title: Okadaic acid induced neurotoxicity leads to central cholinergic dysfunction in rats.
abstract: 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.
authors: Division of Pharmacology, CSIR-Central Drug Research Institute, PO Box 173, Lucknow (UP) 226001, India.
authors: Pradeep Kumar
authors: PK
authors: Kamat
authors: Santoshkumar
authors: S
authors: Tota
authors: Shivika
authors: S
authors: Rai
authors: Rakesh
authors: R
authors: Shukla
authors: Shakir
authors: S
authors: Ali
authors: Abul Kalam
authors: AK
authors: Najmi
authors: Chandishwar
authors: C
authors: Nath
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D000077265:Donepezil; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007189:Indans / Q000494:pharmacology; D008297:Male; D008559:Memantine / Q000494:pharmacology; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D019319:Okadaic Acid / Q000633:toxicity*; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D007189:Indans; D009498:Neurotoxins; D010880:Piperidines; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D019319:Okadaic Acid; D000077265:Donepezil; D000110:Acetylcholinesterase; D000109:Acetylcholine; D008559:Memantine