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 H₂O₂-induced bEnd.3 cell apoptosis and reduced ROS generation. Additionally, TBN alleviated the contraction of rat basilar artery rings induced by H₂O₂ 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.

中文翻译：

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在实验性蛛网膜下腔出血模型中，四甲基吡嗪氮酮可降低氧化应激，减轻脑血管痉挛。

脑血管痉挛是蛛网膜下腔出血（SAH）后的有害并发症之一，导致延迟的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SAH后脑血管痉挛和脑损伤的重要原因。据报道，四甲基吡嗪硝酮（TBN）是临床上使用的抗中风药物四甲基吡嗪的衍生物，具有强大的自由基清除硝酮部分，可预防缺血性中风对脑的损害。本研究旨在探讨TBN对SAH后血管痉挛和脑损伤的影响。使用了两种实验性SAH模型，一种是通过血管内穿孔的大鼠模型，另一种是通过脑池内自体血注射的兔子模型。通过评估基底动脉痉挛，神经元凋亡和神经功能缺损，评估了TBN对SAH的影响。TBN治疗可显着减弱SAH大鼠和兔子的血管痉挛，改善神经行为功能并减少凋亡神经元的数量。从机理上讲，TBN抑制了SAH大鼠大脑皮层中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印迹分析表明，TBN有效逆转了Bcl-2，Bax和细胞色素C的表达变化，并上调了核因子类红细胞衍生的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H 改善了SAH大鼠和兔子的神经行为功能并减少了凋亡神经元的数量。从机理上讲，TBN抑制了SAH大鼠大脑皮层中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印迹分析表明，TBN有效逆转了Bcl-2，Bax和细胞色素C的表达变化，并上调了核因子类红细胞衍生的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H 改善了SAH大鼠和兔子的神经行为功能并减少了凋亡神经元的数量。从机理上讲，TBN抑制了SAH大鼠大脑皮层中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印迹分析表明，TBN有效逆转了Bcl-2，Bax和细胞色素C的表达变化，并上调了核因子类红细胞衍生的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H Bax和细胞色素C，以及上调的核因子类胡萝卜素衍生的2样2（Nrf2）和血红素加氧酶1（HO-1）蛋白表达。在体外研究中，TBN抑制H Bax和细胞色素C，以及上调的核因子类胡萝卜素衍生的2样2（Nrf2）和血红素加氧酶1（HO-1）蛋白表达。在体外研究中，TBN抑制H₂ O ₂诱导bEnd.3细胞凋亡并减少ROS生成。另外，TBN减轻了H ₂ O ₂离体诱导的大鼠基底动脉环的收缩。总之，TBN改善了SAH诱导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。