Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, China.
Foshan Magpie Pharmaceuticals Co., LTD, Foshan, Guangdong Province, China.
Neuromolecular Med. 2019 Sep;21(3):262-274. doi: 10.1007/s12017-019-08543-9. Epub 2019 May 27.
Cerebral vasospasm is one of the deleterious complications after subarachnoid hemorrhage (SAH), leading to delayed cerebral ischemia and permanent neurological deficits or even death. Free radicals and oxidative stress are considered as crucial causes contributing to cerebral vasospasm and brain damage after SAH. Tetramethylpyrazine nitrone (TBN), a derivative of the clinically used anti-stroke drug tetramethylpyrazine armed with a powerful free radical scavenging nitrone moiety, has been reported to prevent brain damage from ischemic stroke. The present study aimed to investigate the effects of TBN on vasospasm and brain damage after SAH. Two experimental SAH models were used, a rat model by endovascular perforation and a rabbit model by intracisternal injection of autologous blood. The effects of TBN on SAH were evaluated assessing basilar artery spasm, neuronal apoptosis, and neurological deficits. TBN treatment significantly attenuated vasospasm, improved neurological behavior functions and reduced the number of apoptotic neurons in both the SAH rats and rabbits. Mechanistically, TBN suppressed the increase in 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine immuno-positive cells in the cortex of SAH rat brain. Western blot analyses indicated that TBN effectively reversed the altered expression of Bcl-2, Bax and cytochrome C, and up-regulated nuclear factor erythroid-derived 2-like 2 (Nrf2) and hemeoxygenase-1 (HO-1) protein expressions. In the in vitro studies, TBN inhibited HO-induced bEnd.3 cell apoptosis and reduced ROS generation. Additionally, TBN alleviated the contraction of rat basilar artery rings induced by HO ex vivo. In conclusion, TBN ameliorated SAH-induced cerebral vasospasm and neuronal damage. These effects of TBN may be attributed to its anti-oxidative stress effect and up-regulation of Nrf2/HO-1.
脑动脉痉挛是蛛网膜下腔出血（SAH）后的一种有害并发症，导致迟发性脑缺血和永久性神经功能缺损，甚至死亡。自由基和氧化应激被认为是导致蛛网膜下腔出血后脑血管痉挛和脑损伤的关键原因。川芎嗪硝酮（TBN）是临床应用的抗中风药物川芎嗪的衍生物，具有强大的自由基清除硝酮部分，据报道可预防缺血性中风引起的脑损伤。本研究旨在探讨 TBN 对蛛网膜下腔出血后血管痉挛和脑损伤的影响。使用了两种实验性蛛网膜下腔出血模型，一种是血管内穿孔的大鼠模型，另一种是自体血脑室内注射的兔模型。通过评估基底动脉痉挛、神经元凋亡和神经功能缺损来评估 TBN 对蛛网膜下腔出血的影响。TBN 治疗显著减轻了血管痉挛，改善了神经行为功能，并减少了 SAH 大鼠和兔脑中凋亡神经元的数量。机制上，TBN 抑制了 SAH 大鼠大脑皮质中 3-硝基酪氨酸和 8-羟基-2-脱氧鸟苷免疫阳性细胞的增加。Western blot 分析表明，TBN 有效地逆转了 Bcl-2、Bax 和细胞色素 C 的改变表达，并上调了核因子红细胞衍生 2 样 2（Nrf2）和血红素加氧酶-1（HO-1）蛋白的表达。在体外研究中，TBN 抑制了 HO 诱导的 bEnd.3 细胞凋亡和减少 ROS 的生成。此外，TBN 减轻了 HO 体外诱导的大鼠基底动脉环收缩。总之，TBN 改善了 SAH 引起的脑血管痉挛和神经元损伤。TBN 的这些作用可能归因于其抗氧化应激作用和 Nrf2/HO-1 的上调。
