Combination Therapy of Donepezil and Environmental Enrichment on Memory Deficits in Amyloid-Beta-Induced Alzheimer's Disease Rats

Abstract

Alzheimer's disease (AD) is progressive neurodegeneration known as the most common cause of dementia, and it is the sixth leading cause of death in older people. Given the promising data on the additive effect of combination therapy with donepezil (Aricept), an acetylcholinesterase inhibitor (AChEI), and regarding the similar neuronal mechanisms through them donepezil and environmental enrichment (EE) exert their enhancing effects on cognition; we asked whether simultaneous treatment with two paradigms in amyloid-beta-induced AD rats may lead to greater cognitive improvements than either treatment individually. AD was induced by intrahippocampal injection of amyloid-beta (1-42, 6 µg), and donepezil was orally administrated (4 mg/kg) for 21 days. Environmental enrichment consisted of housing animals in large cages (50× 50× 50 cm) containing a running wheel and differently shaped objects for 21 days. Spatial learning and memory were assessed in the Morris water maze (MWM) and Real-time PCR was performed to assess the expression of brain-derived neurotrophic factor (BDNF) and M1 muscarinic acetylcholine receptor (AchM1R) within the hippocampus. Spatial memory was impaired in AD animals, and while neither pretreatment with donepezil nor EE alone could significantly restore spatial memory scores in AD rats, combination therapy was effective. BDNF expression was suppressed in AD rats and pretreatment with donepezil plus EE could increase it to the saline levels. The data suggest that a cholinesterase inhibitor and cognitive stimulation can be used effectively in combination to improve cognitive loss in an AD rat model.