Division of Pharmacology, CSIR-Central Drug Research Institute, PO Box 173, Lucknow (UP) 226001, India.
Eur J Pharmacol. 2012 Sep 5;690(1-3):90-8. doi: 10.1016/j.ejphar.2012.06.006. Epub 2012 Jun 29.
Central cholinergic system is involved in regulation of memory and disturbances in these results in memory loss. Previously, we examined the effect of okadaic acid, OKA (200ng, i.c.v.) on memory impairment and mitochondrial dysfunction in rats. In the present study, we investigated effect of OKA (i.c.v) on cholinergic function by observing acetylcholine level (ACh), acetylcholinestrase (AChE) activity, and mRNA expression of acetylcholinestrase and α7nicotinic receptor (α7-nAChR) as a cholinergic markers in brain areas (cerebellum, striatum cortex and hippocampus). In present work OKA, caused a significant decrease in acetylcholine level, acetylcholinestrase activity and mRNA expression of acetylcholinestrase and α7-nicotinic receptor in rat but these changes were mainly observed in cortex and hippocampus. Further, histopathological study by cresyl violet staining showed neuronal loss in cortex and hippocampus after OKA administration indicating neurotoxicity. Pretreatment with anti-dementic drugs donepezil (AChE inhibitor; 5mg/kg, p.o) and memantine (NMDA receptor antagonist; 10mg/kg, p.o) daily for 13 day prevented cholinergic dysfunction and neuronal loss in cortex and hippocampus of OKA treated rat. Daily per se treatment for 13 day with donepezil decreased acetylcholinestrase activity and increased mRNA expression of acetylcholinestrase and α7-nicotinic receptor. Whereas, per se treatment with memantine daily for 13 day did not affect acetylcholinestrase activity, mRNA expression of acetylcholinestrase and α7-nicotinic receptor. Findings of this work shows that OKA (i.c.v.), apart from memory impairment and mitochondrial dysfunction, as our previous study showed, also induced cholinergic dysfunction and neuronal loss, which can be addressed by antidementic drugs like donepezil and memantine.
中枢胆碱能系统参与记忆的调节，其功能障碍导致记忆丧失。此前，我们研究了冈田酸（OKA）（200ng，侧脑室注射）对大鼠记忆障碍和线粒体功能障碍的影响。在本研究中，我们通过观察乙酰胆碱水平（ACh）、乙酰胆碱酯酶（AChE）活性以及脑区（小脑、纹状体皮层和海马体）中乙酰胆碱酯酶和α7 烟碱型乙酰胆碱受体（α7-nAChR）的 mRNA 表达，研究了 OKA（侧脑室注射）对胆碱能功能的影响，作为胆碱能标志物。目前的工作中，OKA 导致大鼠乙酰胆碱水平、乙酰胆碱酯酶活性以及乙酰胆碱酯酶和 α7 烟碱型乙酰胆碱受体的 mRNA 表达显著降低，但这些变化主要观察到在皮层和海马体中。进一步的，通过甲苯胺蓝染色的组织病理学研究显示，OKA 给药后皮层和海马体神经元丢失，表明其具有神经毒性。用抗痴呆药物多奈哌齐（AChE 抑制剂；5mg/kg，po）和盐酸美金刚（NMDA 受体拮抗剂；10mg/kg，po）预处理，每日一次，共 13 天，可预防 OKA 处理大鼠皮层和海马体的胆碱能功能障碍和神经元丢失。多奈哌齐自身每日治疗 13 天可降低乙酰胆碱酯酶活性并增加乙酰胆碱酯酶和 α7 烟碱型乙酰胆碱受体的 mRNA 表达。然而，盐酸美金刚自身每日治疗 13 天并不影响乙酰胆碱酯酶活性、乙酰胆碱酯酶的 mRNA 表达和 α7 烟碱型乙酰胆碱受体。本研究结果表明，OKA（侧脑室注射）除了我们之前的研究表明的记忆障碍和线粒体功能障碍外，还可诱导胆碱能功能障碍和神经元丢失，这可通过多奈哌齐和盐酸美金刚等抗痴呆药物来治疗。
