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Inhibition of cyclooxygenase-1 does not reduce mortality in post-ischemic stroke rats.
Neuroscience Letters ( IF 2.5 ) Pub Date : 2020-08-07 , DOI: 10.1016/j.neulet.2020.135296
Ira S Rostevanov 1 , Matthew Boyko 2 , Savina Ferorelli 3 , Antonio Scilimati 3 , Maria Grazia Perrone 3 , Jacob Kaplanski 1 , Alexander Zlotnik 2 , Abed N Azab 4
Affiliation  

Background

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.

Objective

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.

Methods

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)E2 and tumor necrosis factor (TNF)-α in these brain regions were determined by ELISA kits.

Results

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 PGE2 levels in post-MCAO rats’ brains.

Conclusion

Overall, these results suggest that chronic treatment with the selective COX-1 inhibitor mofezolac did not reduce morbidity or mortality in post-stroke rats.



中文翻译:

抑制环氧合酶-1不会降低缺血性中风后大鼠的死亡率。

背景

缺血性中风是死亡率和发病率的主要原因之一。当前可用的非侵入性治疗选择不够有效。缺血后脑的特征在于突出的炎症反应。关于环氧合酶(COX)-1参与缺血性中风的病理生理知之甚少。

目的

这项研究旨在检查高选择性COX-1抑制剂Mofezolac对中风后大鼠的临床结局和脑炎性标志物的影响。

方法

通过使大鼠受到永久性大脑中动脉闭塞(MCAO)诱导中风。对照大鼠进行假手术。大鼠用莫苯唑酸(50毫克/千克,腹膜内[处理的IP ]),每天一次,持续14天。对照动物用赋形剂处理。在不同时间点监测体温(BT),神经学评分(NS)和累积死亡率。实验结束时,对大鼠实施安乐死并提取三个大脑区域(下丘脑,海马和额叶皮层)。用ELISA试剂盒测定这些脑区域中白介素(IL)-6,前列腺素(PG)E 2和肿瘤坏死因子(TNF)-α的水平。

结果

不论给予何种治疗,MCAO后大鼠的BT,NS和累积死亡率均显着高于假手术大鼠。Mofezolac治疗和假手术的动物之间的BT,NS和死亡率没有显着差异。与媒介物处理后的MCAO大鼠相比,用Mofezolac处理的BT明显更低。Mofezolac在任何时间点都不会显着改变MCAO后大鼠的NS。相比于媒介物治疗的MCAO后大鼠,用Mofezolac治疗的14天累积死亡率无统计学意义(分别为48%21%;P  = 0.184)。通常,MCAO后和假手术大鼠之间的IL-6和TNF-α水平没有差异,并且不受Mofezolac处理的影响。相反,莫非唑酯显着降低PGEMCAO后大鼠大脑中的2个水平。

结论

总体而言,这些结果表明,使用选择性COX-1抑制剂莫非唑酯进行的慢性治疗并未降低中风后大鼠的发病率或死亡率。

更新日期:2020-08-21
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