S2B-3 The Translocator Protein(18 kDa),A Potential Novel Drug Target of Mental Disorders

摘要

Background:Recently,the translocator protein(18 kDa)(TSPO),previously called peripheral benzodiazepine receptor(PBR),has received increased attention in the pathophysiology of several kinds of neuropsychiatric disorders.The aim of the present study was to evaluate the exact role of TSPO in the pathophysiology and treatment of mental disorders.Methods:Firstly,by using TSPO WT/KO mice or the lentiviral vectors mediating TPSO overexpression,we studied the important role of TSPO in the anxiolytic and antidepressant effects.The results obtained in this studies provided new insights into the potential target of TSPO for the treatment of mental disorders.Secondly,we determined the the target profile of YLIPA08,a potent and selective TSPO ligand synthesized by our institute.And we then measured its anti-PTSD,antidepressant and anxiolytic-like effects in various mouse and rat models.Finally,we investigated its potential to cause side effects that are typically associated with conventional benzodiazepines.Results:Our results are the first to suggest that AC-5216,a selective TSPO ligand,produce antidepressant-like and cognitive enhancing behaviors in TSPO+/+mice,but not in TSPO-/-mice.The overexpression of TSPO in the hippocampal dentate gyrus produced anxiolytic and antidepressant-like behavioural effects that are at least partially mediated by downstream allopregnanolone biosynthesis.We also showed that TSPO ligand YL-IPA08 caused significant anti-PTSD,antidepressant and anxiolytic-like effects,but does not cause the side effects that are typically associated with conventional BZDs benzodiazepines,which might be partially mediated by binding to TSPO and the subsequent synthesis of allopregnanolone.Conclusion:These data suggest that TSPO may be the promising targets for the development of TSPO ligands as the novel and promising pharmacotherapies target for the mental disorders.