BDNF-TrkB Signal Channel Pathway And Sirt-1Mediate The Antidepressant-like Effect Of Hydrogen Sulfide On CUMS-induced Depression-like Behaviors

[Background and Objective]Looking for more efficacious antidepressant therapies has meaningfulpractical significance. Hydrogen sulfide (H2S), the third endogenousgasotransmitter, plays important roles in neuroprotection and regulation ofsynaptic plasticity. We have found that H2S antagonizes acute stress-induceddepression-like behaviours. The aim of this study is to further elucidate theantidepressant-like effect of H2S by investigating whether H2S producesantidepressant-like effects on chronic stress-induced depression-like behaviours.Many studies indicate that the pathway of brain derived neurotrophic factor(BDNF)-TrkB (BDNF receptor) and Silent mating type nformation regulation2homolog1(Sirt1) produce antidepressant-like effects. Our studying team haspreviously found that H2S promotes the expression of BDNF and Sirt1in neuronalcells. We speculate that BDNF-TrkB pathway and Sirt-1mediate theantidepressant-like effects of H2S.Therefore, in this study, we used the chronic unpredictable mild stress (CUMS)model to observe antidepressant-like effects on chronic stress-induceddepression-like behaviours. We also investigate whether BDNF-TrkB pathway andSirt-1mediate these antidepressant-like effects of H2S to explore the underlying mechanisms.[Methods]Adult male Wistar rats (200–220g) were randomly distributed to7groups:control, CUMS, low dose NaHS (1.68mg/kg*14d, ip) treatment, high dose NaHS(5.6mg/kg*14d, ip) treatment, low dose NaHS (1.68mg/kg*14d, ip) control,imipramine (15mg/kg*14d, ip)) treatment, blocked by K252a (1μg*14d, icv)group and blocked by Sirtinol (15nmol*14d, icv) group. The rat model ofdepression was established through4weeks of consecutive chronicunpredictable mild stress (CUMS), after2weeks of CUMS, the rats received2-wtreatment of NaHS (1.68、5.6mg/kg), imipramine or K252a or Sirtinol during whichCUMS continued.NaHS (1.68,5.6mg/kg, ip) was used as the donor of H2S. The depression-likebehaviors were tested by tail suspension test (TST), forced swim test (FST), andNovelty suppressed feeding test (NSF). The locomotor activity was tested by OpenField test.[Results]1. H2S inhibited CUMS-induced depression-like behaviors.Compared with CUMS group, the immobility times of NaHS (1.68,5.6mg/kg*14d, ip) treatment groups in tail suspension test and forced swim test and thelatency to feed in novel cage are decrease (P <0.01) and the swimming time ofNaHS (1.68,5.6mg/kg*14d, ip) treatment groups in forced swim test are increase(P <0.01). These results demonstrated that H2S inhibits CUMS-induceddepression-like behaviors.2. Inhibition of BDNF-TrkB Pathway by k252a reversed the antidepressant-likeeffects of H2S. Compared with NaHS (1.68mg/kg*14d, ip) treatment group, the immobilitytimes of blocked by K252a (1μg*14d, icv) group in tail suspension test andforced swim test and the latency to feed in novel cage are increase (P <0.01)and the swimming times of blocked by K252a (1μg*14d, icv) group in forcedswim test are decrease (P <0.01). These results demonstrated that inhibition ofBDNF-TrkB pathway reverses the antidepressant-like effects of H2S.3. Inhibition OF Sirt-1Signaling reversed the antidepressant-like effects of H2S.Compared with NaHS (1.68mg/kg*14d, ip) treatment group, the immobilitytimes of blocked by Sirtinol group (15nmol*14d, icv) in tal siuspension test andforced swim test and the latency to feed in novel cage are increase (P <0.01)and the swimming time of blocked by Sirtinol group (15nmol*14d, icv) in forcedswim test is decrease (P<0.01). These results demonstrated that inhibition of Sirt-1signaling pathway reverses the antidepressant-like effects of H2S.[Conclusion]1. H2S inhibits CUMS-induced depression-like behaviors.2. BDNF-TrkB pathway and Sirt-1mediate the antidepressant effect of H2S.