Zhang Yuan, Tang Qisheng, Yao Jin, Liu Hongwei, Xu Changmin, Guo Zechun, Liu Shuqing, Zhao Ruizhen
Department of Encephalopathy, Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, 101300, China.
Department of Encephalopathy, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, China.
J Neuroimmune Pharmacol. 2025 Apr 11;20(1):35. doi: 10.1007/s11481-024-10167-1.
Post-stroke depression (PSD) poses a serious impact on patients' life quality. Effective drugs to treat this annoying disease are still being sought. Yi-nao-jie-yu (YNJY) prescription has been found to relieve PSD; however, the underlying mechanisms remain unelucidated. This work elucidated the therapeutic effects and mechanisms underlying YNJY prescription in PSD. PSD rat model was treated with YNJY prescription and ML385. Depression-like behaviors of rats was appraised. Hematoxylin-eosin, Nissl, and NeuN immunofluorescence staining were performed to observe hippocampal neuronal damage. Transmission electron microscopy was used to assess hippocampal mitochondrial damage. Commercial kits and western blotting were adopted to research ferroptosis-related factors and Nrf2/GPX4/SLC7A11 signals. In vitro experiments were performed using rat hippocampal neurons to explore the mechanism by which YNJY prescription relieves PSD. In PSD rats, YNJY prescription relieved depression-like behaviors, attenuated hippocampal neuronal damage, mitigated hippocampal ferroptosis and mitochondrial damage, and activated hippocampal Nrf2/GPX4/SLC7A11 pathway. By in vitro experiments, erastin treatment exacerbated hippocampal neuronal damage, ferroptosis, mitochondrial damage, and lipid peroxidation; however, YNJY prescription abolished these erastin-induced effects. In the erastin-treated hippocampal neuronal model of PSD, ML385 treatment increased ferroptosis, hippocampal neuronal damage, and lipid peroxidation; however, YNJY prescription counteracted these ML385-induced effects. By in vivo study, ML385 reversed the relief of YNJY prescription on depressive-like behaviors of PSD rats, and the inhibition on ferroptosis in PSD rats' hippocampus. YNJY prescription relieves PSD by blocking ferroptosis via activating the Nrf2/GPX4/SLC7A11 pathway. It may be a promising agent for treating PSD clinically.
中风后抑郁症（PSD）对患者的生活质量造成严重影响。目前仍在寻找治疗这种恼人疾病的有效药物。已发现益脑解郁（YNJY）方剂可缓解PSD；然而，其潜在机制仍未阐明。本研究阐明了YNJY方剂治疗PSD的疗效及机制。采用YNJY方剂和ML385对PSD大鼠模型进行治疗。评估大鼠的抑郁样行为。进行苏木精-伊红染色、尼氏染色和NeuN免疫荧光染色以观察海马神经元损伤。采用透射电子显微镜评估海马线粒体损伤。采用商业试剂盒和蛋白质印迹法研究铁死亡相关因子及Nrf2/GPX4/SLC7A11信号通路。利用大鼠海马神经元进行体外实验，以探究YNJY方剂缓解PSD的机制。在PSD大鼠中，YNJY方剂可缓解抑郁样行为，减轻海马神经元损伤，减轻海马铁死亡和线粒体损伤，并激活海马Nrf2/GPX4/SLC7A11通路。通过体外实验，厄拉斯汀处理加剧了海马神经元损伤、铁死亡、线粒体损伤和脂质过氧化；然而，YNJY方剂消除了这些厄拉斯汀诱导的效应。在厄拉斯汀处理的PSD海马神经元模型中，ML385处理增加了铁死亡、海马神经元损伤和脂质过氧化；然而，YNJY方剂抵消了这些ML385诱导的效应。通过体内研究，ML385逆转了YNJY方剂对PSD大鼠抑郁样行为的缓解作用以及对PSD大鼠海马铁死亡的抑制作用。YNJY方剂通过激活Nrf2/GPX4/SLC7A11通路阻断铁死亡来缓解PSD。它可能是一种有前景的临床治疗PSD的药物。
