okadaic-acid and Dementia

Several types of animal models have been developed to investigate Alzheimer's disease (AD). Okadaic acid (OA), a potent inhibitor of phosphatases 1 and 2A, induces characteristics that resemble AD-like pathology. Memory impairment induced by intra-hippocampal injection of OA has been reported, accompanied by remarkable neuropathological changes including hippocampal neurodegeneration, a paired helical filament-like phosphorylation of tau protein, and formation of β-amyloid containing plaque-like structures. Rats were submitted to bilateral intrahippocampal okadaic acid-injection (100 ng) and, 12 days after the surgery, behavioral and biochemical tests were performed. Using this model, we evaluated spatial cognitive deficit and neuroglial alterations, particularly astroglial protein markers such as glial fibrillary acidic protein (GFAP) and S100B, metabolism of glutamate, oxidative parameters and alterations in MAPKs. Our results indicate significant hippocampal changes, including increased GFAP, protein oxidation, and phosphorylation of p38(MAPK); and decreases in glutathione content, transporter EAAT2/GLT-1, and glutamine synthetase activity as well as a decrease in cerebrospinal fluid S100B. No alterations were observed in glutamate uptake activity and S100B content. In conclusion, the OA-induced model of dementia caused spatial cognitive deficit and oxidative stress in this model and, for the first time to our knowledge, specific astroglial alterations. Findings contribute to understanding diseases accompanied by cognitive deficits and the neural damage induced by AO administration.

Topics: Animals; Cognition Disorders; Dementia; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Glial Fibrillary Acidic Protein; Glutamate-Ammonia Ligase; Glutamic Acid; Glutathione; Hippocampus; Humans; Male; Microinjections; Mitogen-Activated Protein Kinases; Nerve Growth Factors; Neuroglia; Okadaic Acid; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Wistar; S100 Calcium Binding Protein beta Subunit; S100 Proteins

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.

Topics: Animals; Brain; Calcium Signaling; Cholinesterase Inhibitors; Dementia; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Glutathione; Indans; Injections, Intraventricular; Male; Malondialdehyde; Maze Learning; Memantine; Memory; Memory Disorders; Neuropsychological Tests; Nitrites; Okadaic Acid; Oxidative Stress; Piperidines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Treatment Outcome