Division of Pharmacology, Central Drug Research Institute (CSIR), Lucknow 226001, India.
Behav Brain Res. 2011 Oct 10;224(1):50-7. doi: 10.1016/j.bbr.2011.04.039. Epub 2011 May 20.
The present study was planned to evaluate the cholinergic influence on mitochondrial activity and neurodegeneration associated with impaired memory in intracerebroventricular (ICV) streptozotocin (STZ) treated rats. STZ (3mg/kg), administered ICV twice with an interval of 48h between the two doses, showed significant impairment in spatial memory tested by water maze test 14 days after first dose without altering blood glucose level and locomotor activity. Animals were sacrificed on 21st day of ICV administration. STZ significantly increased malondialdehyde (MDA), reactive oxygen species (ROS), Ca(2+) ion influx, caspase-3 activity and decreased glutathione (GSH) level. Acetylcholinesterase inhibitors tacrine and donepezil (5mg/kg, PO) pretreatment significantly prevented STZ induced memory deficit, oxidative stress, Ca(2+) influx and caspase-3 activity. Carbachol, a muscarinic cholinergic agonist (0.01mg/kg, SC) did not show any significant effect on ROS generation, Ca(2+) ion influx and caspase-3 activity. While nicotinic cholinergic agonist, nicotine, significantly attenuated ICV STZ induced mitochondrial dysfunction and caspase-3 activity. The results indicate that instead of muscarinic receptors nicotinic receptors may be involved in neuroprotection by maintaining mitochondrial functions.
本研究旨在评估与脑室（ICV）链脲佐菌素（STZ）治疗大鼠记忆障碍相关的线粒体活性和神经退行性变的胆碱能影响。STZ（3mg/kg），两次 ICV 给药，两次剂量间隔 48h，在首次给药后 14 天通过水迷宫试验显示出明显的空间记忆损伤，而不改变血糖水平和运动活性。动物在 ICV 给药的第 21 天被处死。STZ 显著增加丙二醛（MDA）、活性氧（ROS）、Ca(2+)离子内流、半胱氨酸天冬氨酸蛋白酶-3 活性，并降低谷胱甘肽（GSH）水平。乙酰胆碱酯酶抑制剂他克林和多奈哌齐（5mg/kg，PO）预处理可显著预防 STZ 诱导的记忆缺陷、氧化应激、Ca(2+)内流和半胱氨酸天冬氨酸蛋白酶-3 活性。毒蕈碱型乙酰胆碱受体激动剂卡巴胆碱（0.01mg/kg，SC）对 ROS 生成、Ca(2+)离子内流和半胱氨酸天冬氨酸蛋白酶-3 活性无显著影响。而烟碱型乙酰胆碱受体激动剂尼古丁显著减轻 ICV STZ 诱导的线粒体功能障碍和半胱氨酸天冬氨酸蛋白酶-3 活性。结果表明，烟碱型受体可能参与了通过维持线粒体功能的神经保护作用，而不是毒蕈碱型受体。
