CN104095849A - Multiple-target effects of isoflavone derivative and its application in improvement of learning and memory - Google Patents
Multiple-target effects of isoflavone derivative and its application in improvement of learning and memory Download PDFInfo
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Abstract
The invention discloses multiple-target effects of an isoflavone derivative and its application in improvement of learning and memory. Specifically, the invention discloses that a compound J39136 has the effects of: upregulating the expression of SIRT1 protein with damage repair and neuroprotective effects; inhibiting the activity of acetylcholinesterase and butyrylcholinesterase, and dose-dependently inhibiting the acetylcholinesterase activity of cells under a safe dose; protecting nerve cells, inhibiting abnormal expression of beta-APP, and reducing Abeta1-42 secretion; and regulating neuroinflammation. Animal experimental results prove that J39136 has low toxicity, can penetrate the blood-brain barrier, and can significantly improve scopolamine caused mouse dementia and strengthen learning and memory functions. Preclinical study results prompt that J39136 is expected to become the drug for prevention and/or treatment of learning and memory disorder and Alzheimer's disease.
Description
Technical field
The present invention relates to there is dual choline esterase inhibition, the natural product derivant of neurocyte protection effect, antiinflammatory action, and the application of this compound in treatment/prevention learning memory disorder and senile dementia.Belong to medical technical field.
Technical background
Alzheimer (Alzheimer ' s disease, AD) be a kind of central nervous system degenerative disease taking behavior, cognition and memory dysfunction as Clinical symptoms, its characteristic pathological change is: neuron loss, neurofibril twine (neurofibrillary tangles, NFTs), senile plaque (senile plaques, SPs).65-74 year crowd's AD sickness rate is about 3%, and 75-84 year crowd's sickness rate can rise to 19%, and more than 84 years old crowd's AD sickness rate can be up to 47%.AD is the fourth-largest killer after elderly population relaying cardiovascular diseases, tumor, cerebrovascular, serious harm elderly population health.Along with population in the world aging trend is on the rise, if there is no effective intervening measure, the AD patient in the whole world will reach 100,000,000 the year two thousand fifty, and medical system is had an immense impact on.Therefore, research and development associated treatment medicine is significant.
The pathogenesis complexity of AD, the many factors such as h and E play a role in its progression.Change according to the multiple pathological biochemistry in AD pathological changes process, produced multiple AD pathology hypothesis, as cholinergic hypothesis, A beta hypothesis, poisoning by aluminum hypothesis, cholesterol transformant doctrine, the impaired hypothesis of calcium channel, inflammatory reaction hypothesis etc.According to the pathological characters of senile dementia and pathogenesis, the treatment approach of taking for old dementia patients comprises: (1) improves the medicine of choline systemic-function.(2) correct calcium homeostasis imbalance and antioxidative medicine.(3) neurotrophic factor.(4) medicine that disturbs A β to form and deposit.(5) anti-neuronal apoptosis agent.
Cholinergic system plays a significant role in learning and memory process.Research since the seventies shows: in AD patient's brain, have many-sided Cholinergic decline, thereby proposed the cholinergic hypothesis (cholinergic hypothesis) of the AD cause of disease: central cholinergic system dysfunction causes AD patient's cognitive decline.According to cholinergic hypothesis, strengthen the medicine of Cholinergic, can be used for the treatment of AD.Improving acetyl choline content by cholinesterase inhibitor (cholinesterase inhibitor, ChEI), strengthen cholinergic nerve meta function, is the Main Means for the treatment of at present AD.
Clinical conventional ChEI mostly is selectivity acetylcholinesterase (acetylcholinesterase, AChE) inhibitor at present, can improve patient's cognitive function, raising patient and ward's quality of life.But also there is certain untoward reaction, undesirable to the treatment of serious symptom AD.Butyrylcholine esterase (butyrylcholinesterase, BuChE) all has distribution at maincenter and periphery, because the physiological function of BuChE is always indefinite, to the affinity of acetylcholine (acetylcholine, ACh) lower than AChE.Think for a long time the target spot that is not used as AD treatment.But not only alternative AChE hydrolysis ACh of BuChE is found in research in recent years, also has effect in AD process, and BuChE can be considered a novel targets of AD treatment.
