| Background: Major depressive disorder(MDD)is a psychiatric disorder with high recurrence,high morbidity and high mortality rates,causing severe burden on the family and society.Although multiple hypotheses for the pathogenesis of depression have been presented,the specific pathogenesis of depression is still undetermined.Increasing evidence supports the view that inflammation is associated with the etiopathogenesis of depression.Pioglitazone(PIO),a PPAR-? agonist,is thiazolidinedione class drug for type 2 diabetes treatment.Recently,in animal depression models,PIO treatment ameliorated depressive-like behaviors.Moreover,clinical studies have demonstrated that PIO could be an adjunctive therapy for treating depression.However,the underlying mechanisms of the action of PIO against depressive-like behaviors remain to be fully elucidated.Objective:(1)Our present study aimed to explore the involvement of the JNK/p38 and PI3K/AKT signaling pathways,and neural apoptosis,in the PFC of mice subjected to LPS with or without pretreatment of PIO and GW9662,a PPAR-? antagonist.(2)To further confirm the involvement of PI3K/AKT and JNK/p38 signaling pathways in the antidepressant-like effect of PIO,we assessed the influence of anisomycin,a JNK/p38 agonist,and LY294002,a PI3K/AKT inhibitor,on the antidepressant-like effect of PIO in mice.Methods:(1)Mice were randomly divided into eight groups(n = 9–12 animals per group): Vehicle group,LPS group,LPS+PIO group,LPS+PIO+GW9662 group,LPS + PIO + LY294002 group,LY294002 group,LPS + PIO + Ani group and Ani group.Inflammation-associated animal model of depression was established by i.c.v.injection of LPS.(The specific experimental timeline and design is shown in Fig.1).24 h after LPS or saline injection,all behavioral tests(Sucrose preference test(SPT),Changes of Body weight(?BW),Open field test(OFT)and Forced swimming test(FST))were performed.(2)The neural apoptosis in PFC of the four groups(Vehicle group,LPS group,LPS + PIO group,LPS + PIO + GW9662 group)was assessed by TUNEL and DAPI staining.(3)The PI3K/AKT and JNK/p38 signaling pathways and apoptosis-related(cleaved caspase-3,Bax,Bcl-2,cyt c)proteins were assessed by western blot.Results:(1)Mice exposed to LPS showed depressive symptoms including longer immobility time in a FST and lower sucrose preference in a SPT(Fig.2),reduced locomotor activity and exploratory activity.However,pretreatment with PIO attenuated these LPS-induced depression-like behaviors and exploratory activity,without affecting locomotor activity.GW9662 significantly blocked the antidepressant-like effect of PIO.(2)TUNEL staining analysis revealed that PIO pretreatment prevented the LPS-induced neural apoptosis in the PFC of mice,supported by the reversal of expression level changes in apoptosis-related markers.At the molecular level,the antidepressant-like effect of PIO may involve activation of the PI3K/AKT signaling pathway and inhibition of the JNK/p38 signaling pathway,which were revealed by up-regulated p-AKT,and down-regulated p-JNK and p-p38 in the PFC of mice pretreated with PIO.(3)In addition,we found that both inhibition of PI3K/AKT by LY294002 and activation of JNK/p38 by anisomycin abolished the antidepressant-like effect of PIO.These results further verified that the PI3K/AKT and JNK/p38 pathways may be associated with the antidepressant-like effect of PIO.Conclusions: Our study revealed that LPS-induced depressive-like behaviors were partially associated with JNK/p38-mediated neural apoptosis in the mouse PFC.PIO pretreatment attenuated depression-like behaviors while reducing neural apoptosis in the PFC.Furthermore,at the molecular level,PIO may modulate the effect of PI3K/AKT/JNK/p38 cascades on the expression of apoptosis-related markers(Bax,Bcl-2,cyt c,cleaved caspase-3)to inhibit neural apoptosis(Fig.8).The underlying molecular mechanisms may provide a novel insight for further research on antidepressant drugs for treating inflammation-related depression. |
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