Study On The Mechanism Of Neuroinflammation In Prefrontal Cortex Of CUMS Rats And The Effect Of Fluoxetine

In modern society,depression is one of public health problems worldwide,seriously threatening human health.The etiology of depression is complicated,but the exact pathological mechanism remains unclear.The inflammation hypothesis of depression is an important pathological mechanism hypothesis.Much attention has been paid to this hypothesis in academic area.However,most of these hypothesis and researches focus on peripheral inflammation.This study focused on the neuroinflammation in functional brain area,and explored the pathological mechanism of the neuroinflammation in prefrontal cortex(PFC),and the effect of clinical antidepressant fluoxetine hydrochloride treatment.Here,we detected biochemical alterations of pro-inflammatory cytokine interleukin-1 beta(IL-1β)in serum,cerebrospinal fluid(CSF)and PFC of chronic unpredictable mild stress(CUMS)-exposed rats,a well-documented model of depression.Furthermore,this study explored the molecular mechanism by which CUMS induced IL-1βdysexpression and activation,and subsequently caused PFC neuroinflammation in rats.Compared with non-CUMS rats,12-week CUMS procedure significantly induced body weight decrease and depression-like behavior(anhedonia,measured as reduction of sucrose solution intake)in rats.Simultaneously,significant elevation of PFC IL-1β mRNA and protein levels and activation(increased 17 kDa mature-IL-1βprotein levels)was detected in CUMS rats,without the alteration of serum and CSF IL-1β levels.Fluoxetine treatment remarkably inhibited the induced IL-1β expression and activation in PFC of CUMS rats,being consistent with its antidepressant effect.Furthermore,CUMS procedure significantly induced the activation of nuclear factor kappa B(NF-κB)inflammatory pathway and the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)inflammasome activation in PFC of rats.Although there was no significantly change of toll like receptor4(TLR4)protein levels,TLR2 and purinergic receptor P2X ligand-gated ion channel 7(P2RX7)protein levels were significantly up-regulated in PFC of CUMS rats,indicating that these inflammatory molecules,element and signal pathway may mediate dysexpression and activation of IL-1β-induced neuroinflammation in PFC of CUMS rats.Furthermore,the results of immunofluorescence staining showed that CUMS caused microglia activation with the impaired astrocytes number and function in PFC of rats.Moreover,the increased co-location of NLRP3 and microglial marker protein(ionized calcium binding adaptor molecule 1,Iba1)expression indicated that it was microglial NLRP3 inflammasome activation,resulting in IL-1β dysexpression and activation,and subsequent neuroinflammation in PFC of CUMS rats.Fluoxetine was found to inhibit microglia1 NLRP3 inflammasome activation in PFC of CUMS rats.It also suppressed dysexpression and activation of these inflammatory molecules,element and signal pathway,and protected the number and function of astrocytes in PFC of CUMS rat.These results confirmed the pathological change and mechanism of the neuroinflammation in PFC of CUMS rats,preliminarily explained a new pathway to antidepressant effect mediated by anti-neuroinflammation.These new findings may provide the experimental evidence for the inflammation hypothesis of depression,and may expand new content of neuroinflammation in depression.The neuroinflammatory molecules,element and signal pathway in PFC may be new potential drug targets for anti-depressants.