Saad M A, Abdelsalam R M, Kenawy S A, Attia A S
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt,
Neurochem Res. 2015 Jan;40(1):139-50. doi: 10.1007/s11064-014-1478-9. Epub 2014 Nov 18.
Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory and immune modulating lipid mediators involved in inflammatory diseases and were boosted in human brain after acute phase of cerebral ischemia. The antagonism of CysLTs receptors may offer protection against ischemic damage. Therefore it seemed interesting to study the possible neuroprotective effect of Montelukast, a CysLTR1 antagonist in global cerebral ischemia/reperfusion (IR) injury in rats. Global cerebral ischemia-reperfusion was induced by bilateral carotid artery occlusion for 15 min followed by 60 min reperfusion period. Animals were randomly allocated into three groups (n = 30 per group): Sham operated, I/R control and rats treated with montelukast (0.5 mg/kg, po) daily for 7 days then I/R was induced 1 h after the last dose of montelukast. After reperfusion rats were killed by decapitation, brains were removed and both hippocampi separated and the following biochemical parameters were estimated; lactate dehydrogenase activity, oxidative stress markers (lipid peroxides, nitric oxide and reduced glutathione), inflammatory markers (myeloperoxidase, tumor necrosis factor-alpha, nuclear factor kappa-B, interleukin-6 and interleukin-10), apoptotic biomarkers (caspase 3 and cytochrome C), neurotransmitters (glutamate, gamma aminobutyric acid), Cys-LTs contents and CysLT1 receptor expression; as well as total brain infarct size and histopathological examination of the hippocampus were assessed. Montelukast protected hippocampal tissue by reducing oxidative stress, inflammatory and apoptotic markers. Furthermore, it reduced glutamate and lactate dehydrogenase activity as well as infarct size elevated by I/R. These results were consistent with the histopathological findings. Montelukast showed a neuroprotective effects through antioxidant, anti-inflammatory and antiapoptotic mechanisms.
半胱氨酰白三烯（CysLTs）是强效的促炎和免疫调节脂质介质，参与炎症性疾病，并且在脑缺血急性期后人脑内其水平会升高。CysLTs受体的拮抗作用可能对缺血损伤起到保护作用。因此，研究孟鲁司特（一种CysLTR1拮抗剂）对大鼠全脑缺血/再灌注（IR）损伤可能的神经保护作用似乎很有意义。通过双侧颈动脉闭塞15分钟，随后进行60分钟再灌注期来诱导全脑缺血-再灌注。动物被随机分为三组（每组n = 30）：假手术组、I/R对照组以及每天口服孟鲁司特（0.5 mg/kg）共7天，然后在最后一剂孟鲁司特给药1小时后诱导I/R的大鼠组。再灌注后，通过断头处死大鼠，取出大脑，分离双侧海马，并评估以下生化参数；乳酸脱氢酶活性、氧化应激标志物（脂质过氧化物、一氧化氮和还原型谷胱甘肽）、炎症标志物（髓过氧化物酶、肿瘤坏死因子-α、核因子κ-B、白细胞介素-6和白细胞介素-10）、凋亡生物标志物（半胱天冬酶3和细胞色素C）、神经递质（谷氨酸、γ-氨基丁酸）、Cys-LTs含量和CysLT1受体表达；同时评估全脑梗死面积以及海马的组织病理学检查。孟鲁司特通过降低氧化应激、炎症和凋亡标志物来保护海马组织。此外，它还降低了谷氨酸和乳酸脱氢酶活性以及I/R引起的梗死面积增加。这些结果与组织病理学发现一致。孟鲁司特通过抗氧化、抗炎和抗凋亡机制显示出神经保护作用。
