Department of Neurology, Affiliated Nanhua Hospital, University of South China, Hengyang, 421001, Hunan, PR China.
Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Institute of Neuroscience, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, PR China.
Neurotoxicology. 2021 Jul;85:201-208. doi: 10.1016/j.neuro.2021.05.016. Epub 2021 Jun 1.
We have previously demonstrated that hydrogen sulfide (HS), 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 HS-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 HS, 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 HS-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 HS in STZ-induced diabetic rats and enhance our understanding of the robustness of HS as a therapeutic strategy for treatment of depression in diabetes mellitus.
我们之前已经证明，第三种内源性气体递质硫化氢（H2S）可以改善糖尿病大鼠的抑郁和焦虑样行为，但具体机制尚不清楚。本研究旨在探讨海马磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）通路是否通过改善海马神经发生来介导 H2S 改善糖尿病大鼠的抑郁和焦虑样行为。通过悬尾试验（TST）检测抑郁样行为，通过高架十字迷宫试验（EPM）检测焦虑样行为，通过旷场试验（OFT）检测运动活性。通过 Western blot 分析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）、磷酸化 AKT（p-AKT）和 AKT 的表达。结果表明，H2S 供体 NaHS 不仅激活了海马 PI3K/AKT 通路，表现为磷酸化 AKT 的增加，而且还可以改善链脲佐菌素（STZ）引起的糖尿病大鼠海马神经发生障碍，表现为 DCX 和 NeuN 的表达增加，GFAP 的表达减少。此外，PI3K/AKT 通路抑制剂 LY294002 显著消除了 H2S 对 STZ 诱导的糖尿病大鼠海马神经发生改善和抗抑郁、抗焦虑样作用。综上所述，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 H2S 在 STZ 诱导的糖尿病大鼠中的抗抑郁和抗焦虑样作用中起着重要作用，并增强了我们对 H2S 作为治疗糖尿病相关抑郁症的治疗策略的稳健性的理解。