Research is found, silent message regulatory factor 2 relevant enzyme 1 (sirtuin1, Sirt1) high expressed in mammal cerebral tissue, under different nervous tissue's structures and physiological status, its expression is inconsistent, prompting Sirt1 participates in function of nervous system's activity adjustment ［ Ramadori G et al.Brain SIRT1:anatomical distribution and regulation by energy availability.J Neurosci.2008,28 (40): 9989-9996 ］.Sirt1 grows in Neural Differentiation, injury repairing, neuroprotective aspect plays a significant role, Sirt1 can resist dorsal root ganglion aixs cylinder Hua Le (family name) degeneration, the Rho kinase expression of inhibitory neuron cell, increase α secretase activity, promote amyloid protein precursor degraded, also the Sirt1 that finds high expressed in the CR of Mus model can reduce amyloid beta, alleviate AD symptom ［ Jun Gao et al.A novel pathway regulates memory and plasticity via SIRT1and miR-134.Nature.2010, 466 (26): 1105-1109.. ］.Therefore, in highly active people SIRT1 gene expression, adjust and will become the anti-AD medicine of novel development prospect.
Recent study shows, microglia (microglia, MG) plays a part " double-edged sword " in AD europathology changes.On the one hand, the MG of activation can pass through phagocytosis, removes amyloid beta (amyloid beta protein, A β), thereby reduces A β to neuronic toxic action; On the other hand, overactive MG can produce a large amount of inflammatory mediators, as TNF-α, IL-1 β etc., and the formation of these inflammatory mediator induction chronic inflammatory reactions, and then accelerate development and the deterioration of AD.Therefore, using MG as target, research and develop relative anti-inflammatory drug, for significant [the Teeling JL of control AD, Perry VH.Systemic infection and inflammation in acute CNS injury and chronic neurodegeneration:underlying mechanisms.Neuroscience, 2009,158 (3): 1062-1073].
AD pathogenesis is not monistic, except cholinergic damage, also relate to factors, as nerve injury, neural inflammation, therefore single target drug is difficult to obtain desirable therapeutic effect, and the medicine that design and development have multiple target effect will become the available strategy of antagonism AD.
Summary of the invention
The technical problem to be solved in the present invention is, provide compound (J39136) as shown in the formula (I) preparation prevention and or treatment treatment neurodegenerative diseases medicine in application
Application during J39136 adjusts in the highly active people SIRT1 of preparation gene expression.
The application of J39136 in preparation second, butyrylcholine esterase double inhibition drugs with function.
J39136 is preparing neuroprotective cell, improve the application in A β Developmental and Metabolic Disorder medicine.
J39136 regulates the application in neuritis's disease drug in preparation.
J39136 improves the application in learning and memory function medicine in preparation.
For completing object of the present invention, can adopt following technical scheme:
1.J39136 is the rise effect to people SIRT1 gene expression at cellular level
The Dominant Plat adjusted in people SIRT1 gene expression based on having set up, has detected the rise effect of tens thousand of compounds to people SIRT1 gene expression.Primary dcreening operation and sieve again result and show, J39136 can obviously raise SIRT1 gene expression.
The 2.J39136 inhibitory action research of level to second, the activity of BuChE in vitro
Acetylcholinesteraseinhibitors inhibitors based on having set up and the Dominant Plat of butyrylcholinesterase inhibitor, detected more than 100,000 compound.Found that, J39136 all has significant inhibitory action to second, butyrylcholine esterase.
3.J39136 to the inhibitory action research of cell acetylcholine esterase active
Detected the impact of J39136 on neurocyte cell viability and acetylcholine esterase active, result shows the acetylcholine esterase active of the inhibition cell that J39136 can dose dependent in the situation that not affecting the nerves cell viability.
The effect research of 4.J39136 on AD cell model
(1) detect the impact of J39136 on cell viability in AD cell model, result shows that J39136 can improve cell survival rate, the effect of performance neurocyte protection.
(2) detect the impact that J39136 expresses β in cell in AD cell model-APP, result shows that J39136 can suppress the pathogenic unconventionality expression that stimulates lower β-APP.
(3) detect the impact of J39136 on cell A β 1-42 secretion in AD cell model, result shows that J39136 can suppress the pathogenic abnormal rising that stimulates lower A β 1-42 secretion
5.J39136 to the effect research of neural inflammation
Detect J39136 on neural Activated Microglia after the impact that discharges of the related inflammatory factor, result shows that J39136 can effectively suppress the release of inflammatory factor.
6.J39136 the research on AD animal model
Detect J39136 causes learning memory disorder mouse model improvement effect to scopolamine, result shows that J39136 can effectively improve the damage in learning and memory of model mice.
