Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Colleges and Universities Laboratory of Neurosurgery in Heilongjiang Province, Harbin, China; Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, China.
Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Colleges and Universities Laboratory of Neurosurgery in Heilongjiang Province, Harbin, China; Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, China.
Free Radic Biol Med. 2024 Sep;222:173-186. doi: 10.1016/j.freeradbiomed.2024.05.045. Epub 2024 Jun 11.
Regulation of the redox system by branched-chain amino acid transferase 1 (BCAT1) is of great significance in the occurrence and development of diseases, but the relationship between BCAT1 and subarachnoid hemorrhage (SAH) is still unknown. Ferroptosis, featured by iron-dependent lipid peroxidation accompanied by the depletion of glutathione peroxidase 4 (GPX4), has been implicated in the pathological process of early brain injury after subarachnoid hemorrhage. This study established SAH model by endovascular perforation and adding oxyhemoglobin (Hb) to HT22 cells and delved into the mechanism of BCAT1 in SAH-induced ferroptotic neuronal cell death. It was found that SAH-induced neuronal ferroptosis could be inhibited by BCAT1 overexpression (OE) in rats and HT22 cells, and BCAT1 OE alleviated neurological deficits and cognitive dysfunction in rats after SAH. In addition, the effect of BCAT1 could be reversed by the Ly294002, a specific inhibitor of the PI3K pathway. In summary, our present study indicated that BCAT1 OE alleviated early brain injury EBI after SAH by inhibiting neuron ferroptosis via activation of PI3K/AKT/mTOR pathway and the elevation of GPX4. These results suggested that BCAT1 was a promising therapeutic target for subarachnoid hemorrhage.
支链氨基酸转氨酶 1（BCAT1）对氧化还原系统的调节在疾病的发生和发展中具有重要意义，但 BCAT1 与蛛网膜下腔出血（SAH）之间的关系尚不清楚。铁死亡是一种依赖铁的脂质过氧化，伴随着谷胱甘肽过氧化物酶 4（GPX4）的耗竭，已被认为与蛛网膜下腔出血后早期脑损伤的病理过程有关。本研究通过血管内穿孔和向 HT22 细胞中添加氧合血红蛋白（Hb）建立了 SAH 模型，并探讨了 BCAT1 在 SAH 诱导的铁死亡性神经元细胞死亡中的作用机制。结果发现，BCAT1 过表达（OE）可抑制大鼠和 HT22 细胞中 SAH 诱导的神经元铁死亡，BCAT1 OE 可减轻大鼠 SAH 后的神经功能缺损和认知功能障碍。此外，BCAT1 的作用可被 PI3K 通路的特异性抑制剂 Ly294002 逆转。总之，本研究表明，BCAT1 OE 通过激活 PI3K/AKT/mTOR 通路和提高 GPX4 来抑制神经元铁死亡，从而减轻 SAH 后的早期脑损伤。这些结果表明，BCAT1 是蛛网膜下腔出血的一个有前途的治疗靶点。
