Department of Clinical Biochemistry and Pharmacology, Israel.
Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Neurosci Lett. 2020 Oct 15;737:135296. doi: 10.1016/j.neulet.2020.135296. Epub 2020 Aug 7.
Ischemic stroke is one of the leading causes of mortality and morbidity. The currently available non-invasive therapeutic options are not sufficiently efficacious. Post-ischemic brain is characterized by a prominent inflammatory response. Little is known about the involvement of cyclooxygenase (COX)-1 in the pathophysiology of ischemic stroke.
This study was undertaken to examine the effects of a highly selective COX-1 inhibitor - mofezolac - on clinical outcomes and brain inflammatory markers in post-stroke rats.
Stroke was induced by subjecting rats to permanent middle cerebral artery occlusion (MCAO). Control rats underwent a sham surgery. Rats were treated with mofezolac (50 mg/kg, intraperitoneally [ip]) once daily for 14 days. Control animals were treated with vehicle. Body temperature (BT), neurological score (NS) and cumulative mortality were monitored at different time points. At the end of the experiment, rats were euthanized and three brain regions (hypothalamus, hippocampus and frontal cortex) were extracted. Levels of interleukin (IL)-6, prostaglandin (PG)E and tumor necrosis factor (TNF)-α in these brain regions were determined by ELISA kits.
BT, NS and cumulative mortality were all significantly higher in post-MCAO rats than in sham-operated rats, irrespective of the treatment given. BT, NS and mortality rate did not differ significantly between mofezolac-treated and vehicle-treated sham-operated animals. BT was significantly lower in mofezolac-treated as compared to vehicle-treated post-MCAO rats. Mofezolac did not significantly alter NS in post-MCAO rats at any time-point. Cumulative 14-day mortality was non-significantly higher in mofezolac-treated as compared to vehicle-treated post-MCAO rats (48 % vs. 21 %, respectively; P = 0.184). Mostly, IL-6 and TNF-α levels did not differ between post-MCAO and sham-operated rats and were not affected by mofezolac treatment. In contrast, mofezolac significantly decreased PGE levels in post-MCAO rats' brains.
Overall, these results suggest that chronic treatment with the selective COX-1 inhibitor mofezolac did not reduce morbidity or mortality in post-stroke rats.
缺血性中风是导致死亡率和发病率的主要原因之一。目前可用的非侵入性治疗选择并不足够有效。缺血后的大脑以明显的炎症反应为特征。关于环氧化酶 (COX)-1 在缺血性中风的病理生理学中的参与，知之甚少。
本研究旨在研究高度选择性 COX-1 抑制剂莫洛芬 (mofezolac) 对中风后大鼠临床结果和脑炎症标志物的影响。
通过使大鼠接受永久性大脑中动脉闭塞 (MCAO) 来诱导中风。对照大鼠接受假手术。大鼠每天腹腔内 (ip) 给予莫洛芬 (50mg/kg) 治疗 14 天。对照动物给予载体治疗。在不同时间点监测体温 (BT)、神经评分 (NS) 和累积死亡率。在实验结束时，处死大鼠并提取三个脑区 (下丘脑、海马和额叶皮质)。通过 ELISA 试剂盒测定这些脑区白细胞介素 (IL)-6、前列腺素 (PG)E 和肿瘤坏死因子 (TNF)-α 的水平。
MCAO 后大鼠的 BT、NS 和累积死亡率均明显高于假手术大鼠，而不论给予何种治疗。莫洛芬治疗和载体治疗的假手术动物之间的 BT、NS 和死亡率没有显着差异。与载体治疗的 MCAO 大鼠相比，莫洛芬治疗的大鼠 BT 显着降低。莫洛芬在任何时间点均未显着改变 MCAO 大鼠的 NS。与载体治疗的 MCAO 大鼠相比，莫洛芬治疗的大鼠 14 天累积死亡率非显着升高 (分别为 48%和 21%；P=0.184)。大多数情况下，MCAO 后和假手术大鼠的 IL-6 和 TNF-α 水平没有差异，并且不受莫洛芬治疗的影响。相比之下，莫洛芬显着降低了 MCAO 大鼠大脑中的 PGE 水平。
总体而言，这些结果表明，慢性使用选择性 COX-1 抑制剂莫洛芬并未降低中风后大鼠的发病率或死亡率。
