Zhang Yuling, Li Yichen, Wu Yafang, Tan Xiying, Ji Tingting, Tang Chaozhi
School of Biological Science and Technology, Liupanshui Normal University, Liupanshui, China.
College of Life Sciences, Henan Normal University, Xinxiang, China.
Front Pharmacol. 2025 Sep 3;16:1643343. doi: 10.3389/fphar.2025.1643343. eCollection 2025.
Although approximately one-third of stroke survivors develop post-stroke depression (PSD), clinically recommended preventive treatments currently are unavailable. Cilostazol, an established stroke therapeutic, has demonstrated potential in preventing PSD, however, its neuroprotective mechanisms remain unclarified. This study elucidates the molecular pathways via which cilostazol may protect against PSD development.
Middle cerebral artery occlusion (MCAO) was performed on C57BL/6J mice to establish an ischemic stroke (IS) model. Subsequently, the IS mice were treated with cilostazol and subjected to chronic unpredictable mild stress (CUMS) to induce PSD. Cilostazol's PSD prevention efficacy was evaluated using the sucrose preference, open field, tail suspension, and Morris water maze. Nissl staining and immunofluorescence labeling were used to detect cilostazol's effects on hippocampal neuronal apoptosis and microglial activation. Western blot and quantitative polymerase chain reaction were used to investigate cilostazol's regulation of hippocampal inflammation and apoptosis factors. Cilostazol's potential PSD-preventive mechanism was further explored by examining the primary hippocampal neuronal apoptosis induced by RhoA-activated BV2 microglia.
Cilostazol intervention significantly suppressed hippocampal microglial proliferation and activation and decreased pro-inflammatory cytokine expression. These changes were associated with attenuated hippocampal neuronal swelling and apoptosis and were accompanied by apparent alleviation of depressive behaviors in CUMS-subjected IS mice. Mechanistically, experiments demonstrated that cilostazol inhibited RhoA/NF-κB signaling pathway activation in BV2 microglia, leading to decreased tumor necrosis factor-alpha and interleukin-1β secretion. The neuroprotective effects of cilostazol, potentially mediated via a cAMP-dependent reduction of microglia-induced neuronal damage, may contribute to the improvement of depressive-like behaviors in mice with PSD.
Cilostazol may alleviate hippocampal inflammation by inhibiting RhoA/NF-κB signaling pathway activation in the microglia, providing neuronal protection and PSD prevention effects.
尽管约三分之一的中风幸存者会发生中风后抑郁（PSD），但目前临床上尚无推荐的预防性治疗方法。西洛他唑是一种已确立的中风治疗药物，已显示出预防PSD的潜力，然而，其神经保护机制仍不清楚。本研究阐明了西洛他唑可能预防PSD发生的分子途径。
对C57BL/6J小鼠进行大脑中动脉闭塞（MCAO）以建立缺血性中风（IS）模型。随后，对IS小鼠用西洛他唑治疗，并施加慢性不可预测轻度应激（CUMS）以诱导PSD。使用蔗糖偏好、旷场、悬尾和莫里斯水迷宫评估西洛他唑预防PSD的疗效。采用尼氏染色和免疫荧光标记检测西洛他唑对海马神经元凋亡和小胶质细胞激活的影响。采用蛋白质免疫印迹法和定量聚合酶链反应研究西洛他唑对海马炎症和凋亡因子的调节作用。通过检测RhoA激活的BV2小胶质细胞诱导的原代海马神经元凋亡，进一步探索西洛他唑潜在的预防PSD机制。
西洛他唑干预显著抑制海马小胶质细胞增殖和激活，并降低促炎细胞因子表达。这些变化与海马神经元肿胀和凋亡减轻相关，并伴随着CUMS处理的IS小鼠抑郁行为的明显缓解。机制上，实验表明西洛他唑抑制BV2小胶质细胞中RhoA/NF-κB信号通路激活，导致肿瘤坏死因子-α和白细胞介素-1β分泌减少。西洛他唑的神经保护作用可能通过cAMP依赖性减少小胶质细胞诱导的神经元损伤介导，这可能有助于改善PSD小鼠的抑郁样行为。
西洛他唑可能通过抑制小胶质细胞中RhoA/NF-κB信号通路激活来减轻海马炎症，从而提供神经元保护和PSD预防作用。
