Okadaic acid (ICV) induced memory impairment in rats: A suitable experimental model to test anti-dementia activity

• Published in: Brain research Vol. 1309; pp. 66 - 74
• Main Authors: Kamat, Pradeep K, Tota, Santoshkumar, Saxena, Gunjan, Shukla, Rakesh, Nath, Chandishwar
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 14.01.2010; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Calcium Signaling - drug effects; Calcium Signaling - physiology; Cholinesterase Inhibitors - pharmacology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia - chemically induced; Dementia - drug therapy; Dementia - physiopathology; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical - methods; Enzyme Inhibitors - toxicity; Excitatory Amino Acid Antagonists - pharmacology; Excitotoxicity; Glutathione - metabolism; Indans - pharmacology; Injections, Intraventricular; Male; Malondialdehyde - metabolism; Maze Learning - drug effects; Maze Learning - physiology; Medical sciences; Memantine; Memantine - pharmacology; Memory - drug effects; Memory - physiology; Memory Disorders - chemically induced; Memory Disorders - drug therapy; Memory Disorders - physiopathology; Memory impairment; Morris water maze; Neurology; Neuropsychological Tests; Nitrites - metabolism; Okadaic acid; Okadaic Acid - toxicity; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Piperidines - pharmacology; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Treatment Outcome; Oxidative stress; AD; Morris water maze; OKA; okadaic acid; Memory impairment; Memantine; Excitotoxicity; Donepezil; CSF; cerebrospinal fluid; intracerebroventricular; Alzheimer's disease; ICV; Okadaic acid; Memory disorder; Cognitive disorder; Rat; Toxicity; Space perception; Acquisition process; Degenerative disease; Nervous system diseases; Rodentia; Cerebral disorder; Senile dementia; Vertebrata; Mammalia; Animal; Central nervous system disease; Intracerebral administration; Models; Perceptive learning
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2009.10.064

Abstract 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 [Ca2 ]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 [Ca2+ ]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.