Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh-160014, India.
Pharmacol Biochem Behav. 2012 Nov;103(1):43-52. doi: 10.1016/j.pbb.2012.07.015.
There is an evolving consensus that mild cognitive impairment (MCI) serves as a prodrome to Alzheimer's disease. Antioxidants and COX-2 (cyclo-oxygenase-2) inhibitors have also been reported to have beneficial effects against conditions of memory impairment. Newer drugs like cysteinyl leukotriene inhibitors have shown neuroprotective effect in animal models of ischemia. Thus, the present study purports to explore the potential role of montelukast (a cysteinyl leukotriene inhibitor) in concert with rofecoxib (COX-2 inhibitor) and caffeic acid (a 5-LOX inhibitor and potent antioxidant) against kainic acid induced cognitive dysfunction in rats. In the experimental protocol, kainic acid (0.4 μg/2 μl) in artificial cerebrospinal fluid (ACSF) was given intrahippocampally (CA3 region) to induce a condition similar to MCI. Memory performance was measured on days 10-14 and the locomotor activity was measured on days 1, 7 and 14. For estimation of biochemical, mitochondrial and histopathological parameters, animals were sacrificed on day 14, stored at -80 °C and the estimation was done on the 15th day. The treatment groups consisting of montelukast (0.5 and 1 mg/kg), rofecoxib (5 and 10 mg/kg) and caffeic acid (5 and 10 mg/kg) showed significant improvement in memory performance, oxidative stress parameters and mitochondrial function as compared to that of control (kainic acid treated), however, combination of montelukast with rofecoxib showed significant improvement in their protective effect. Thus the present study emphasizes the positive modulation of cysteinyl leukotriene receptor inhibition on COX (cyclooxygenase) and LOX (lipoxygenase) pathways in the control of the neuroinflammation in kainic acid induced cognitive dysfunction in rats.
目前有一种共识认为，轻度认知障碍（MCI）是阿尔茨海默病的前驱症状。抗氧化剂和 COX-2（环氧化酶-2）抑制剂也被报道对记忆障碍有有益的作用。像半胱氨酰白三烯抑制剂这样的新药在缺血性动物模型中显示出神经保护作用。因此，本研究旨在探讨孟鲁司特（半胱氨酰白三烯抑制剂）与罗非昔布（COX-2 抑制剂）和咖啡酸（5-LOX 抑制剂和有效的抗氧化剂）联合应用于红藻氨酸诱导的大鼠认知功能障碍的潜在作用。在实验方案中，红藻氨酸（0.4 μg/2 μl）在人工脑脊液（ACSF）中被注入海马内（CA3 区），以诱导类似于 MCI 的状态。在第 10-14 天测量记忆表现，在第 1、7 和 14 天测量运动活性。为了评估生化、线粒体和组织病理学参数，动物在第 14 天被处死，储存在-80°C，并在第 15 天进行评估。由孟鲁司特（0.5 和 1 mg/kg）、罗非昔布（5 和 10 mg/kg）和咖啡酸（5 和 10 mg/kg）组成的治疗组在记忆表现、氧化应激参数和线粒体功能方面与对照组（红藻氨酸处理组）相比有显著改善，然而，孟鲁司特与罗非昔布的联合治疗显示出其保护作用的显著改善。因此，本研究强调了半胱氨酰白三烯受体抑制对 COX（环氧化酶）和 LOX（脂氧合酶）途径的积极调节，以控制红藻氨酸诱导的大鼠认知功能障碍中的神经炎症。
