the cloth
Adopt Accelrys Discovery Studio V2.5 software to carry out molecular docking.Download high-resolution X-ray crystalline structure (the PDB code: 1C2B) of electric eel (Elecyrophorus electricus) AChE from albumen database.3-D structure through quinone molecule in Chem Office Ultra 2008 V1 Cambridge softwares drafting cloth.Then these two molecules are defined as acceptor and part respectively.Select the incorporation range (binding sphere) of acceptor from proteic reactive site.Add Wasserstoffatoms then and utilize the CHARMm field of force.Adopt LigandFit (LibDock) module that part is docked with incorporation range.All other parameters all are set to acquiescence.The interaction energy that calculates and optimize integration comprises whole energy and electrostatic energy.The butt joint conformation, the conformational analysis bonded with butt joint interacts then.
The result shows that the main binding site of quinone and AChE all is achieved through C-12O atom and the direct hydrogen bond between the OH group of the Ser203 amino-acid residue on the AChE avtive spot in the cloth.Also can form hydrogen bond (data not shown goes out) between the OH group on C-8OH group and O atom and the Tyr124 amino-acid residue.
Embodiment 8: contain the thalline of the thin rhabdolith stamen of purple or the preparation of cultivating the tablet of quinone in extract or the cloth
Component content
The thalline of the thin rhabdolith stamen of purple or cultivation extract 200mg, perhaps quinone 1mg in the cloth
W-Gum 68mg
Lactose 90mg
Microcrystalline Cellulose 40mg
Magnesium Stearate 2mg
According to the working method of conventional finishing agent (refinement), according to specifying content to add mentioned component and uniform mixing.Then, stir also prilling.Dry back use tabletting machine is produced thalline that contains the thin rhabdolith stamen of activeconstituents purple in per 1 finishing agent or the finishing agent of cultivating the expection of quinone in extract or the cloth.
Embodiment 9: contain the thalline of the thin rhabdolith stamen of purple or the preparation of cultivating the capsule of quinone in extract or the cloth
Component content
The thalline of the thin rhabdolith stamen of purple or cultivation extract 200mg, perhaps quinone 1mg in the cloth
W-Gum 68mg
Lactose 90mg
Microcrystalline Cellulose 40mg
Magnesium Stearate 2mg
According to the working method of conventional capsule, according to specifying content to add mentioned component and uniform mixing.Then, be filled in the gelatine capsule of suitable specification, make the thalline that contains the thin rhabdolith stamen of 200mg purple in per 1 capsules or cultivate quinone in extract or the 1mg cloth, produce the capsule of expection.
Embodiment 10: contain the thalline of the thin rhabdolith stamen of purple or the preparation of cultivating the chewable tablet of quinone in extract or the cloth
Component content
The thalline of the thin rhabdolith stamen of purple or cultivation extract 200mg, perhaps quinone 1mg in the cloth
Granulated sugar syrup 240mg
Spices (minty note or lemon) 2mg
W-Gum 60mg
N.F,USP MANNITOL 100mg
Magnesium Stearate 20mg
An amount of purified water
According to the working method of conventional chewable tablet, mentioned component is mixed with an amount of purified water.Then, heating for dissolving, mould is put in cooling, and the chewable tablet of production anticipated shape makes the thalline that contains the thin rhabdolith stamen of 200mg purple in per 1 or cultivates quinone in extract or the 1mg cloth.
Embodiment 11: contain the thalline of the thin rhabdolith stamen of purple or the preparation of cultivating the candy of quinone in extract or the cloth
Component content
The thalline of the thin rhabdolith stamen of purple or cultivation extract 200mg, perhaps quinone 1mg in the cloth
Granulated sugar syrup 640mg
Spices (minty note or lemon) 2mg
Starch syrup 230mg
50% tartrate 20mg
An amount of purified water
Melt in less water fully the granulated sugar syrup and after being heated to 110 ℃, to remaining melt to add in the body melt thalline that the thin rhabdolith stamen of purple is arranged or surplus water and the granulated sugar syrup of cultivating quinone in extract or the cloth.Temperature is increased to 145 ℃.Flame-out.Adding spices and tartrate mixes.After temperature is cooled to 75～80 ℃, adopt star roller (star roller) to be pressed, produce thalline that contains the thin rhabdolith stamen of purple or the candy of cultivating quinone in extract or the cloth.
