Antioxidant and neuroprotective effects of ubiquinol diacetate: Insights from SH-SY5Y cell line and Caenorhabditis elegans models of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra and the presence of misfolded α-synuclein in the brain. Mitochondrial dysfunction and oxidative stress are factors contributing to the death of these neurons. Coenzyme Q10 (CoQ10) serve as an antioxidant and cofactor for mitochondrial enzymes, and its deficiency can exacerbate neurodegenerative processes in PD. However, the clinical efficacy of CoQ10 is limited by its low bioavailability and instability. Ubiquinol diacetate (CoQ10 Ac), an esterified form of CoQ10, shows improved pharmacokinetic properties and potential as a prodrug, converting into the reduced antioxidant form of CoQ10 by esterases in the body. This study aimed to investigate the antioxidant and neuroprotective effects of CoQ10 Ac compared to CoQ10 in SH-SY5Y cell line and Caenorhabditis elegans models of PD. CoQ10 Ac showed higher antioxidant activity than CoQ10 at both extracellular and intracellular levels, particularly in the membrane and cytosolic compartments. It exhibited superior neuroprotection against 6-hydroxydopamine toxicity, showing a greater ability to reduce the activation of caspase-3 and PARP1 compared to CoQ10. Both compounds decreased the increased ratio of mitochondrial fission protein, DRP1, to fusion protein, OPA1, induced by 6-hydroxydopamine in SH-SY5Y cells, enhancing OPA1 levels and promoting antiapoptotic death. However, CoQ10 Ac was more effective than CoQ10 in preserving mitochondrial structural integrity and mass. Additionally, both compounds significantly inhibited the aggregation of α-synuclein induced by 6-hydroxydopamine. Furthermore, CoQ10 Ac showed stronger neuroprotective effects than CoQ10 in C. elegans models of PD. It demonstrated greater anti-aggregant activity in C. elegans expressing human α-synuclein, suggesting higher bioavailability. These findings highlight CoQ10 Ac as a promising prodrug candidate and support further investigation in in vivo PD models.