Coenzyme Q10 ameliorates cyclophosphamide-induced chemobrain by repressing neuronal apoptosis and preserving hippocampal neurogenesis: Mechanistic roles of Wnt/ β-catenin signaling pathway

• Published in: Neurotoxicology (Park Forest South) 2024-12, Vol.105, p.21-33
• Main Authors: Hussein, Zeina, Michel, Haidy E., El-Naga, Reem N., El-Demerdash, Ebtehal, Mantawy, Eman M.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Alkylating - toxicity; apoptosis; Apoptosis - drug effects; Chemobrain; Chemotherapy-Related Cognitive Impairment; Coenzyme Q10; Cyclophosphamide; Cyclophosphamide - toxicity; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Male; neurogenesis; Neurogenesis - drug effects; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - pharmacology; Oxidative Stress - drug effects; Rats; Rats, Sprague-Dawley; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacology; Wnt Signaling Pathway - drug effects; Wnt/β-catenin signaling pathway
• ISSN: 0161-813X; 1872-9711; 1872-9711
• DOI: 10.1016/j.neuro.2024.08.003

Deterioration in the neurocognitive function of cancer patients referred to as “Chemobrain” is a devastating obstacle associated with cyclophosphamide (CYP). CYP is an alkylating agent, clinically utilized as an efficient anticancer and immunosuppressant. Coenzyme Q10 (CoQ10) is a worthwhile micronutrient with diverse biological activities embracing antioxidant, anti-apoptotic, and neuroprotective effects. The current experiment was designed for investigating the neuroprotective capability of CoQ10 versus CYP-elicited chemobrain in rats besides elucidating the causal molecular mechanisms. Male Sprague Dawley rats received CoQ10 (10 mg/kg, orally, once daily, for 10 days) and/or a single dose of CYP (200 mg/kg i.p. on day 7). CoQ10 counteracted CYP-induced cognitive and motor dysfunction as demonstrated by the findings of neurobehavioral tests (passive avoidance, Y maze, locomotion, and rotarod tests). Histopathological analysis further affirmed the neuroprotective abilities of CoQ10. CoQ10 effectually diminished CYP-provoked oxidative injury by restoring the antioxidant activity of catalase (CAT) enzyme while reducing malondialdehyde (MDA) levels. Besides, CoQ10 efficiently repressed CYP-induced neuronal apoptosis by downregulating the expression of Bax and caspase-3 while upregulating the Bcl-2 expression. Moreover, CoQ10 hampered CYP-provoked upregulation in acetylcholinesterase (AChE) activity. Furthermore, CoQ10 considerably augmented hippocampal neurogenesis by elevating the expressions of brain-derived neurotrophic factor (BDNF) and Ki-67. These promising neuroprotective effects can be credited to upregulating Wnt/β-catenin pathway as evidenced by the elevated expressions of Wnt-3a, β-catenin, and Phoshpo-glycogen synthase kinase-3 β (p-GSK-3β). Collectively, these findings proved the neuroprotective capabilities of CoQ10 against CYP-induced chemobrain through combating oxidative injury, repressing intrinsic apoptosis, boosting neurogenesis, and eventually upregulating the Wnt/β-catenin pathway. [Display omitted] •CoQ10 alleviates CYP-induced cognitive deficits and motor dysfunction.•CoQ10 represses CYP-induced hippocampal oxidative injury and neuronal apoptosis.•CoQ10 preserves hippocampal neurogenesis and cholinergic transmission.•Neuroprotective effect of CoQ10 was mediated by upregulating Wnt/β catenin pathway.