We have previously demonstrated that hydrogen sulfide (H₂S), the third endogenous gasotransmitter, ameliorates the depression- and anxiety-like behaviors in diabetic rats, but the underlying mechanism remains unclear. The present was aimed to investigate whether the hippocampal phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway mediates H₂S-ameliorated depression- and anxiety-like behaviors in diabetic rats by improving the hippocampal neurogenesis. The depression-like behaviors were examined by Tail suspension test (TST), the anxiety-like behaviors were examined by Elevated plus maze test (EPM), and the locomotor activity was detected by Open Field Test (OFT). The expressions of doublecortin (DCX), neuron-specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), p-AKT, and AKT in the hippocampus were determined by Western blot analysis. Results showed that NaHS, a donor of exogenous H₂S, not only activated the hippocampal PI3K/AKT pathway, as evidenced by the increase of phosphorylated AKT, but also favorably reversed streptozotocin (STZ)-disturbed hippocampal neurogenesis, as evidenced by the increases in the expressions of DCX and NeuN as well as the decrease in the expression of GFAP in the hippocampus of STZ-induced diabetic rats. Furthermore, inhibited PI3K/AKT pathway by LY294002 significantly abolished H₂S-exerted the improvement of hippocampal neurogenesis and the antidepressant- and anxiolytic-like effects in the STZ-induced diabetic rats. Taken together, these results uncover that the activation of hippocampal PI3K/AKT pathway plays an important role to restore hippocampal neurogenesis and subsequently to mediate the antidepressant- and anxiolytic-like roles of H₂S in STZ-induced diabetic rats and enhance our understanding of the robustness of H₂S as a therapeutic strategy for treatment of depression in diabetes mellitus.

我们之前已经证明硫化氢 (H ₂ S) 是第三种内源性气体递质，可改善糖尿病大鼠的抑郁和焦虑样行为，但其潜在机制仍不清楚。本研究旨在研究海马磷酸肌醇 3-激酶 (PI3K)/蛋白激酶 B (AKT) 通路是否介导 H ₂S-通过改善海马神经发生来改善糖尿病大鼠的抑郁和焦虑样行为。类抑郁行为采用悬尾试验(TST)检测，类焦虑行为采用高架十字迷宫试验(EPM)检测，运动活性采用旷场试验(OFT)检测。免疫印迹法检测海马中双皮质素（DCX）、神经元特异性核蛋白（NeuN）、胶质纤维酸性蛋白（GFAP）、p-AKT和AKT的表达。结果表明，NaHS是外源性H _2的供体S，不仅激活海马 PI3K/AKT 通路，如磷酸化 AKT 的增加所证明的那样，而且有利地逆转链脲佐菌素 (STZ) 干扰的海马神经发生，如 DCX 和 NeuN 的表达增加所证明的。 STZ诱导的糖尿病大鼠海马GFAP表达降低。此外，LY294002 抑制 PI3K/AKT 通路显着消除了 H ₂ S 对 STZ 诱导的糖尿病大鼠海马神经发生的改善以及抗抑郁和抗焦虑样作用。总之，这些结果揭示了海马 PI3K/AKT 通路的激活在恢复海马神经发生以及随后介导 H _{2的抗抑郁和抗焦虑样作用中起重要作用。}S 在 STZ 诱导的糖尿病大鼠中的作用，并增强我们对 H ₂ S 作为治疗糖尿病抑郁症的治疗策略的稳健性的理解。