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Multiple-target effects of isoflavone derivative and its application in improvement of learning and memory

A technology for learning and memory impairment and function, which can be applied to medical preparations containing active ingredients, drug combinations, organic active ingredients, etc., and can solve the problem that single-target drugs are difficult to achieve ideal therapeutic effects.

Active Publication Date: 2014-10-15
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The pathogenesis of AD is not unitary. In addition to cholinergic damage, it also involves many factors, such as nerve damage and neuroinflammation. Therefore, it is difficult for single-target drugs to achieve ideal therapeutic effects. Drugs with multi-target effects are designed and developed Will be an effective strategy against AD

Method used

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  • Multiple-target effects of isoflavone derivative and its application in improvement of learning and memory
  • Multiple-target effects of isoflavone derivative and its application in improvement of learning and memory
  • Multiple-target effects of isoflavone derivative and its application in improvement of learning and memory

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1. Research on the up-regulation effect of J39136 on the expression of human SIRT1 gene at the cell level in vitro

[0047] Methods: The cell line stably transfected with human SIRT1 gene promoter reporter gene was used to express luciferase under drug stimulation, and the luciferase activity was expressed by the number related to light absorption (relative luminescence unit, RLU). Add 5 μl of screening samples (final concentration 10 μg / ml) to stably transfected cells in a 384-well plate, and after incubation for 24 hours, discard the drug-containing culture supernatant and add ONE-Glo TM Luciferase Assay System (Promega, U.S.A.) 10 μl of serum-free culture solution of the reaction reagent was shaken for 3 minutes, and M5 was used to detect the luminescence value. Up-regulation rate (%)=A / Bx100, wherein, A is the cell luciferase activity (RLU) measured after adding the sample to be tested, and B is the cell luciferase activity (RLU) measured after adding the bl...

Embodiment 2

[0049] Example 2. Study on the inhibitory effect of J39136 on the activity of ACHE and BuCHE at the molecular level in vitro

[0050] Methods: The AChE inhibitor screening model and the BuChE inhibitor screening model were established by DTNB method, the inhibitory activity of J39136 on AChE and BuChE was evaluated at 0.08-50 μmol / L, and the IC was calculated 50 . Repeat three times, calculate the mean and SD value.

[0051] Results: IC of J39136 inhibiting AChE and BuChE activities 50 All lower than 10μmol / L, IC for inhibiting BuChE activity 50 It is close to the positive control tetramethylisopropylpyrophosphate amine (iso-OMPA, a selective butyrylcholinesterase inhibitor), and far lower than the commercially available drug donepezil (a selective acetylcholinesterase inhibitor).

[0052] Table 1 IC of J39136 inhibiting ACHE / BuCHE activity 50

[0053]

Embodiment 3

[0054] Example 3, Research on the inhibitory effect of J39136 on AChE activity of nerve cells

[0055] Method 1: SY5Y cells are cultured in DMEM / F12 medium containing 10% fetal bovine serum. When the cells are in the logarithmic growth phase, press 5*10 4 Individuals / ml, 100ul / well density were inoculated in 96-well culture plate. After 24 hours, replace with serum-free DMEM / F12 medium for culture, and after 12 hours, replace with serum-free DMEM / F12 medium with different concentrations of J39136 (0.3-10 μmol / L), and treat with donepezil and Exelon (final concentration: 10 μmol / L) Similarly, after 24 hours, the cell viability was measured by the MTS method, and the AChE activity in the cell supernatant was detected by the DTNB method.

[0056] Results: Compared with the normal group, J39136 had no significant effect on the cell viability within the concentration range of administration, and the cell viability of the positive control group administered with donepezil was signi...

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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 [0001] The invention relates to a natural product derivative with double cholinesterase inhibitory effect, nerve cell protection effect and anti-inflammation effect, and the application of the compound in the treatment / prevention of learning and memory impairment and senile dementia. It belongs to the field of medical technology. technical background [0002] Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized clinically by behavioral, cognitive and memory dysfunction, and its characteristic pathological changes are: neuron loss, neuron fiber tangle ( neurofibrillary tangles (NFTs), senile plaques (SPs). The incidence of AD in people aged 65-74 is about 3%, the incidence rate can rise to 19% in people aged 75-84, and the incidence rate of AD in people over 84 years old can be as high as 47%. AD is the fourth major killer of the elderly after cardiovascular disease, tumor, and cerebrovascular disease, and seriously ...

Claims

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Application Information

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IPC IPC(8): A61K31/453A61P25/28
Inventor 杜冠华吴松刘艾林周丹王冬梅冯章英李莉刘前
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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