The present invention shows that J39136 has good people SIRT1 gene expression rise effect, second, the effect of butyrylcholine esterase double inhibition, and neuroprotective cell, regulates neural inflammation, can effectively improve learning and memory function in whole animal level.
Brief description of the drawings
Fig. 1, J39136 have concentration dependent to people SIRT1 gene expression rise effect, and its EC50 is 2.07ug/ml.
Fig. 2, J39136 suppress the amount effect curve of AChE, BuChE
Fig. 3, the J39136 impact on SY5Y cell viability
Fig. 4, the J39136 impact on SY5Y cell AChE activity
Fig. 5, the J39136 impact on APPsw-SY5Y cell viability
Fig. 6, the J39136 impact on APPsw-SY5Y cell AChE activity
Fig. 7, J39136 are to Cu
2+the impact of the APPsw-SY5Y cell injury model cell vigor of induction
Fig. 8, J39136 are to Cu
2+the impact that the APPsw-SY5Y cell injury model β-APP of induction expresses
Fig. 9, the J39136 impact on A β 1-42 content in APPsw-SY5Y cell conditioned medium liquid
The impact of Figure 10,39136 on activation microglia IL-1 β secretion
Figure 11, the J39136 impact on activation microglia IL-6 secretion
Figure 12, J39136 be the impact on learning and memory in diving tower experiment
Figure 13, J39136 are keeping away the impact on learning and memory in dark experiment
Figure 14, J39136 be the impact on learning and memory in water maze laboratory
Detailed description of the invention
Embodiment 1, the J39136 rise effect research of cellular level to people SIRT1 gene expression in vitro
Method: utilize the cell strain of stable transfection people SIRT1 gene promoter reporter gene, expressing luciferase under medicine irritation, the relevant numeral of absorbing amount for uciferase activity (relative luminous unit, RLU).5 μ l screening samples (final concentration is 10 μ g/ml) are added in the cell of stable transfection in 384 orifice plates, hatch after 24 hours, abandon pastille culture supernatant, add containing ONE-Glo
tMthe serum-free medium 10 μ l of Luciferase Assay System (Promega, U.S.A.) reaction reagent, vibrate 3 minutes, and M5 detects luminous value.Rise rate (%)=A/Bx100, wherein, A adds the cell fluorescence element enzymatic activity (RLU) of measuring after testing sample, and B is for adding the cell fluorescence element enzymatic activity (RLU) of measuring after blank sample (0.1%DMSO).What the rise rate of testing sample was 200% is considered as the primary dcreening operation positive, enters next step screening after replication.
Result: primary dcreening operation final concentration 10ug/ml, result shows that J39136 reaches 450% to the rise rate of people SIRT1 gene expression, positive control drug rise rate is only 172%.Multiple sieve is established 5 Concentraton gradient, and final concentration is respectively 50ug/ml, 10ug/ml, and 2ug/ml, 0.4ug/ml, 0.08ug/ml, in triplicate, carries out dose-effect analysis, EC
50for 2.07ug/ml, the results are shown in Figure 1.
Embodiment 2, J39136 in vitro molecular level to ACHE, the inhibitory action research of BuCHE activity
Method: utilize DTNB method to set up AChE inhibitor screening model and BuChE inhibitor screening model, J39136 is evaluated the inhibition activity of AChE, BuChE when the 0.08-50 μ mol/L, and calculate IC
50.In triplicate, computation of mean values and SD value.
Result: J39136 suppresses the IC of AChE, BuChE activity
50all, lower than 10 μ mol/L, suppress the IC of BuChE activity
50approach positive control tetramethyl isopropyl pyrophosphoric acid amine (iso-OMPA, selectivity butyrylcholinesterase inhibitor), far below marketed drugs donepezil (selectivity acetylcholinesteraseinhibitors inhibitors).
Table 1J39136 suppresses the IC of ACHE/BuCHE activity
50
Embodiment 3, the J39136 inhibitory action research to neurocyte AChE activity
Method 1:SY5Y cell is with containing the DMEM/F12 culture medium culturing of 10% hyclone, until cell during in exponential phase, by 5*10
4individual/ml, the density in 100ul/ hole is inoculated in 96 well culture plates.After 24h, change the culture medium culturing with serum-free DMEM/F12, after 12h, change the serum-free DMEM/F12 culture medium with variable concentrations J39136 (0.3-10 μ mol/L), donepezil and Exelon (final concentration is 10 μ mol/L) are processed identical, after 24h, MTS method is measured cell viability, and DTNB method detects AChE activity in cell conditioned medium.
