Donepezil treatment mitigates cholinergic system alterations, oxidative stress, neuroinflammation and memory impairment induced by branched-chain amino acid administration in rats.

Abstract

Maple Syrup Urine Disease (MSUD) is an inherited metabolic disorder biochemically characterized by tissue accumulation of leucine, isoleucine, and valine and their derivatives. Patients present with neurological disabilities and treatment is limited. Donepezil, a drug used for neurodegenerative disorders, has been shown to improve memory and counteract oxidative stress and inflammation. In the present study, we investigated whether donepezil administration could improve alterations in the cholinergic system, oxidative stress, inflammation, and behavior changes in rats submitted to a chemical MSUD model based on the administration of branched-chain amino acids (BCAA) leucine, isoleucine, and valine. Our results showed a decrease in short- and long-term memory in the object recognition task in rats submitted to BCAA administration. We also verified an increase in acetylcholinesterase (AChE) activity and a decrease in choline acetyltransferase in the cerebral cortex of the BCAA control group. Increased reactive species production, alterations in the antioxidant defenses, and inflammation were further observed. Additionally, we found that donepezil treatment attenuated alterations in AChE activity, reactive species production, lipids oxidative damage, inflammation, and memory. Our findings contribute to the understanding of the pathophysiology of MSUD and suggest that donepezil is a potential pharmacological treatment for this disorder.