Effect of piracetam, vincamine, vinpocetine, and donepezil on oxidative stress and neurodegeneration induced by aluminum chloride in rats

In this study, we investigated the effects of the memory-enhancing drugs piracetam, vincamine, and vinpocetine or the cholinesterase inhibitor donepezil on the development of oxidative stress, inflammation, and brain damage induced in rat brain by aluminum chloride (AlCl₃). Saline (control), piracetam (100 or 300 mg/kg), vincamine (10 or 20 mg/kg), vinpocetine (10 or 20 mg/kg), piracetam 100 mg/kg plus vincamine 10 mg/kg, piracetam 100 mg/kg plus vinpocetine 10 mg/kg, or donepezil 5 mg/kg were administered once daily intraperitoneally for 45 days along with AlCl₃ (10 mg/kg, intraperitoneally). Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, acetylcholinesterase (AChE), butrylcholinesterase (BChE), paraoxonase (PON1) activities, and prostaglandin E₂ (PGE₂) concentrations were measured in brain. Histopathology and caspase-3 immunohistochemistry (an apoptotic marker) were also performed. Results indicated that (1) compared to controls, injection of AlCl₃ significantly increased brain lipid peroxidation (MDA) and nitric oxide concentrations together with decreased GSH concentrations. PON1 activity in brain was significantly decreased, while AChE and BChE activities were significantly increased compared to control animals. Cortical atrophy, neuronal shrinkage, red neurons, surrounded by vacuolations with cytoplasmic neurofibrillary tangles, intense caspase-3 expression in degenerated neurons, and amyloid deposition were observed; (2) in AlCl₃-treated rats, (i) lipid peroxidation was significantly decreased by the lower doses of piracetam, vincamine, and vinpocetine as well as by piracetam plus either vincamine or vinpocetine; (ii) nitric oxide was significantly decreased by the lower doses of piracetam, and vinpocetine, by both doses of vincamine, and by piracetam plus either vincamine or vinpocetine; (iii) nitric oxide also showed significant decrease after treatment with donepezil; (iv) both GSH and PON1 activity showed significant increase following the administration of the test drugs; (v) PGE₂ significantly increased by the higher dose of piracetam, vincamine, vinpocetine, and piracetam plus either vincamine or vinpocetine; (vi) AChE and BChE activities decreased after treatment with the lower dose of piracetam, vinpocetine, and piracetam plus either vincamine or vinpocetine; (vii) AChE activity decreased following 20 mg/kg vincamine, and BChE activity decreased following 10 mg/kg vincamine; (viii) AChE but not BChE activity decreased after donepezil; (ix) on histopathology, the low dose of singly used drugs and donepezil had the best improvement in neuronal look, cortical thickness, and degree of vascular congestion. Rats treated with 10 mg/kg vinpocetine showed decreased capsase-3 immunoreactivity in brain and regenerating neurons. These results suggest that while the low therapeutic doses of the nootropic drugs piracetam, vincamine, and vinpocetine display anti-oxidant and neuroptotective effects, their high doses are likely to have prooxidant and proinflammatory properties.