Embodiment 12: contain the thalline of the thin rhabdolith stamen of purple or the preparation of cultivating the beverage of quinone in extract or the cloth
Component content
The thalline of the thin rhabdolith stamen of purple or cultivation extract 200mg, perhaps quinone 1mg in the cloth
Fruit juice concentrate 2g
Sucrose 12g
Trisodium Citrate 100mg
Spices 70mg
An amount of purified water
According to the working method of conventional beverage, according to specifying content that mentioned component is mixed with an amount of purified water.After heating and the dissolving, cooled beverage, and be filled in the container.Produce thalline that contains the thin rhabdolith stamen of 200mg purple in the beverage of per 1 bottle of 200ml capacity or the beverage of cultivating quinone in extract or the 1mg cloth thus.
Describing with above-mentioned specific embodiments when of the present invention, those skilled in the art will be appreciated that the various modifications that the present invention is carried out and change all to fall into and like enclosed in the scope of the present invention that claim limits.
Claims (7)
1. the extract that derives from the thin rhabdolith stamen of purple (Cladonia macilenta purple) thalline or its culture that has inhibiting activity of acetylcholinesterase.
2. have quinone (Biruloquinone) or its pharmaceutical salts in the cloth of the Formula I that derives from the thin rhabdolith stamen of purple of inhibiting activity of acetylcholinesterase,,
< Formula I >
3. be used to prevent or treat gravis, or the glaucomatous pharmaceutical composition of nerve degenerative diseases, gi tract or smooth muscle of bladder; It comprises at least a material that is selected from down group: the pharmaceutical salts of quinone and Bu Li quinone in the cloth of the thalline of the thin rhabdolith stamen of purple or cultivation extract, Formula I
< Formula I >
4. pharmaceutical composition according to claim 3, wherein said nerve degenerative diseases is selected from down group: Alzheimer, parkinson's disease, ischemic encephalopathy, myasthenia gravis, hypomnesis and alcohol addiction.
5. be used to prevent or treat gravis, or the glaucomatous method of nerve degenerative diseases, gi tract or smooth muscle of bladder, it comprises uses claim 3 or 4 described pharmaceutical compositions to individuality.
6. be used to prevent or alleviate gravis, or the glaucomatous heath food of nerve degenerative diseases, gi tract or smooth muscle of bladder; It comprises at least a material that is selected from down group: the pharmaceutical salts of quinone and Bu Li quinone in the cloth of the thalline of the thin rhabdolith stamen of purple or cultivation extract, Formula I
< Formula I >
7. food according to claim 6, wherein said nerve degenerative diseases is selected from down group: Alzheimer, parkinson's disease, ischemic encephalopathy, myasthenia gravis, hypomnesis and alcohol addiction.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| KR10-2009-0114401 | 2009-11-25 | ||
| KR1020090114401A KR101140583B1 (en) | 2009-11-25 | 2009-11-25 | Acetylcholinesterase inhibitors comprising the extracts of Cladonia macilenta purple or culture borth and/or biruloquinone |
| PCT/KR2010/008416 WO2011065769A2 (en) | 2009-11-25 | 2010-11-25 | Cell or culture extract of cladonia macilenta purple and/or biruloquinone as acetylcholinesterase inhibitors |
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| CN113373098B (en) * | 2021-07-28 | 2022-07-01 | 西安医学院 | Stenotrophomonas H2 strain for treating Alzheimer disease and application thereof |
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| KR100509440B1 (en) | 2003-01-14 | 2005-08-22 | 임강현 | Pharamceutical preparation comprising extract of Yak-kong (Rhynchosia nolubilis) for Alzheimer's disease, dementia, amyosthenia of smooth muscle, and glaucoma |
| KR100550358B1 (en) | 2005-05-20 | 2006-02-08 | 임강현 | Food product and feed product comprising extract of Yak-kong (Rhynchosia nolubilis or Rhynchosia volubilis) for Alzheimer's disease, dementia, amyosthenia of smooth muscle, and glaucoma |
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Non-Patent Citations (3)
| Title |
|---|
| GULIJIAHAN: "Research Progress on Biological Activites of Lichens Secondary Metabolites", 《食品科学》 * |
| LUO: "Aceltycholinesterase inhibitor from secondary metabolites of lichen forming fungi Cladonia macilenta", 《THE 8TH ANNUAL MEETING OF THE JAPANESE SOCIETY FOR LICHENOLOGY》 * |
| PODTEROB: "Chemical composition of lichens and their medical applications", 《PHARMACEUTIAL CHEMISTRY JOURNAL》 * |
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