Chen Yanxi, Xu Zhidong, Ma Yifu, Liu Tingting, Tian Xin, Zhu Zixin, Zheng Wenrong, Wang Yufeng, Zheng Ruifang, Xing Jianguo, Wang Wen, Sun Fangling
Department of Experimental Animal Center, Xuanwu Hospital of Capital Medical University, Beijing Municipal Geriatric Medical Research Center, Beijing, China.
School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, China.
Front Pharmacol. 2024 Dec 4;15:1457309. doi: 10.3389/fphar.2024.1457309. eCollection 2024.
Until now, there has been an unmet need for treatments promoting chronic-phase post-stroke functional recovery. We previously found that morroniside promoted endogenous neurogenesis in ischemic stroke, but its therapeutic window was limited to the first 48 h. Here, we aimed to explore whether deep brain stimulation (DBS) combined with morroniside could enhance neurogenesis in rats subjected to focal ischemic stroke and contributes to functional recovery.
Beginning 2 weeks after the endothelin-1-induced stroke, rats were administered DBS of lateral cerebellar nucleus consecutively for 14 days, followed by morroniside for 7 consecutive days post-stimulation. Behavioral tests were used for assessing motor function. Local field potentials were recorded to evaluate neuronal excitability. Nissl staining was used to assess infarct volume. Immunofluorescence staining and Western blotting were carried out to uncover the stroke recovery mechanisms of DBS combined with morroniside treatment.
The results showed that this combined treatment improved behavioral outcomes, enhanced cortical local field potentials, and diminished infarct volumes at 35 days post-stroke. Moreover, it notably amplified neurogenic responses post-stroke, evidenced by the proliferation of BrdU/SOX2 and BrdU/DCX in the subventricular zone, and their subsequent differentiation into BrdU/NeuN and BrdU/VgulT1 in the ischemic penumbra. Moreover, the combined treatment also elevated the amount of BrdU/Olig2 and the level of axonal sprouting-related proteins in the perilesional cortex.
Our results demonstrated that the combined treatment extended the neurorestorative efficacy of morroniside, reduced infarct size, enhanced neuronal excitability and accelerated sensorimotor function recovery. This therapeutic approach may emerge as a potential clinical intervention for chronic ischemic stroke.
迄今为止，对于促进中风后慢性期功能恢复的治疗方法仍存在未满足的需求。我们之前发现莫诺苷可促进缺血性中风后的内源性神经发生，但其治疗窗口仅限于最初的48小时。在此，我们旨在探讨深部脑刺激（DBS）联合莫诺苷是否能增强局灶性缺血性中风大鼠的神经发生并促进功能恢复。
在内皮素-1诱导的中风后2周开始，对大鼠连续14天进行小脑外侧核的DBS治疗，随后在刺激后连续7天给予莫诺苷。采用行为测试评估运动功能。记录局部场电位以评估神经元兴奋性。使用尼氏染色评估梗死体积。进行免疫荧光染色和蛋白质印迹分析以揭示DBS联合莫诺苷治疗的中风恢复机制。
结果显示，这种联合治疗改善了行为结果，增强了皮质局部场电位，并在中风后35天时减小了梗死体积。此外，它显著增强了中风后的神经源性反应，表现为脑室下区BrdU/SOX2和BrdU/DCX的增殖，以及它们随后在缺血半暗带分化为BrdU/NeuN和BrdU/VgulT1。此外，联合治疗还增加了病灶周围皮质中BrdU/Olig2的数量和轴突发芽相关蛋白的水平。
我们的结果表明，联合治疗扩展了莫诺苷的神经修复功效，减小了梗死面积，增强了神经元兴奋性，并加速了感觉运动功能恢复。这种治疗方法可能成为慢性缺血性中风的一种潜在临床干预措施。
