Affiliations: DR. NOAH Biotech Inc., Suwon, Republic of Korea
Correspondence:
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Correspondence to: Eun Jung Kim, New Drug Research Center, DR. NOAH Biotech Inc., 91, Changnyong-daero 256beon-gil, Yeongtong-gu, Suwon-si, Gyeonggi-do, Republic of Korea. E-mail: ejkim@drnoahbiotech.com and Ji-Hyun Lee, DR. NOAH Biotech Inc., 91, Changnyong-daero 256beon-gil, Yeongtong-gu, Suwon-si, Gyeonggi-do, Republic of Korea. E-mail: jhlee@drnoahbiotech.com.
Note: [1] These authors contributed equally to this work.
Abstract: Background:Drug-induced adverse symptoms affect patients’ quality of life (QoL) during treatment. Understanding the underlying mechanisms of drug-induced adverse effects could help prevent them. As current drugs have limited effects in halting the progress of Alzheimer’s disease (AD), patients are required to take these drugs over a long period. The main obstacles to long-term compliance are drug-elicited side effects that deteriorate patient QoL. Objective:Donepezil, the most popular acetylcholinesterase inhibitor (AChEI) drug for AD, induces various side effects, especially at high doses. This study aimed to identify a drug that can attenuate the side effects of donepezil and investigate the underlying mechanisms. Methods:Five-week-old Sprague-Dawley rats received daily oral donepezil and N-acetylcysteine (NAC) for four weeks. General symptoms following administration were monitored daily to address drug-related adverse effects. Cytosolic calcium influx and generation of reactive oxygen species (ROS) after drug treatment were measured in vitro using C2C12 myotubes. Results:High-dose donepezil induced numerous adverse symptoms in male and female rats, which were markedly attenuated by co-treatment with NAC. NAC significantly reduced both acute and chronic muscle-related symptoms caused by donepezil. Additionally, in vitro studies showed that high-dose donepezil increased ROS and intracellular calcium ([Ca2+]i) levels in muscle cells, contributing to these adverse effects. NAC co-treatment dramatically reduced ROS and [Ca2+]i levels in muscle cells. Conclusions:Combined treatment with NAC effectively diminishes the adverse effects elicited by donepezil by regulating ROS and [Ca2+]i levels in the skeletal muscle, which could contribute to improving donepezil treatment in patients.
