CN104490865A - Medical application of amentoflavone - Google Patents
Medical application of amentoflavone Download PDFInfo
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- CN104490865A CN104490865A CN201510003146.6A CN201510003146A CN104490865A CN 104490865 A CN104490865 A CN 104490865A CN 201510003146 A CN201510003146 A CN 201510003146A CN 104490865 A CN104490865 A CN 104490865A
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- amentoflavone
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- parkinsonian
- prodrug
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Abstract
The invention relates to the field of medicine and pharmacology, and in particular relates to a medical application of amentoflavone and a medicinal composition thereof. The amentoflavone provided by the invention can be used for preparing medicaments or health products for preventing and curing Parkinson's disease.
Description
Technical field
The present invention relates to Medicines and Health Product field, particularly relate to a kind of medical usage and pharmaceutical composition thereof of amentoflavone.
Background technology
Parkinson disease (Parkinson's disease, PD), have another name called paralysis agitans, are mainly in middle-aged and elderly people, are the common neurodegenerative diseases of a class.Infer itself and brain bottom substrate core and black substance brain cell fast degradation, cannot produce enough neural guidance dopamine strengthens relevant with choline effect, its pathological characteristic is the handicapped chronic degenerative sexual maladjustment of central nervous system's extrapyramidal system, drops to key feature with substantia nigra of midbrain compact part dopaminergic neuron Progressive symmetric erythrokeratodermia degeneration disappearance, striatal dopamine energy level.Different from parkinson disease, stages alzheimer's disease (AD) i.e. senile dementia is a kind of persistence higher nerve functional activity obstacle, it is the most general origin cause of formation of dementia, its major pathologic features is atrophy of cerebral cortex, and reduces and the formation of senile plaque with amyloid-beta deposition, neurofibrillary tangles, mass memory neuron number.Have difference in essence based on above-mentioned two kinds of neurodegenerative diseases, those skilled in the art generally believes: a kind of medicine can treat AD and can it treat between PD and there is no necessary connection.
Parkinson disease incidence of occult, course advancement is slow, clinical main manifestations is the motor symptomses such as static tremor, bradykinesia, myotonia and posture gait disorder, and some patients can with non-athletic symptoms such as hyposmia, autonomic nervous function imbalance, sleep disorder, cognitive impairments, quality of life is badly damaged, and finally causes losing self care ability.
Current research is thought, parkinson disease are the coefficient results of many factors, after the middle age, to the individuality of environmental toxin susceptible, after touching toxin, because of its function of detoxification obstacle, occur that subclinical black substance damages, and increase the weight of with advancing age, the gradual continuous dead degeneration of dopaminergic neuron, the Parkinsonian clinical symptoms of final appearance.Just find that the false heroin of synthesis (MPTP) is poisonous as far back as Langston, Ballard and Burns in 1984, black substance brain cell can be endangered by selectivity, the mitochondrion of dopamine neuron is poisoned to death, and produce parkinson disease.The Parkinson disease model of inducing with regard to this MPTP is in the industry cycle extensively approved then.In fact, the parkinson disease laboratory animal of MPTP and 6-OH Induced by Dopamine and isolated cells model are also uniquely by the large classical model of industry confessed two in the research of current antiparkinsonism drug.
Treatment parkinson disease, mainly with the signal transduction obstacle that medicine goes supplementary dopamine or treatment to cause because of dopamine deficiency in brain, comprise levodopa amine (usually combining dopa decarboxylase inhibitor or COMT inhibitor), dopamine agonist both at home and abroad at present.Cholinergic antagonist or amantadine have good therapeutic effect on the motor complication such as to tremble in addition.But after Long-term taking medicine, neuron reduces drug susceptibility in brain, the appearance of " unusual fluctuation disease " or " drug effect fluctuation " may be caused.Such as " agent end is worsened " or title " on-off phenomenon ", namely duration of efficacy shortens, before taking medicine next time, just return to the parkinson disease morbid state without drug effect ahead of time, need to adjust dosage frequency, use levodopa controlled release agent instead, DR agonist increase long half-lift or increase MAO-B inhibitor etc. reduce the puzzlement of middle and late stage sufferer to curative effect instability.And except Drug therapy, also operative treatment can be considered, as dark brain stimulation art (DeepBrain Stimulation), pale core cautery (Pallidotomy), duodenum dopamine are inculcated art (DuoDopa) etc. and treated for using the not good patient of effect of drugs.Function treatment, naturopathy and speech therapy etc. can recover holding function for patient and language, function of deglutition are offered help.Reasonable selection medicine and physical therapy can control or alleviate motor complication, prevent insecondary dysfunction, but existing medical skill temporarily can't effect a radical cure parkinson disease.
