Okadaic acid induced neurotoxicity leads to central cholinergic dysfunction in rats
Okadaic acid induced neurotoxicity leads to central cholinergic dysfunction in rats
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DOI：
10.1016/j.ejphar.2012.06.006
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发表时间：
2012-09-05
影响因子：
5
通讯作者：
Nath, Chandishwar
中科院分区：
文献类型：
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作者：
Kamat, Pradeep Kumar;Tota, Santoshkumar;Nath, Chandishwar
中枢胆碱能系统参与记忆的调节，这些干扰导致记忆丧失。在此之前，我们研究了冈田酸，OKA （200ng, icc.v）对大鼠记忆障碍和线粒体功能障碍的影响。本研究通过观察脑区（小脑、纹状体皮质和海马）乙酰胆碱水平（ACh）、乙酰胆碱酯酶（AChE）活性以及乙酰胆碱酯酶和α 7-nAChR作为胆碱能标志物的mRNA表达，探讨了OKA （icy）对胆碱能功能的影响。在本研究中，OKA引起大鼠乙酰胆碱水平、乙酰胆碱酯酶活性以及乙酰胆碱酯酶和α 7-烟碱受体mRNA表达的显著降低，但这些变化主要发生在皮质和海马。此外，甲酚紫染色的组织病理学研究显示，给药后皮质和海马的神经元丢失表明神经毒性。每日给予抗痴呆药物多奈哌齐（AChE抑制剂，5 mg/kg, p.o）和美金刚（NMDA受体拮抗剂，10 mg/kg, p.o）预处理，连续13天，可预防OKA治疗大鼠皮质和海马胆碱能功能障碍和神经元丢失。多奈哌齐连用13天，降低了乙酰胆碱酯酶活性，增加了乙酰胆碱酯酶和- 7-烟碱受体mRNA的表达。而每日美金刚处理13 d对乙酰胆碱酯酶活性、乙酰胆碱酯酶mRNA表达和α - 7-烟碱受体没有影响。本研究结果表明，除了我们之前的研究显示的记忆障碍和线粒体功能障碍外，OKA （i.c.v）还会引起胆碱能功能障碍和神经元丢失，这可以通过多奈哌齐和美金刚等抗痴呆药物来解决。(C) 2012 Elsevier B.V.版权所有
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 (200 ng, i.c.v.) on memory impairment and mitochondrial dysfunction in rats. In the present study, we investigated effect of OKA (icy) on cholinergic function by observing acetylcholine level (ACh), acetylcholinestrase (AChE) activity, and mRNA expression of acetylcholinestrase and alpha 7nicotinic receptor (alpha 7-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 alpha 7-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; 5 mg/kg, p.o) and memantine (NMDA receptor antagonist; 10 mg/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 alpha 7-nicotinic receptor. Whereas, per se treatment with memantine daily for 13 day did not affect acetylcholinestrase activity, mRNA expression of acetylcholinestrase and alpha 7-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. (C) 2012 Elsevier B.V. All rights reserved.