Calpain Inhibitors Ameliorate Depression-like Behaviors Through Reducing Astrocytic Activation,Inflammatory Reaction And Promoting Synaptic-related Protein Expression

Depression is an emotional neurological disorder with the clinical manifestations of depression include continuous depression and loss of pleasant sensation,which seriously affect the physical and mental health of people.The mechanism of depression is mainly related to neuroinflammation,abnormal synaptic plasticity,and disorder of monoamine neurotransmitters release.Calpain is a type of calcium-dependent protease,which is closely related to synaptic plasticity and the occurrence of inflammation.However,it is still unclear whether calpain is involved in the occurrence of depression and its possible mechanism.Objective: To investigate the effect of inhibiting calpain on depression-like behavior,and to elaborate the molecular mechanisms from the perspective of neuroinflammation and hippocampal synaptic plasticity.Methods: The lipopolysaccharide(LPS)-and chronic unpredictable mild stress(CUMS)-induced depression models were used to evaluate the antidepressant effects of calpain inhibitors.The effects of calpain inhibitor on depression-like behavior were explored by observing the behavioral changes of depressed mice after i.p.injection or lateral ventricle injection of calpain inhibitors.ELISA assay was used to detect cytokines(TNF-?,IL-1?),western blot and immunofluorescence were used to detect changes of glial cells and synaptic plasticity-related protein(PSD95,Arc,BDNF).Results: I.p.injection of calpeptin inhibits LPS and CUMS-induced depression-like behavior,astrocyte activation,cytokine release and reduction of synaptic proteins.Calpeptin inhibits calpain activation,SCOP degradation and Erk phosphorylation induced by LPS and CUMS.Moreover,calpeptin inhibits the reduction of Arc and PSD95 in the hippocampus.And calpain inhibitor promotes the expression of Glu A1 and Glu A2,and reduces the expression of Glu N2 A and Glu N2 B.Intraventricular injection of calpain-1inhibitor or Erk inhibitor can improve LPS-induced depression-like behavior,release of cytokines,and reduction of synaptic plasticity-related protein.In addition,memantine can also inhibit LPS-induced SCOP degradation.Conclusions: Inhibiting of calpainimproves the depression-like behavior induced by LPS and CUMS.The possible mechanism is related to the degradation of the calpain substrate,inflammatory response and regulation of synaptic plasticity-related protein expression.This study provides new targets for the treatment of depression.