Result: compared with normal group, J39136 does not make significant difference to cell viability within the scope of administration concentration, positive control donepezil administration group cell viability significantly reduces (p < 0.05).J39136 can dose dependent the AChE activity of inhibition SY5Y cell.
The impact of table 2J39136 on SY5Y cell viability
The impact of table 3J39136 on SY5Y cell AChE activity
#with relatively P<0.05 of normal group,
##with relatively P<0.01 of normal group
Method 2: wild type APPsw transgenic SY5Y (APPsw-SY5Y) cell is with containing 10% hyclone, the DMEM/F12 culture medium culturing of 400ug/ml G418, until cell during in exponential phase, by 5*10
4individual/ml, the density in 100ul/ hole is inoculated in 96 well culture plates.After 24h, change the culture medium culturing with serum-free DMEM/F12, after 12h, change the serum-free DMEM/F12 culture medium with variable concentrations J39136 (0.3-10 μ mol/L), donepezil and Exelon (final concentration is 10 μ mol/L) are processed identical, after 24h, MTS method is measured cell viability, and DTNB method detects AChE activity in cell conditioned medium.
Result: compared with normal group, J39136 does not make significant difference to cell viability within the scope of administration concentration, the AChE activity of inhibition APP-sw SY5Y cell that can dose dependent.
The impact of table 4J39136 on APP-sw SY5Y cell viability
The impact of table 5J39136 on APP-sw SY5Y cell AChE activity
#with relatively P<0.05 of normal group,
##with relatively P<0.01 of normal group
Embodiment 4, the J39136 effect research on AD cell model
Method: APPsw-SY5Y cell is with the DMEM/F12 culture medium culturing containing 10% hyclone, 400ug/ml G418, until cell during in exponential phase, by 5*10
4individual/ml, the density in 100ul/ hole is inoculated in 96 well culture plates.After 24h, change with serum-free DMEM/F12 culture medium and continue to cultivate 12h, after adding final concentration to be the J39136 of 10,3,1 μ mol/L and the donepezil of 10 μ mol/L, Exelon preincubate 2h, adding final concentration is the Cu of 200 μ mol/L
2+process cell, after 24h, measure A β 1-42 content in cell viability, cellular immunofluorescence method detection cell β-APP expression, Elisa method mensuration cell conditioned medium liquid with MTS method respectively.
Result:
1) compared with normal group, Cu
2+process after 24h, model group cell survival rate significantly reduces (p < 0.01).Compared with model group, the each dosage group of J39136 cell survival rate is improved, and the J39136 of 10 μ mol/L can significantly improve cell survival rate (P < 0.05).J39136 can dose dependent in 1-10 μ mol/L dosage range antagonism Cu
2+to the toxic action of cell.
Table 6J39136 is to Cu
2+the impact of the APPsw-SY5Y cell injury model cell vigor of induction
##with relatively P<0.01 of normal group,
*with relatively P<0.05 of model group
2), compared with normal group, the average fluorescent strength of model group cell β-APP significantly strengthens (p < 0.01).J39136 can significantly reduce the fluorescence intensity (p < 0.05) of β-APP in the time of 10 μ mol/L, in the concentration range of 1-10 μ mol/L, the fluorescence intensity of β-APP raises and reduces with the concentration of J39136, and the inhibition Cu that J39136 can dose dependent is described
2+β-the APP of induction expresses rising.
Table 7J39136 is to Cu
2+the impact that the APPsw-SY5Y cell injury model β-APP of induction expresses
##with relatively P<0.01 of normal group,
*with relatively P<0.05 of model group
3) compared with normal group, the content of A β 1-42 significantly raise (p < 0.01) in model group cell conditioned medium liquid.Compared with model group, J39136 in the time of 10 μ mol/L, can significantly reduce cell conditioned medium liquid in the content (p < 0.05) of A β 1-42, in the concentration range of 1-10 μ mol/L, the secretion of the reduction APPsw-SY5Y cell A β 1-42 that J39136 can dose dependent.
