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Application of Notch signaling pathway inhibitor in preparation of drugs treating autism

A signaling pathway and inhibitor technology, applied in the application field of Notch signaling pathway inhibitors in the preparation of autism treatment drugs, can solve problems such as no clear reports, social interaction behavior, learning and memory defects, etc., to improve autism Effects of behavioral abnormalities, superior clinical treatment, and drug development value

Active Publication Date: 2018-08-03
XINXIANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Is the Notch signaling pathway involved in the occurrence of autism? Is the generation of the VPA autism model related to the conduction disorder of the Notch signaling pathway that regulates individual development, thus leading to the occurrence of autism? Can DAPT, a Notch signaling pathway inhibitor, improve autism-like behavioral abnormalities, such as repetitive rigid-like behaviors, social interaction behaviors, and learning and memory deficits? The prior art does not clearly report

Method used

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  • Application of Notch signaling pathway inhibitor in preparation of drugs treating autism
  • Application of Notch signaling pathway inhibitor in preparation of drugs treating autism
  • Application of Notch signaling pathway inhibitor in preparation of drugs treating autism

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Experimental program
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Effect test

Embodiment 1

[0027] The establishment of embodiment 1 VPA autism animal model

[0028] Healthy adult Wistar male (300-350g) and female (200-250g) rats were purchased from the Department of Experimental Animals, Chinese Academy of Sciences (Shanghai), and raised in the special animal room of the Department of Human Anatomy, Histology and Embryology, Xinxiang Medical College, and given sufficient feed and drinking water. All experimental animal feeding and experimental procedures were strictly in accordance with the terms of protection of experimental animals of Xinxiang Medical College.

[0029] The basic process of establishing the autism rat model is as follows: several adult female and male Wistar rats were fed for several days under the conditions of periodic light (7:00AM-7:00PM), constant temperature 25°C and constant humidity 55%. to adapt to the environment. Then, according to the female: male 2:1 cage overnight. The next morning, the female mice whose vaginal thrombus was detect...

Embodiment 2

[0033] Example 2 VPA autism model Notch signaling pathway activity changes

[0034] The expression of NICD (Notch receptor intracellular segment, NICD) and HES-1 protein in the prefrontal cortex (PFC), hippocampus (HC) and cerebellum (CB) of the VPA group was determined by Western blot. The total protein of rat prefrontal cortex, hippocampus and cerebellum was extracted with protein lysate, and the protein concentration of the samples was determined by BCA method. After adding 5×loading buffer, heat denaturation at 100°C for 3 minutes. Perform 12% SDS-PAGE, transfer the protein to PVDF membrane, and block with 5% bovine serum albumin TBST shaker at room temperature for 2h. Add Antibody I and shake overnight at 4°C; add Antibody II and GAPDH on a shaker at room temperature for 1 hour, develop color with chemiluminescent reagents, and then place the PVDF membrane on a Bio-rad developer to obtain digital images of the reaction bands and display them Grayscale measurement was ca...

Embodiment 3

[0035] Example 3 Notch signaling pathway inhibitor DAPT treatment inactivates Notch signaling pathway activity

[0036] In order to further determine the role of Notch signaling pathway in the occurrence of autism, DAPT, an inhibitor of Notch signaling pathway, was used to intervene. DAPT exerts its effect by inhibiting γ-secretase to hydrolyze and release Notch receptor intracellular domain (Notchintracellular domain, NICD), resulting in the reduction of free NICD and the activation of downstream pathways by NICD.

[0037] Western blot results showed that there were significant differences in the expression of NICD protein in the CB tissues of the two groups, and the VPA+DAPT group was lower than the VPA group, and the difference was statistically significant ( figure 2 ). The expression of HES-1 protein in CB tissues of the two groups was significantly different, and the VPA+DAPT group was lower than the VPA group, and the difference was statistically significant ( figur...

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Abstract

The invention provides application of a Notch signaling pathway inhibitor in preparation of drugs treating autism. Researches of the brain area of an autism animal model find that the Notch signalingpathway of the VPA autism model is more active and protein expression of NICD and downstream target molecule HES-1 is increased; meanwhile, the researches further find that application of DAPT reducesprotein expression of NICD and HES-1 and reduction of activity of the Notch signaling pathway can improve repeated, rigid behaviors of the autism animal model and increase the social contact abilityof the autism animal model so as to improve space learning and memory ability. The Notch signaling pathway inhibitor can reduce the activity of the Notch signaling pathway of an autism mouse model andimprove autism behavior abnormalities, thereby providing experimental basis and theoretical basis for research of drugs treating autism and clinical treatment of autism, and having excellent clinicaltreatment and drug research and development values.

Description

technical field [0001] The present invention relates to a new application of Notch signaling pathway inhibitors, in particular to the application of Notch signaling pathway inhibitors in the preparation of drugs for the treatment of autism. Background technique [0002] Autism has three major clinical features: delayed language development, social behavior disorders, and rigid and limited behavior. The etiology of autism is not clear at present, it is generally believed that its occurrence is due to the joint action of genetic and environmental factors leading to the occurrence of autism. Non-genetic factors in the occurrence of autism may be related to interference with the normal signal pathway conduction of embryonic brain development, while genetic factors may be caused by gene mutations caused by abnormal signal pathway conduction. [0003] The Notch signaling pathway plays a vital role in the development of the nervous system, affecting various programs such as cell d...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61P25/00
CPCA61K45/00A61P25/00
Inventor 张应花崔卫刚项哲申凤鸽孙春莉贾云杰
Owner XINXIANG MEDICAL UNIV
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