Amentoflavone (Amentoflavone, AF) is the active monomer component that in Herba Selaginellae, separation and Extraction obtains, and research shows: amentoflavone has the effects such as antiinflammatory, antitumor, radioprotective, scavenging free radicals.
Summary of the invention
Object of the present invention aims to provide a kind of new medical usage and pharmaceutical composition thereof of amentoflavone.
Specifically, a first aspect of the present invention there is provided amentoflavone or the application in the preparation parkinsonian medicine of control or health product of its pharmaceutically acceptable salt, hydrate or prodrug.
In a preference, described amentoflavone is applied in the preparation of the parkinsonian medicine of control or health product as unique active component.
A second aspect of the present invention there is provided one can prevent and treat parkinsonian pharmaceutical composition, and it comprises amentoflavone or its pharmaceutically acceptable salt, hydrate or the prodrug for the treatment of effective dose.
A third aspect of the present invention there is provided one can prevent and treat parkinsonian health product, and it includes amentoflavone or its pharmaceutically acceptable salt, hydrate or the prodrug of effective amount.
The details of various aspects of the present invention is able to detailed description by chapters and sections subsequently.By hereafter and the description of claim, feature of the present invention, object and advantage will be more obvious.
Accompanying drawing explanation
Fig. 1. amentoflavone is to MPP
+impact (* *, the P<0.01 for the treatment of S H-SY5Y cell viability; * *, P<0.001; Positive drug: baicalin, Baicalein).
Fig. 2. amentoflavone induces impact (*, the P<0.05 of mouse model of Parkinson's disease Substantia Nigra gene expression to MPTP; *, P<0.01; * *, P<0.001; Amentoflavone, AF; Positive drug: madopar, Madopar)
Fig. 3. amentoflavone significantly regulates MPTP to induce protein expression (*, the P<0.05 of mouse model of Parkinson's disease Substantia Nigra; *, P<0.01; * *, P<0.001; Amentoflavone, AF; Positive drug: madopar, Madopar).
Detailed description of the invention
Appearance part of the present invention is based on so unexpected discovery: amentoflavone induces parkinson mouse model midbrain dopaminergic neuron to have protective effect to MPTP; MPP can be alleviated
+the apoptosis of induction and cellular morphology change; And namely the key molecule that can regulate and control Neuron Apoptosis path is further lowered the expression of Bax gene, is raised the expression of TH gene and Bcl-2 gene.Point out its using value in parkinson disease, be expected to be developed as the Parkinsonian medicine of control and health product.
And then a first aspect of the present invention there is provided amentoflavone or the application in the preparation parkinsonian medicine of control or health product of its pharmaceutically acceptable salt, hydrate or prodrug.
Preferably, described amentoflavone is applied in the preparation of the parkinsonian medicine of control or health product as unique active component.
A second aspect of the present invention there is provided one can prevent and treat parkinsonian pharmaceutical composition, and it comprises amentoflavone or its pharmaceutically acceptable salt, hydrate or the prodrug for the treatment of effective dose.
A third aspect of the present invention there is provided one can prevent and treat parkinsonian health product, and it includes amentoflavone or its pharmaceutically acceptable salt, hydrate or the prodrug of effective amount.
