BDNF‐TrkB pathway mediates antidepressant‐like roles of H₂S in diabetic rats via promoting hippocampal autophagy

Abstract

Hydrogen sulfide (H2S) plays antidepressant‐like roles in diabetic rats. However, the underlying mechanisms remain unclear. Brain‐derived neurotropic factor (BDNF), a neurotrophic factor, plays important regulatory roles in depression by its high‐affinity tropomysin‐related kinase B (TrkB) receptor. Autophagy also is implicated in modulation of depression. Previous work confirmed the modulatory roles of H2S in BDNF protein expression and autophagy. Thus, in this study, we explored whether the BDNF‐TrkB pathway mediates the antidepressant‐like effects of H2S in diabetic rats and whether this process is achieved via promoting hippocampal autophagy. We demonstrated that H2S upregulated the expressions of BDNF and p‐TrkB proteins in the hippocampus of streptozotocin (STZ)‐induced diabetic rats. K252a (an inhibitor of BDNF‐TrkB pathway) reversed the antidepressant‐like roles of H2S, as evidenced by the tail suspension, forced swimming, novelty suppressed feeding, and elevated plus‐maze tests. Furthermore, K252a abolished H2S‐promoted hippocampal autophagy in diabetic rats, as evidenced by a decrease in the number of autolysosome, downregulation of Beclin‐1 (a regulator of autophagy in the early stage of the formation of autophagosomal membranes and its level is positively correlated with autophagic activity) expression, and upregulation of P62 (a substrate of autophagic degradation and its level is inversely correlated with autophagic activity) expression, in the hippocampus of rats co‐treated with NaHS and STZ. Taken together, these data indicated that the BDNF‐TrkB pathway mediates the antidepressant‐like roles of H2S in diabetic rats by enhancing hippocampal autophagy.

EA Ameliorated Depressive Behaviors in CUMS Rats and Was Related to Its Suppressing Autophagy in the Hippocampus

“…In the circumstances, the effect of autophagy on depression may be bilateral. For example, hydrogen sulfide, an antidepressant-like compound for diabetic rats, could improve the depression-like behavior of rats by enhancing hippocampal autophagy through BDNF-TrkB pathway [ 46 ], but the similar improvement was explained by opposite mechanism in another research, in which the upregulating BDNF-TrkB pathway was along with the decreasing autophagy in hippocampus [ 47 ]. Maybe the effect of autophagy on depression varies from different types or treatments.…”

Exogenous Hydrogen Sulfide Plays an Important Role by Regulating Autophagy in Diabetic-Related Diseases

“…K252a (an inhibitor of the BDNF-TrkB pathway) abolished the antidepressant effects of H 2 S. Furthermore, K252a inhibited exogenous H 2 S-promoted hippocampal autophagy in diabetic rats by decreasing the number of autolysosomes and Beclin-1 expression and increasing P62 expression in the hippocampus of diabetic rats. In conclusion, exogenous H 2 S can improve diabetic depression by promoting autophagy via the BDNF-TrkB pathway [99], which provides a potential therapeutic value for depression caused by diabetes. The above conclusion still needs to be further studied by using an autophagy inhibitor, and in-depth research is needed to determine whether exogenous H 2 S can prevent diabetes depression by improving damaged hippocampal neurons and reducing synaptic plasticity-related proteins.…”

“…With the further research on the improvement of diabetes by H 2 S regulating autophagy, it may provide a new strategy for the treatment of diabetes. Diabetic cardiomyopathy Activating autophagy through activating AMPK/mTOR signaling pathway [59] Diabetes-induced myocardial fibrosis Inhibiting autophagy via activating PI3K/AKT1 signaling pathway [63] Diabetes-induced myocardial fibrosis Suppressing myocardial cell senescence via activating autophagy through activating SIRT6/AMPK signaling pathway [66] High glucose-induced endothelial cell dysfunction Inhibiting autophagy via the Nrf2/ROS/AMPK signaling pathway [75] Diabetes-induced renal fibrosis Activating autophagy via inhibiting TGFβ1/NF-κB/AKT pathways [83] Diabetic dysfunctional vascular smooth muscle Inhibiting autophagy via suppressing the AMPK/mTOR pathway [92] Diabetic depression Promoting autophagy via activating BDNF/TrkB pathway [99]…”

Sildenafil Alleviates Murine Experimental Autoimmune Encephalomyelitis by Triggering Autophagy in the Spinal Cord

“…However, other studies have shown that BDNF can also promote autophagy ( 67 ). In diabetic rats, BDNF-TrkB pathway exerted antidepressant effect of hydrogen sulfide (H 2 S) by triggering autophagy in the hippocampus ( 68 ). In another study with cortical neurons submitted to oxygen deprivation in vitro , BDNF exerted neuroprotective effects by increasing autophagy via the PI3K/Akt/mTOR/p70S6K pathway.…”