Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China.
Brain Res Bull. 2022 Jul;185:162-173. doi: 10.1016/j.brainresbull.2022.05.008. Epub 2022 May 16.
Subarachnoid hemorrhage (SAH), a type of hemorrhagic stroke, is a neurological emergency with high morbidity and mortality. Early brain injury (EBI) after SAH is the leading cause of poor prognosis in SAH patients. TRX system is a NADPH-dependent antioxidant system which is composed of thioredoxin reductase (TRXR), thioredoxin (TRX). The pentose phosphate pathway (PPP), a pathway through which glucose can be metabolized, is a major source of NADPH. Thioredoxin 1 (TRX1) is a member of thioredoxin system mainly located in cytoplasm. Serine/threonine kinases ataxia telangiectasia mutated (ATM) is an important oxidative stress receptor, and TRX1 can regulate ATM phosphorylation and then affect the activity of PPP key enzyme glucose 6-phosphate dehydrogenase (G6PD). However, whether TRX1 is involved in the regulation of PPP pathway after subarachnoid hemorrhage remains unclear. The results showed that after SAH, the level of TRX1 and phosphor-ATM decreased while the level of TRXR1 increased. G6PD protein level remained unchanged but the activity decreased, and the NADPH contents decreased. Overexpression of TRX1 by lentivirus upregulates the level of phosphor-ATM, G6PD activity and NADPH content. TRX1 overexpression improved short-term and long-term neurobehavioral outcomes and alleviated neuronal impairment in rats. Nissl staining showed that upregulation of TRX1 reduced cortical neuron injury. Our study shows that TRX1 participates in the PPP pathway by regulating phosphorylation ATM, which is accomplished by affecting G6PD activity. TRX1 may be an important target for EBI intervention after SAH.
蛛网膜下腔出血（SAH）是一种出血性中风，是一种发病率和死亡率都很高的神经急症。SAH 后的早期脑损伤（EBI）是导致 SAH 患者预后不良的主要原因。TRX 系统是一种 NADPH 依赖性抗氧化系统，由硫氧还蛋白还原酶（TRXR）和硫氧还蛋白（TRX）组成。戊糖磷酸途径（PPP）是一种葡萄糖可以代谢的途径，是 NADPH 的主要来源。硫氧还蛋白 1（TRX1）是一种主要位于细胞质中的硫氧还蛋白系统成员。丝氨酸/苏氨酸激酶共济失调毛细血管扩张突变（ATM）是一种重要的氧化应激受体，TRX1 可以调节 ATM 磷酸化，进而影响 PPP 关键酶葡萄糖 6-磷酸脱氢酶（G6PD）的活性。然而，TRX1 是否参与 SAH 后 PPP 途径的调节尚不清楚。结果表明，SAH 后 TRX1 和 phosphor-ATM 水平降低，而 TRXR1 水平升高。G6PD 蛋白水平不变但活性降低，NADPH 含量减少。慢病毒过表达 TRX1 上调 phosphor-ATM、G6PD 活性和 NADPH 含量。TRX1 过表达改善了大鼠的短期和长期神经行为结果，并减轻了神经元损伤。尼氏染色显示，TRX1 的上调减少了皮质神经元损伤。我们的研究表明，TRX1 通过调节磷酸化 ATM 参与 PPP 途径，这是通过影响 G6PD 活性来完成的。TRX1 可能是 SAH 后 EBI 干预的一个重要靶点。
