Okadaic acid (ICV) induced memory impairment in rats: a suitable experimental model to test anti-dementia activity.
Okadaic acid (OKA) is a potent and selective inhibitor of protein phosphatases, PP2A and PP1. In the present study, we evaluated effect of intracerebroventricular (ICV) bilateral injection of OKA (100 and 200 ng) on memory function and oxidative stress in rats. ICV injection of OKA (200 ng) produced memory impairment as evidenced by no significant decrease in latency time to reach the hidden platform in water maze test. It produced increase in malondialdehyde (MDA), nitrite level, reactive oxygen species (ROS) generation, mitochondrial calcium ion [Ca(2)](i) level and decreased glutathione (GSH) level in rat brain areas, indicating oxidative stress. Furthermore, we evaluated the effect of anti-dementia drugs memantine, a NMDA antagonist, and donepezil, a cholinesterase inhibitor, on OKA ICV induced memory impairment. Administration of memantine (10 mg/kg, p.o.) and donepezil (5 mg/kg, p.o.) for 13 days starting from the OKA injection improved performance in memory tests and also significantly restored GSH, MDA, nitrite levels, ROS generation and [Ca(2+)](i) level. This study demonstrates that the clinically used anti-dementic drugs are effective in OKA induced free radical generation and memory impairment in rats. Thus, OKA ICV induced memory impairment in rat appeared as a useful test model to screen anti-dementia drugs.
Kamat
Pradeep K
PK
Division of Pharmacology, Central Drug Research Institute, Lucknow (U.P.), India.
Tota
Santoshkumar
S
Saxena
Gunjan
G
Shukla
Rakesh
R
Nath
Chandishwar
C
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003704:Dementia / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D000077265:Donepezil; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D007189:Indans / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008559:Memantine / Q000494:pharmacology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D009483:Neuropsychological Tests; D009573:Nitrites / Q000378:metabolism; D019319:Okadaic Acid / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D016896:Treatment Outcome
D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D009573:Nitrites; D010880:Piperidines; D017382:Reactive Oxygen Species; D019319:Okadaic Acid; D008315:Malondialdehyde; D000077265:Donepezil; D005978:Glutathione; D008559:Memantine