As known to persons skilled in the art, amentoflavone (Amentoflavone, AF) of the present invention has following general structure:
Molecular formula: C
30h
18o
10molecular weight: 538.46
The present invention also comprises all accordingly pharmaceutically acceptable salt of above-claimed cpd, hydrate or prodrug.These salt can be formed by part (such as, amido) positively charged in compound and electronegative (such as, the trifluoracetic acid) with opposite-sign; Or formed by part (such as, carboxyl) electronegative in compound and positive charge (such as, sodium, potassium, calcium, magnesium).Compound can contain a nonaromatic double bond, has one or more asymmetric center.So these compounds can exist as racemic mixture, independent enantiomer, independent diastereomer, non-enantiomer mixture, cis or transisomer.All these isomers are all expected.Described " prodrug of amentoflavone " is often referred to a kind of material, after using by suitable method, can carry out metabolism or chemical reaction and be transformed into amentoflavone or its salt in subject.
Amentoflavone of the present invention can be separated and prepare from the plants such as Herba Selaginellae; Or bought by commercial sources and obtain, its purity all meets medicinal standard; Or utilize marketable material, obtained by compou nd synthesis method traditional in prior art synthesis.Those of ordinary skill in the art can synthesize compound of the present invention according to existing known technology.The compound of synthesis can be further purified further by modes such as column chromatography, high performance liquid chromatography or crystallizations.
Synthetic chemistry transformation, protection functional group methodology (protect or go protection) are helpful to synthesis application compound, and be technology commonly known in the art, as R.Larock, Comprehensive Organic Transformations, VCHPublishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 3
rded., John Wiley and Sons (1999); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for OrganicSynthesis, John Wiley and Sons (1994); And L.Paquette, ed., Encyclopedia of Reagents for OrganicSynthesis, has open in John Wiley and Sons (1995).
So that amentoflavone of the present invention is made medicine.Amentoflavone of the present invention can be used alone or uses with the form of pharmaceutical composition.Pharmaceutical composition comprises amentoflavone of the present invention as active component and pharmaceutically suitable carrier.Preferably, pharmaceutical composition of the present invention contains the amentoflavone of the present invention as active component of 0.1 ~ 99.9% percentage by weight." pharmaceutically suitable carrier " can not destroy the pharmaceutical active of amentoflavone of the present invention, simultaneously its effective dose, and consumption when can play pharmaceutical carrier effect is to human non-toxic.
Described pharmaceutically suitable carrier includes but not limited to: soft phospholipid, aluminium stearate, aluminium oxide, ion exchange material, self-emulsifying drug delivery system, tween or other surfactants, serum albumin, buffer substance are if phosphate, glycine, sorbic acid, water, salt, electrolyte are as sulfate protamine, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, magnesium silicate, satisfied fatty acid partial glyceride mixtures etc.
Other conventional excipient substances are as binding agent (as microcrystalline Cellulose), filler (as starch, glucose, Lactis Anhydrous and lactose beadlet), disintegrating agent (as cross-linked pvp, crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose), lubricant (as magnesium stearate) and absorption enhancer, absorption carrier, flavouring agent, sweeting agent, excipient, diluent, wetting agent etc.
Amentoflavone of the present invention and its pharmaceutical composition can by the preparations of this area conventional method and can by intestinal or non-bowel or topical routes.Oral formulations comprises capsule, tablet, oral liquid, granule, pill, powder, sublimed preparation, unguentum etc.; Non-intestinal drug delivery agent comprises injection etc.; Local administration preparation comprises cream, patch, ointment, spray etc.Be preferably oral formulations.
The route of administration of amentoflavone of the present invention and its pharmaceutical composition can be oral, Sublingual, through muscle or subcutaneous, vein, urethra, vagina etc.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, the usually conveniently conditioned disjunction condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percent, ratio, ratio or number by weight.
Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art the same meaning be familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
The above-mentioned feature that the present invention mentions, or the feature that embodiment is mentioned can combination in any.All features that patent specification discloses can with any composition forms and use, each feature disclosed in description, anyly can provide identical, alternative characteristics that is impartial or similar object replaces.Therefore apart from special instruction, the feature disclosed is only general example that is impartial or similar features.
