Effect of donepezil and tacrine on oxidative stress in intracerebral streptozotocin-induced model of dementia in mice.
Oxidative stress is a major factor implicated in the degeneration of cholinergic neurons in Alzheimer's disease. Presently, cholinesterase inhibitors are the mainstay of therapy for Alzheimer's disease. However, the potential of cholinesterase inhibitors as antioxidants, an important aspect for neuroprotection, has not been properly investigated. Therefore, the present study was designed to investigate the influence of antidementia drugs, tacrine and donepezil, on biochemical markers of oxidative stress, glutathione (GSH) and malondialdehyde (MDA), and acetylcholinesterase activity in the brain in a streptozotocin-induced experimental model of dementia in mice. Intracerebral (i.c.) injection of streptozotocin at a dose of 0.5 mg/kg on 1st and 3rd days caused significant deficits in memory function, as evaluated in a passive avoidance test and Morris Water Maze (spatial memory) test 14 days after the 1st dose. Mice were treated with tacrine and donepezil at a dose of 5 mg/kg orally in separate groups. Both tacrine- and donepezil-treated mice showed a significant improvement of the streptozotocin (i.c.)-induced memory impairment. Streptozotocin (i.c.) administration caused a significant decrease in GSH and increase in MDA as compared to control, indicating a state of oxidative stress in the brain of streptozotocin (i.c.) amnesic mice. Treatment of streptozotocin (i.c.) amnesic mice with tacrine or donepezil did not cause significant changes in GSH and MDA levels in the brain as compared to control. Streptozotocin amnesic mice had raised acetylcholinesterase activity in the brain while there was a significant decrease in brain acetylcholinesterase activity in tacrine- and donepezil-treated streptozotocin (i.c.) mice. Thus, results indicate that tacrine and donepezil, beside inhibition of acetylcholinesterase, may also suppress oxidative stress.
Saxena
Gunjan
G
Division of Pharmacology, Central Drug Research Institute, PO Box 173, Lucknow UP 226001, India.
Singh
Sheelendra Pratap
SP
Agrawal
Rahul
R
Nath
Chandishwar
C
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D003704:Dementia / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D000077265:Donepezil; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D007189:Indans / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy; D051379:Mice; D018697:Nootropic Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D013311:Streptozocin; D013619:Tacrine / Q000494:pharmacology*
D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D013619:Tacrine; D008315:Malondialdehyde; D013311:Streptozocin; D000077265:Donepezil; D000110:Acetylcholinesterase; D005978:Glutathione