Application of Chuanxiongzine derivative to preparation of medicine for preventing and treating Parkinson's disease

A technology for Parkinson's disease and drug preparation, which is applied in the field of medicine and can solve problems such as limited clinical application, low biological activity, and limited clinical efficacy

Inactive Publication Date: 2018-08-10
GUANGZHOU MAGPIE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the biological activity of TMP is low, the clinical effi

Method used

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  • Application of Chuanxiongzine derivative to preparation of medicine for preventing and treating Parkinson's disease
  • Application of Chuanxiongzine derivative to preparation of medicine for preventing and treating Parkinson's disease
  • Application of Chuanxiongzine derivative to preparation of medicine for preventing and treating Parkinson's disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1. Effect of T-006 on the transcriptional activity of MEF2, PGC1α and ARE

[0045] MEF2-PGC1α-ARE transcriptional activity is particularly important for regulating mitochondrial biogenesis and respiratory chain function, and is an important target for the treatment of neurodegenerative diseases. PC12 cells were transfected by cloning the MEF2 reporter gene pGreenFire1TM-MEF2-EF1 lentiviral vector (lentivector). The stably transfected PC12 cells were cultured according to conventional methods, inoculated in 96-well plates, and added different concentration gradients of T-006 (10 and 30 μM) or J147 (30 μM) after adhering to the wall and incubated for 24 hours, according to the luciferase reporter gene detection reagent Box (Luciferase reporter assay kit, Promega, USA) method detects activity, the result is as follows figure 2 Shown in A: T-006 can significantly activate MEF2 transcriptional activity in PC12 cells, but the control drug J147 has no such effect. T...

Embodiment 2

[0047] Example 2. Effect of T-006 on PGC-1α and Nrf2 protein expression and protein nuclear translocation in the nucleus of cerebellar granule cells

[0048] Cerebellar granule cells were seeded in 25cm 2 After 24 hours of drug action in the culture bottle, the original culture medium in the bottle was sucked away. Use the kit to extract the protein in the nucleus. The BCA method was used for protein quantification, after adding 5× loading buffer at a ratio of 1:4, boiling at 100°C for 5 min, cooling and loading by electrophoresis. Western blot results showed that incubation with T-006 alone could significantly increase the expression of PGC-1α and Nrf2 proteins in the nucleus ( image 3 A-C). In addition, the cells were seeded in a 24-well plate containing cell slides, and after 24 hours, T-006 (10 μM) was added for pre-incubation for 6 hours. The original medium was aspirated and fixed with 4% paraformaldehyde at room temperature for 10-15 minutes. The pre-cooled HBSS wa...

Embodiment 3

[0049] Embodiment 3.T-006 to MPP + Protection of cerebellar granule cells induced by injury

[0050] The cerebellar granule cells were cultured on the seventh day to start the experiment. They were pre-treated with drugs of specified concentration (T-006 in the experimental group and TMP in the positive control group) for 2 hours, and then added 150 μM MPP +Injury was induced for 24h. Cell viability was detected by MTT, cell apoptosis was detected by Hoechst33342 staining, ROS was detected by DCFH-DA probe, mitochondrial membrane potential was detected by JC-1 probe, and intracellular ATP content was detected by ATP kit. Experimental results such as Figure 4 Shown: T-006 can significantly reduce MPP + induced cytotoxicity and increased cell viability; in addition, T-006 can also inhibit MPP + The induced apoptosis of cerebellar granule cells, the production of free radicals, the decrease of mitochondrial membrane potential and the decrease of ATP are stronger than those o...

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Abstract

The invention belongs to the technical field of medicines and discloses application of a Chuanxiongzine derivative T-006 or a medicinal composition thereof to preparation of a medicine, wherein the medicine is used for preventing and treating nervous system diseases which comprise central nervous system diseases, particularly Parkinson's disease. The action mechanism of the derivative is related to activated MEF2D-PGC1alpha, PI3K-Akt and Nrf2-ARE signal channels, so that dopamine neurons are protected, loss of dopaminergic neurons of substantia nigra pars compacta is reduced, the content of dopamine in striatum is increased and the damaged movement function of patients is improved. When the derivative and the medicinal composition thereof is used for preparing the medicine for preventing and treating the nervous system diseases, the derivative and the medicinal composition thereof as well as useable medicine carriers can be prepared into various dosage forms, and the derivative and themedicinal composition thereof can be used in combination with other related medicines.

Description

technical field [0001] The invention belongs to the technical field of medicines, and relates to the application of a ligustrazine derivative T-006 and its pharmaceutical composition in the preparation of medicines, and the medicines are used for treating and preventing nervous system diseases, especially Parkinson's disease. Background technique [0002] Parkinson's disease (PD) is the second most common neurodegenerative disease. The incidence rate of people over 65 years old in my country has reached 1.7%, and the number of patients accounts for about 50% of the world. With the intensification of population aging, its incidence rate is still increasing year by year, and the number of patients worldwide will increase to 9 million by 2030. [0003] The pathophysiological process of PD is extremely complex, and there is no medicine to completely cure this disease clinically. Currently clinically used anti-PD drugs, such as DA substitutes, DA receptor agonists, monoamine oxi...

Claims

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Application Information

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IPC IPC(8): A61K31/4965A61P25/28A61P25/16
CPCA61K31/4965A61P25/16A61P25/28
Inventor 王玉强张在军张高小孙业伟易鹏陈海云
Owner GUANGZHOU MAGPIE PHARMA
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