The Effect Of Ketamine Chronic Administration On Microglia And Inflammatory Cytokines In Depression-like Rat Hippocampus

Objective: Depression is a clinical common mental disorder,it is estimated that will be become the second global burden of disease behind ischemic heart disease by 2020.Traditional antidepressants need several weeks to produce antidepressant effect,and with lower remission rate.Recent studies have shown ketamine with rapid antidepressant,anti-inflammatory and neuroprotection effect.A single sub-anaesthetic dose of ketamine administration displayed rapid and high remission rate antidepressant properties,but the antidepressant effect of ketamine just maintains a short time.Studies have demonstrated that repeated ketamine administration can maintain ketamine's antidepressant effects.Ketamine can inhibit microglia activation stimulated by lipopolysaccharide(LPS)and pulmonary inflammatory responses inducted by sepsis.New developments in psychiatric research have led to the hypothesis that inflammatory processes and brain-immune interactions are involved in the pathogenesis of major depression However,whether the central microglial cells and inflammatory cytokines mediated ketamine's antidepressant effect is unclear.Thus,we investigated whether ketamine's antidepressant-like effects is accompanied by the transform of microglia and the change of inflammatory cytokines in CUMS models of depression,it will open the way for the treatment of depression and antidepressants research.Methods1.Chronic unpredictable mild stress(CUMS)procedure was carried out to establish the depression-like rats model.2.Ketamine was injected into rats chronically after the model established,and the behavioral tests were conducted after ketamine administration.3.Enzyme-linked immunosorbent assay(ELISA)were performanced to detect expression of inflammatory cytokines,such as tumour necrosis factor-?(TNF-?),interleukin(IL)-1? and IL-6,in the hippocampus of depression-like rats.4.Western blotting were performanced to detect expression of CD11 b and Iba1 in the hippocampus of depression-like rats.5.Immunohistochemistry(IHC)were performanced to detect the number of CD11b-positive cells in the CA3 and DG region of the depression-like rats hippocampus.Results1.Chronic unpredictable mild stress(CUMS)procedure induced decrease of sucrose solution intake and increase of immobility time in FST,however,unaffected locomotor activities.chronic treatment of ketamine prevented the CUMS-induced decrease of sucrose solution intake and increase of immobility time in FST,however,unaffected locomotor activities.2.The levels of TNF-?,IL-1?,and IL-6 were significantly increased in the depression-like rats hippocampus.After chronic treatment of ketamine,the levels of TNF-?,IL-1?,and IL-6 in hippocampus were significantly decreased(p < 0.05).3.The levels of Iba1 and CD11 b were significantly increased in the depression-like rats hippocampus.After chronic treatment of ketamine,the levels of Iba1 and CD11 b in hippocampus were significantly decreased(p< 0.05).4.The number of CD11b-positive cells were significantly increased in the CA3 and DG region of the depression-like rat hippocampus.After chronic treatment of ketamine,the number of CD11b-positive cells were significantly decreased(p < 0.05).Conclusions1.CUMS elicits depressive-like behavioural changes in rats,which were improved by chronic administration of ketamine.2.CUMS up-regulated the hippocampal levels of inflammatory cytokines and proteins relate to microglias activation,which were attenuated by chronic administration of ketamine.3.CUMS up-regulated the number of activated microglias in hippocampal,which were attenuated by chronic administration of ketamine.