Donepezil Protects Against Doxorubicin-Induced Chemobrain in Rats via Attenuation of Inflammation and Oxidative Stress Without Interfering With Doxorubicin Efficacy

• Published in: Neurotherapeutics Vol. 18; no. 3; pp. 2107 - 2125
• Main Authors: Ongnok, Benjamin, Khuanjing, Thawatchai, Chunchai, Titikorn, Pantiya, Patcharapong, Kerdphoo, Sasiwan, Arunsak, Busarin, Nawara, Wichwara, Jaiwongkam, Thidarat, Apaijai, Nattayaporn, Chattipakorn, Nipon, Chattipakorn, Siriporn C.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.07.2021; Springer Nature B.V
• Subjects: Acetylcholinesterase; Alzheimer's disease; Animals; Antibiotics, Antineoplastic - toxicity; Apoptosis; Biomedical and Life Sciences; Biomedicine; Brain injury; Breast cancer; Chemotherapy; Chemotherapy-Related Cognitive Impairment - metabolism; Chemotherapy-Related Cognitive Impairment - prevention & control; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Cognitive ability; Dendritic spines; Donepezil; Donepezil - pharmacology; Donepezil - therapeutic use; Doxorubicin; Doxorubicin - toxicity; Female; Homeostasis; Humans; Inflammation; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Male; MCF-7 Cells; Mitochondria; Necroptosis; Neurobiology; Neurodegenerative diseases; Neurogenesis; Neurological diseases; Neurology; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurosciences; Neurosurgery; Original; Original Article; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Rats; Rats, Wistar; Treatment Outcome; Chemotherapy; Neurotoxicity; Acetylcholinesterase inhibitor; Chemobrain; Doxorubicin; Donepezil
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1007/s13311-021-01092-9

Summary Although doxorubicin (Dox) is an effective chemotherapy medication used extensively in the treatment of breast cancer, it frequently causes debilitating neurological deficits known as chemobrain. Donepezil (DPZ), an acetylcholinesterase inhibitor, provides therapeutic benefits in various neuropathological conditions. However, comprehensive mechanistic insights regarding the neuroprotection of DPZ on cognition and brain pathologies in a Dox-induced chemobrain model remain obscure. Here, we demonstrated that Dox-treated rats manifested conspicuous cognitive deficits and developed chemobrain pathologies as indicated by brain inflammatory and oxidative insults, glial activation, defective mitochondrial homeostasis, increased potential lesions associated with Alzheimer’s disease, disrupted neurogenesis, loss of dendritic spines, and ultimately neuronal death through both apoptosis and necroptosis. Intervention with DPZ co-treatment completely restored cognitive function by attenuating these pathological conditions induced by DOX. We also confirmed that DPZ treatment does not affect the anti-cancer efficacy of Dox in breast cancer cells. Together, our findings suggest that DPZ treatment confers potential neuroprotection against Dox-induced chemobrain.