卒中后抑郁(PSD)是卒中患者的重要并发症,增加长期死亡率,并夸大了缺血引起的脑损伤。然而,与PSD相关的潜在分子机制和有效治疗靶点仍然难以捉摸。这里,我们采用PSD的动物行为模型,结合大脑中动脉闭塞(MCAO)和空间约束应激,研究PSD的分子基础和潜在治疗方法.有趣的是,我们发现,亚慢性应用天麻素(气体),一种传统的中草药天麻提取,缓解抑郁相关的行为缺陷,增加突触传递相关蛋白的受损表达,恢复PSD动物海马CA1区脊柱密度改变。此外,我们的结果表明,Gas的抗PSD作用依赖于膜大麻素-1受体(CB1R)的表达。PSD小鼠海马中磷酸化蛋白激酶A(p-PKA)和磷酸化Ras同源基因家族成员A(p(ser188)-RhoA)的含量降低,这被气体处理逆转了,和CB1R消耗导致气体对p-PKA和p-RhoA表达的功效降低。此外,气体的抗PSD作用被PKA抑制或RhoA激活部分阻断,说明Gas的抗PSD作用与CB1R介导的PKA/RhoA信号通路有关。一起,我们的研究结果表明,气体治疗对卒中后抑郁样状态具有保护作用;CB1R参与的PKA/RhoA信号通路在介导Gas的抗PSD效能中至关重要,提示气体应用可能有利于PSD的预防和辅助治疗。
Post-stroke depression (PSD) is a significant complication in stroke patients, increases long-term mortality, and exaggerates ischemia-induced brain injury. However, the underlying molecular mechanisms and effective therapeutic targets related to PSD have remained elusive. Here, we employed an animal behavioral model of PSD by combining the use of middle cerebral artery occlusion (MCAO) followed by spatial restraint stress to study the molecular underpinnings and potential therapies of PSD. Interestingly, we found that sub-chronic application of gastrodin (Gas), a traditional Chinese medicinal herb Gastrodia elata extraction, relieved depression-related behavioral deficits, increased the impaired expression of synaptic transmission-associated proteins, and restored the altered spine density in hippocampal CA1 of PSD animals. Furthermore, our results indicated that the anti-PSD effect of Gas was dependent on membrane cannabinoid-1 receptor (CB1R) expression. The contents of phosphorated protein kinase A (p-
PKA) and phosphorated Ras homolog gene family member A (p(ser188)-RhoA) were decreased in the hippocampus of PSD-mice, which was reversed by Gas treatment, and CB1R depletion caused a diminished efficacy of Gas on p-
PKA and p-RhoA expression. In addition, the anti-PSD effect of Gas was partially blocked by
PKA inhibition or RhoA activation, indicating that the anti-PSD effect of Gas is associated with the CB1R-mediated
PKA/RhoA signaling pathway. Together, our findings revealed that Gas treatment possesses protective effects against the post-stroke depressive-like state; the CB1R-involved
PKA/RhoA signaling pathway is critical in mediating Gas\'s anti-PSD potency, suggesting that Gas application may be beneficial in the prevention and adjunctive treatment of PSD.