The impact of table 8J39136 reactive compound on A β 1-42 content in APPsw-SY5Y cell conditioned medium liquid
##with relatively P<0.01 of normal group,
*with relatively P<0.05 of model group,
*with relatively P<0.01 of model group
Embodiment 5, the J39136 effect research to neural inflammation
Method: final concentration is the J39136 of 10,2 μ mol/L, final concentration is that Exelon, nicotine and the rat cerebral cortex microglia of 10 μ mol/L hatched after 2h jointly, except blank group, it is 1 μ g/ml LPS that model group and administration group all add final concentration, continue to hatch collecting cell supernatant after 24h, Elisa method is measured IL-1 β, IL-6 content in cell conditioned medium liquid.
Result: compared with normal group, LPS stimulates after 24h, IL-1 β, IL-6 content significantly raise (p < 0.05) in model group cell conditioned medium liquid.J39136 can reduce the content of IL-1 β, IL-6 in cell conditioned medium, when dosage is 10 μ mol/L, and IL-1 β, IL-6 content remarkable reduction compared with model group (p < 0.01, p < 0.05) in cell conditioned medium.
The impact of table 8J3913 on activation microglia IL-1 β, IL-6 secretion
##with relatively P<0.01 of normal group,
*with relatively P<0.05 of model group,
*with relatively P<0.01 of model group
Embodiment 6, the J39136 research on AD animal model
Method: build mice study, dysmnesia model with scopolamine, with the positive control drug of Exelon (rivastigmine), observe the effect of compound J39136.Learning and memory of little mouse function with diving tower, keep away dark, water maze behavioristics index evaluation, the relatively difference between Normal group, model group and medicine group.The dosage of compound pharmacodynamic evaluation is to determine in conjunction with the acute toxicity tests according to the conventional amount used computational methods of medicine.High dose, middle dosage and low dose when compound J39136 pharmacodynamic evaluation, are selected: high dose group is that in 10mg/kg, dosage group is 5mg/kg, and small dose group is 1mg/kg.
ICR mice is used in experiment, for dementia animal model pharmacodynamic evaluation, mice is divided into 6 groups at random, normal group, model group, Exelon group, compound J39136 high dose group, middle dosage group and small dose group, and every group of mice 13-15 is only.
Result: compound J39136 is on scopolamine model mice diving tower experiment impact.After scopolamine model group mice training 24h, the time (incubation period) on diving tower is very short, and compare incubation period with blank group, significant difference (P<0.05).Compound J39136 is high, in, low dose all can obviously extend incubation period, with model group comparison, significant difference (P<0.05).
Table 9J39136 is the impact (mean ± SEM) on learning and memory in diving tower experiment
#with relatively P<0.05 of normal group,
*with relatively P<0.05 of model group,
*with relatively P<0.01 of model group
Compound J39136 keeps away dark experiment impact to scopolamine model mice.After scopolamine model group training 24h, the time (incubation period) that enters darkroom is very long, and compare incubation period with blank group, significant difference (P<0.05).Compound J39136 is high, in, low dose all has the preclinical trend of prolongation.
Table 10J39136 is keeping away the impact on learning and memory (mean ± SEM) in dark experiment
##with relatively P<0.01 of normal group,
*with relatively P<0.01 of model group
Compound J39136 affects scopolamine model mice water maze laboratory.After injected in mice scopolamine, model group compares with blank group, mice finds the time of platform obviously to increase (P<0.05), the dosage of compound J39136 all can resist the learning memory disorder that scopolamine causes, with model group comparison, significant difference (P<0.05).
Table 11J39136 impact on learning and memory (mean ± SEM) in water maze laboratory
Claims (6)
- Compound as shown in the formula (I) preparation prevention and or treatment treatment neurodegenerative diseases medicine in application
- 2. according to the application of claim 1, it is characterized in that, described neurodegenerative diseases is taking learning memory disorder as feature.
- 3. according to the application of claim 1, it is characterized in that, prevention and or treatment neurodegenerative diseases be by raising SIRT1 gene expression, performance repairing of neural injury and neuroprotective.
- 4. according to the application of claim 1, it is characterized in that, prevention and or treatment neurodegenerative diseases be by acetylcholine esterase inhibition activity and or suppress the activity of BuChE, reduce the decomposition of acetylcholine, improve the content of acetylcholine.
- 5. according to the application of claim 1, it is characterized in that, prevention and or treatment neurodegenerative diseases be the injury protection by neurocyte, improve A β Developmental and Metabolic Disorder.
- 6. according to the application of claim 1, it is characterized in that, prevention and or treatment neurodegenerative diseases are by regulating neural inflammation.
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