Embodiment 1 amentoflavone treats parkinsonian activity research
1.SH-SY5Y cell culture
SH-SY5Y cell culture is in the DMEM culture medium (100UmL containing 10% hyclone
-1penicillin and 100 μ gmL
-1streptomycin), 37 DEG C, 5%CO
2cultivate and subculture in incubator.
2.MTT method detects cytoactive
Take the logarithm trophophase SH-SY5Y cell with 1 × 10
5individual/mL concentration is inoculated in overnight incubation in 96 orifice plates.In experiment after amentoflavone (10,25,50,75,100 μMs) pretreatment 4h, add the MPP of 1mM
+effect 24h.Then every hole adds the MTT solution continuation cultivation 4h of 10 μ L containing 5g/L, and every hole adds 150 μ L DMSO and fully vibrates, and measures the absorbance at 570nm place, quantitative response cell survival rate after blue particle dissolves completely by full-automatic microplate reader.
3. animal model foundation and grouping administration
48 C57BL/6 male mices, in 12 week age, are divided into 4 groups at random, often organize 12, are respectively matched group, model group, amentoflavone administration group (50mgkg
-1) and positive drug madopar group (50mgkg
-1).Continuous gavage 15 days, 1h lumbar injection MPTP 30mgkg before starting gavage in the 11st day
-1(matched group gives equal-volume normal saline), continuous 5 days, last administration was put to death one day after, is drawn materials.
4. real-time quantitative PCR gene expression detection
Total serum IgE is extracted from mice Substantia Nigra, Nanodrop protein nucleic acid analysis-e/or determining RNA concentration by Trizol method.Get 2 μ g total serum IgE, Reverse Transcription box (Thermo) is reversed into cDNA.By above-mentioned transcription product cDNA, use ddH
2o presses as template after 1:5 dilution proportion, and carry out real-time quantitative PCR reaction, detect TH and Bcl-2 gene expression in Substantia Nigra, reference gene selects GAPDH, and primer sequence is as shown in table 1.PCR reaction condition is as follows: after 95 DEG C of denaturation 30sec, carries out 95 DEG C of 5sec degeneration, 60 DEG C of 30sec annealing, totally 40 circulations.
Table 1 mice PCR primer sequence
5.Western blot method detects protein expression
Mice Substantia Nigra tissue homogenate, adds 250 μ l lysates (inhibitors of phosphatases and protease inhibitor containing 1%)
Ultrasonic, on ice after cracking 30min, 12000rpm, 4 DEG C of centrifugal 15min.Get supernatant, BCA method measures protein concentration.Get 30 μ g samples respectively, carry out SDS-PAGE electrophoresis.After electrophoresis terminates, wet method transferring film 1h, 1h closed by 5% skim milk, hatch corresponding primary antibodie (antibody dilution carries out with reference to description) respectively, 4 DEG C of overnight incubation, then resist with the goat anti-mouse of HRP labelling and two of goat antirabbit respectively and hatch, room temperature shaking table 1h, finally with the colour developing of ECL-prime test kit, dark place exposure, developing and fixing.
Result:
1. amentoflavone is to MPP
+the impact of the SH-SY5Y cell viability of process
As shown in Figure 1A, MTT causes SH-SY5Y cell survival rate to drop to 66.2% after detecting and finding MPP+ effect 24h, and after amentoflavone pretreatment 4h, (50,75,100 μMs) obviously suppress MPP
+the cell injury caused, and rely in doses; Morphological observation shows, SH-SY5Y cell is at MPP
+under effect, in obvious shrinkage and apoptosis, amentoflavone and positive drug baicalin then obviously can suppress MPP
+the apoptosis (Figure 1B) caused.Further, amentoflavone effective dose concentration will lower than positive drug baicalin.
