Kumar Anil, Seghal Neha, Padi Satyanaryana Venketeshwara, Naidu Pattipati Sreenivaslu
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India.
Eur J Pharmacol. 2006 Dec 3;551(1-3):58-66. doi: 10.1016/j.ejphar.2006.08.076. Epub 2006 Sep 9.
Alzheimer's disease is a progressive neurological and psychiatric disorder. Oxidative stress and neuroinflammation have been implicated in pathophysiology of Alzheimer's disease. Inflammatory cells, such as astrocytes and microglia, are activated in areas of the brain affected by amyloid plaques and inflammatory mediators including cytokines, chemokines, prostaglandins, oxygen free radicals and reactive nitrogen species may have a crucial role in Alzheimer's disease pathogenesis. Central administration of colchicine, a microtubule-disrupting agent, causes loss of cholinergic neurons and cognitive dysfunction that is associated with excessive free radical generation. The present study was aimed to evaluate the effects of cyclooxygenase inhibitors against colchicine-induced cognitive dysfunction and oxidative stress in rats. Following intracerebroventricular (i.c.v.) administration of colchicine (15 microg/5 microl), rats exhibited poor retention of memory in Morris water maze and elevated plus maze task paradigms and oxidative stress in rats. Chronic treatment with naproxen (per se; 20 and 40 mg/kg, p.o.) or valdecoxib (per se; 5 and 10 mg/kg, p.o.) daily respectively for a period of 25 days beginning 4 days prior to colchicine injection significantly improved colchicine-induced cognitive impairment. Intracerebroventricular colchicine injection resulted in free radical generation characterized by alterations in oxidative stress markers with a significant increase in malondialdehyde and nitrite levels and depletion of reduced glutathione levels in the brains of rats. It also caused a decrease in acetylcholinesterase activity. Besides, improving cognitive dysfunction, chronic administration of cyclooxygenase inhibitors (naproxen and valdecoxib) significantly reduced elevated malondialdehyde, nitrite levels and restored reduced glutathione levels and acetylcholinesterase activity. The results of the present study indicated that naproxen (per se; 20 and 40 mg/kg, p.o.) or valdecoxib (per se; 5 and 10 mg/kg, p.o.) treatment has a neuroprotective role against colchicine-induced cognitive impairment and associated oxidative stress. The present findings further support the potential use of cyclooxygenase inhibitors in treatment of neurodegenerative diseases such as Alzheimer's disease.
阿尔茨海默病是一种进行性神经和精神障碍。氧化应激和神经炎症与阿尔茨海默病的病理生理学有关。炎症细胞，如星形胶质细胞和小胶质细胞，在受淀粉样斑块影响的脑区被激活，包括细胞因子、趋化因子、前列腺素、氧自由基和活性氮物质在内的炎症介质可能在阿尔茨海默病发病机制中起关键作用。中枢给予秋水仙碱（一种微管破坏剂）会导致胆碱能神经元丧失和认知功能障碍，这与过量自由基生成有关。本研究旨在评估环氧化酶抑制剂对秋水仙碱诱导的大鼠认知功能障碍和氧化应激的影响。脑室内（i.c.v.）注射秋水仙碱（15微克/5微升）后，大鼠在莫里斯水迷宫和高架十字迷宫任务范式中表现出记忆保留不佳以及氧化应激增加。分别在秋水仙碱注射前4天开始，每天用萘普生（本身；20和40毫克/千克，口服）或伐地昔布（本身；5和10毫克/千克，口服）进行为期25天的慢性治疗，可显著改善秋水仙碱诱导的认知障碍。脑室内注射秋水仙碱导致自由基生成，其特征为氧化应激标志物发生改变，大鼠脑内丙二醛和亚硝酸盐水平显著升高，还原型谷胱甘肽水平降低。它还导致乙酰胆碱酯酶活性降低。此外，除改善认知功能障碍外，慢性给予环氧化酶抑制剂（萘普生和伐地昔布）可显著降低升高的丙二醛、亚硝酸盐水平，并恢复还原型谷胱甘肽水平和乙酰胆碱酯酶活性。本研究结果表明，萘普生（本身；20和40毫克/千克，口服）或伐地昔布（本身；5和10毫克/千克，口服）治疗对秋水仙碱诱导的认知障碍及相关氧化应激具有神经保护作用。本研究结果进一步支持环氧化酶抑制剂在治疗如阿尔茨海默病等神经退行性疾病中的潜在应用。
