Studt On Antidepressant Effect Of Integrative Stress Response Inhibitor ISRIB

[Background and Objective] Integrated stress Response(ISR)is an evolutionarily conserved intracellular signal regulatory network induced by protein homeostasis imbalance,mainly through eukaryotic translation initiator factor 2α(e IF2α)control the rate of protein synthesis to regulate the ISR.Studies have shown that ISR is involved in the occurrence and development of a variety of neurological diseases,but whether it is involved in the regulation of depressive emotional response remains unclear.This study preliminarily investigated the effect of chronic stress on ISR and evaluated the antidepressant effect of ISRIB,which is an inhibitor of ISR.[Methods] Firstly,Chronic social defeat stress(CSDS)induced Chronic depression model was established in mice,and social interaction test was performed to detect social avoidance behavior.The expression levels of p-EIF2 α,e IF2α and Glial fibrillary acidic protein(GFAP)in hippocampal tissues were determined by Western Blotting.Immunofluorescence was used to observe the number of astrocytes in the hippocampus of CSDS mice.Astrocyte neurite tracing was performed using Image J software and neurite branch length measurements were analyzed with sholl.Secondly,the mice Forced Swimming Test(FST)model was used to evaluate the potential of ISRIB antidepressant effect by detecting the immotility time of mice,and to determine the dose and time effect of ISRIB antidepressant effect.Spontaneous activity and anxiety were evaluated by open field test.Finally,based on the mouse CSDS model,FST test,sugar water preference test and open field test were used to detect the immobility time,sugar water preference coefficient,spontaneous activity ability and anxiety level of mice,respectively,to further clarify the antidepressant effect of ISRIB。[Results](1)CSDS significantly reduced body weight,induced social avoidance behavior,and up-regulated expression level of p-e IF2αin the hippocampus,but had no effect on the expression level of e IF2α.Meanwhile,CSDS down-regulated the expression level of GFAP in hippocampus,and significantly reduced the number of hippocampal astrocytes and total scores.(2)In the FST model,ISRIB significantly reduced the immovable time of mice,and the effect was dose-dependent and time-dependent.In addition,ISRIB did not affect the spontaneous activity and anxiety level of mice.(3)In the CSDS model,injection of ISRIB during stress or after stress could significantly reverse the increase of immobility time and decrease of sugar water preference coefficient induced by CSDS.In addition,ISRIB did not affect the spontaneous activity and anxiety level of mice.[Conclusion] Chronic stress enhances ISR,and the ISR inhibitor ISRIB has antidepressant effect.