2. amentoflavone induces the impact of parkinson mice Substantia Nigra gene expression on MPTP
As shown in Figure 2, compared with blank group, MPTP process significantly can lower the gene expression of mice Substantia Nigra TH (P<0.001) and Bcl-2 (P<0.001); Through 50mgkg
-1after amentoflavone process, the expression of mice Substantia Nigra TH (P<0.05) and Bcl-2 (P<0.05) gene is significantly raised.Further, its rise TH gene (P<0.05) and Bcl-2 gene expression effect are better than positive drug madopar.
3. amentoflavone significantly regulates MPTP to induce the protein expression of parkinson mice Substantia Nigra
As shown in Figure 3A, compare with matched group, in disease model mice Substantia Nigra, bring out Bax and increase the reduction with Bcl-2 after MPTP process, the ratio of the expression of Bcl-2 and Bax significantly declines (P<0.01); Corresponding, the expression of Substantia Nigra TH significantly declines (Fig. 3 B, P<0.01).After amentoflavone process, animal pattern Substantia Nigra Bax increases and is significantly suppressed with the reduction of Bcl-2, the ratio of Bcl-2 and Bax significantly rises (P<0.05), and TH expression also significantly raises (P<0.05) simultaneously.With the contrast of positive drug group, the TH cytoprotection of amentoflavone obviously (P<0.05).
Conclusion:
This research proves that amentoflavone induces parkinson mouse model midbrain dopaminergic neuron to have protective effect to MPTP by experiment; MPP can be alleviated
+the apoptosis of induction and cellular morphology change; And namely the key molecule that can regulate and control Neuron Apoptosis path is further lowered the expression of Bax gene, is raised the expression of TH gene and Bcl-2 gene.Point out its using value in parkinson disease, be expected to be developed as the Parkinsonian medicine of control.
Many aspects involved in the present invention have been done and have as above been set forth.It is to be understood, however, that put before not departing from spirit of the present invention, those skilled in the art can carry out equivalent change and modification to it, and described change and modification fall into the coverage of the application's claims equally.
Claims (4)
1. amentoflavone or the application in the preparation parkinsonian medicine of control or health product of its pharmaceutically acceptable salt, hydrate or prodrug.
2. apply as claimed in claim 1, it is characterized in that, described amentoflavone is applied in the preparation of the parkinsonian medicine of control or health product as unique active component.
3. can prevent and treat a parkinsonian pharmaceutical composition, it is characterized in that, it comprises amentoflavone or its pharmaceutically acceptable salt, hydrate or the prodrug for the treatment of effective dose.
4. can prevent and treat parkinsonian health product, it is characterized in that, it includes amentoflavone or its pharmaceutically acceptable salt, hydrate or the prodrug of effective amount.
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|---|---|---|---|
| CN201510003146.6A CN104490865A (en) | 2015-01-04 | 2015-01-04 | Medical application of amentoflavone |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510003146.6A CN104490865A (en) | 2015-01-04 | 2015-01-04 | Medical application of amentoflavone |
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| CN104490865A true CN104490865A (en) | 2015-04-08 |
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| CN201510003146.6A Pending CN104490865A (en) | 2015-01-04 | 2015-01-04 | Medical application of amentoflavone |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101361733A (en) * | 2008-09-17 | 2009-02-11 | 暨南大学 | Use of flavone derivates and preparation method thereof |
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2015
- 2015-01-04 CN CN201510003146.6A patent/CN104490865A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101361733A (en) * | 2008-09-17 | 2009-02-11 | 暨南大学 | Use of flavone derivates and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| I.O. ISHOLA ET AL.: "Evaluation of amentoflavone isolated from Cnestis ferruginea Vahl ex DC (Connaraceae) on production of inflammatory mediators in LPS stimulated rat astrocytoma cellline(C6) and THP-1 cells", 《JOURNAL OF ETHNOPHARMACOLOGY》 * |
| MUTHUSAMY JEYAM ET AL.: "MOLECULAR UNDERSTANDING AND INSILICO VALIDATION OF TRADITIONAL MEDICINES FOR PARKINSON’S DISEASE", 《ASIAN JOURNAL OF PHARMACEUTICAL AND CLINICAL RESEARCH》 * |
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Application publication date: 20150408 |