Application of valeric acid derivatives in the treatment of hereditary cerebellar ataxia

A technology for ataxia and spinocerebellum, applied in the field of pharmacy, can solve problems such as the lack of effective drug treatment and the unclear mechanism of SCAR20

Active Publication Date: 2022-04-22
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the mechanism of SNX14 mutation leading to SCAR20 is still unclear, let alone effective drug treatment

Method used

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  • Application of valeric acid derivatives in the treatment of hereditary cerebellar ataxia
  • Application of valeric acid derivatives in the treatment of hereditary cerebellar ataxia
  • Application of valeric acid derivatives in the treatment of hereditary cerebellar ataxia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Example 1. Construction and identification of conditional knockout mice in the brain of Snx14

[0106] The animals used in the experiment were Snx14 brain conditional knockout mice constructed using the LoxP-Cre system, that is, Snx14 f / f ; Nestin-cre mice. Involved transgene Snx14 flox / + (Snx14 f / + ) mice were commissioned by Saiye (Guangzhou) Co., Ltd. to build them, and B6.Cg-Tg(Nes-cre)1Kln / J(Nestin-cre) mice were purchased from Jackson lab in the United States. First set the Snx14 f / + Snx14 obtained by mating with Nestin-cre f / + ; Nestin-cre mice, which were then combined with Snx14 f / f Conditional knockout of Snx14 in the brain obtained by mating f / f ;Nestin-cre( figure 1 A), in addition to get Snx14 f / + , Snx14 f / f and Snx14 f / + ; Nestin-cre mice. Through the genotype identification of offspring mice, four genotype mice ( figure 1 B). As verified by immunoblotting, Snx14 f / f ; Nestin-cre mice do not express SNX14 in the brain regions of the central ...

Embodiment 2

[0107] Example 2. Experimental process of VPA administration

[0108] The drug VPA used was purchased from sigma-Aldrich Company (P4543), and was formulated with normal saline (NS) at 20 mg / kg for later use. The experiments were divided into three groups: Snx14 f / + ; Nestin-cre+NS group, Snx14 f / f ; Nestin-cre + NS group and Snx14 f / f ; Nestin-cre+VPA group. The mice in the administration group received intraperitoneal injection of VPA (250 mg / kg body weight / day) from P25 days, and continued for 35 days, while the mice in the control group received the same volume of NS ( figure 2 A). Behavioral tests were performed 3 days after the administration (P63). After the tests, the mice were sacrificed, and the brains were removed for subsequent experiments.

Embodiment 3

[0109] Example 3. VPA treatment has no significant effect on the body weight of mice.

[0110] see figure 2 B and 2C, during treatment (P25, P40, P50 and P60), Snx14 f / f ; Body weight and Snx14 of male mice in Nestin-cre+VPA group f / f ; Compared with Nestin-cre+NS group, there was no significant difference, and female mice also had no significant difference. It suggested that long-term VPA treatment had no obvious adverse effects on the physical condition of male and female mice. The data are represented by mean ± standard error (Mean ± SEM), and statistical analysis is performed by Two-way ANOVA, and the number of mice in each group is 8-11. NS stands for no significant difference.

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Abstract

The invention discloses the use of the compound represented by formula I in preventing, treating or improving hereditary cerebellar ataxia, especially autosomal recessive spinocerebellar ataxia 20 (SCAR20). The compound of the invention can significantly improve the motor ataxia of model mice and slow down the death of Purkinje cells, thereby providing clinical support for the treatment of hereditary cerebellar ataxia, especially SCAR20.

Description

technical field [0001] The present invention relates to the field of pharmacy. Specifically, the present invention relates to the application of valeric acid derivatives in the treatment, prevention and improvement of hereditary cerebellar ataxia, especially autosomal recessive spinocerebellar ataxia 20 (SCAR20). Background technique [0002] Hereditary ataxia is a highly heterogeneous disease. The clinical manifestations are poor motor balance function, gait instability, eye movement and dysarthria, etc. The incidence rate is about 8.9 / 100,000. According to the mode of inheritance, it can be divided into autosomal dominant, autosomal recessive and X-linked inheritance. Among them, the incidence of autosomal recessive ataxia is about 3 / 100,000. Patients show early-onset motor balance and coordination disorders, often accompanied by cerebellar atrophy or hypoplasia. Autosomal recessive spinocerebellar ataxia 20 (Autosomal recessive spinocerebellar ataxia 20, SCAR20) is a se...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/20A61P25/00A61P25/28A61P25/16
CPCA61K31/20A61P25/00A61P25/28A61P25/16
Inventor 王鑫张洪峰洪育娟杨伟杰王睿敏
Owner XIAMEN UNIV
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