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Medical application of camptothecin and its derivative in resisting Alzheimer disease

A technology for Alzheimer's disease and derivatives, applied in the field of medical use of structural analogues in anti-Alzheimer's disease

Inactive Publication Date: 2013-01-30
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when abnormal conditions such as amyloid precursor protein (APP) gene mutations, signaling pathway disorders, or Aβ-degrading enzyme dysfunction occur, the balance between Aβ production and clearance will be broken, and Aβ will be released in the brain. Abnormal aggregate deposition

Method used

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  • Medical application of camptothecin and its derivative in resisting Alzheimer disease
  • Medical application of camptothecin and its derivative in resisting Alzheimer disease
  • Medical application of camptothecin and its derivative in resisting Alzheimer disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] AlphaLISA method to evaluate the activity of camptothecin and its derivatives to inhibit Aβ production

[0026] HEK293sw cells (stable transgenic cell line, containing Swidish APP mutant fragments, can produce and secrete Aβ in large quantities 40 With Aβ 42 ) And SHSY5Ysw cells (a stable transgenic cell line of glioma cells, containing Swiss APP mutant fragments, which can secrete large amounts of Aβ 40 With Aβ 42 ) Were seeded in 96-well plates with a cell density of 5×104 / 100μl / well. Candidate compounds will be screened (% inhibition rate> 50%) For concentration gradient analysis, the initial concentration of the compound is 10 μM, diluted 3 times, and there are 11 concentration points in total. Set up DAPT (known γ-secretase inhibitor) as a positive drug control group, cells treated with no compound as a positive control group, cells without a compound as a background control group, and cells treated with a compound to be tested as a test group. The positive compound t...

Embodiment 2

[0030] Analysis of cell viability and apoptosis activity

[0031] Both cytotoxicity and cell apoptosis can cause the reduction of Aβ production. Therefore, in order to rule out the cell death caused by compound toxicity and the reduction of Aβ caused by apoptosis, we used WST-1 model and casapse 3 / 7 activity analysis kit to detect the above The effect of positive compounds on SHSY5Ysw cells.

[0032] Such as figure 1 Shown: 100μM, 10μM camptothecin and its derivative compounds were treated with SHSY5Ysw cells, incubated overnight, and cell viability was detected by WST-1 kit. Among them, 10μM staurosporine was set up as a positive compound control with cytotoxic effect, and 1% dimethyl sulfoxide (DMSO) was set up as a normal control. The results showed that CPT and its structural analog compounds at 100 μM and 10 μM had no significant effect on cell viability.

[0033] figure 2 It shows that 1μM, 100nM camptothecin and its derivatives have no obvious effect on apoptosis activity c...

Embodiment 3

[0035] Notch signaling pathway influence

[0036] HEK293 cells were seeded in a 3cm well plate at 3×105 / 300μl / well, and the plasmid pcDNA 3.2sp NtochΔE-GVP (this plasmid contains a fragment encoding NtochΔE-GVP (acid 1694-2205) and Gal4 / VP16 DNA with transcriptional activation activity) Fragment) and plasmid pGL4.31 (luc2P / GAL4UAS / Hygro purchased from promega, with fluorescence excitation activity) were transiently transfected into HEK293 cells, and the transfected cells were treated with the test compound (test group), 100μM DAPT (positive drug) Control group), and set up no compound-treated co-transfected cells as a positive signal control group, and set up no-transfected cells as a background group. 37℃5%CO 2 After incubating for 24 hours, set the chemical fluorescence mode on the Envision instrument to detect the activity of the Notch signaling pathway. Calculate the% inhibition rate.

[0037] Because Notch signaling pathway is a pathway that conducts interaction signals betw...

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Abstract

The invention relates to the field of crude drugs, specifically relates to a medical application of camptothecin and its derivative in resisting Alzheimer disease. Pharmacological experiments prove that: the camptothecin and its derivative have significant effect on inhibiting production of A beta, the IC50 is within the range of 0.1-10 nM, and the molecular weights of the compounds are all less than 500 Dalton, which mean the compounds has latent capacity of permeating a blood cerebral barrier. More importantly, the camptothecin and its analogues have no influence on cytotoxicity and apoptosis in inhibiting the concentration range of A beta, and simultaneously have no side effect on Notch signal passages.

Description

Technical field [0001] The invention relates to the field of natural medicines, in particular to the medical use of camptothecin and its derivative structural analogs in anti-Alzheimer's disease. Background technique [0002] Alzheimer's disease (AD) is a degenerative disease of the central nervous system that often occurs in middle-aged and elderly people. Its main pathological changes include diffuse brain atrophy and β-amyloid peptide (β-amyloid peptide, Aβ) deposited senile plaques (SP) and a large number of neurofibrillary tangles (NFTs). The typical clinical symptoms of patients are progressive memory impairment and cognitive decline. [0003] A large number of studies have shown that the abnormal production and deposition of Aβ is an important link leading to AD. Under normal circumstances, the production and degradation of Aβ are balanced. But when there are abnormal conditions such as amyloid precursor protein (APP) gene mutation, signal pathway disorder or Aβ degrading ...

Claims

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Application Information

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IPC IPC(8): A61K31/4745A61P25/28
Inventor 李萍徐晓军石子琪陈君王菊
Owner CHINA PHARM UNIV
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