Neuroprotective effects of idebenone in a zebrafish model of Parkinson's disease via regulating autophagy, mitigating apoptosis and oxidative stress.

Abstract

Idebenone (IDE), an analog of ubiquinone, has demonstrated therapeutic potential across various neurodegenerative disorders. Clinically, IDE has been shown to exert neuroprotective effects in Parkinson's disease (PD), being capable of alleviating motor symptoms as well as reducing depressive and anxious moods. However, the mechanism of action of IDE in PD has not been fully elucidated. Thus, the present study aims to investigate the potential effects of IDE on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models in zebrafish, as well as the underlying mechanisms involved. The results demonstrated that IDE alleviated MPTP-induced locomotor dysfunction, preserved dopaminergic (DA) neuronal integrity, and mitigated cerebrovascular degeneration. Biochemical and molecular analyses revealed that IDE significantly reduced intracellular reactive oxygen species (ROS) accumulation and neuronal apoptosis, increased the activity of antioxidant enzymes (SOD, GSH-Px), and decreased malondialdehyde (MDA) levels. Real-time quantitative PCR (RT-qPCR) showed that IDE upregulated the expression of antioxidant stress-related genes (nrf2, ho-1), and anti-apoptotic genes (pi3k, akt1, akt2), while modulated the expression of autophagy-related markers (prkn, pink1, park7, atg5, atg7, p62). Western blot (WB) assays confirmed that IDE enhanced autophagic flux by upregulating Beclin1 expression and the LC3-II/LC3-I ratio, and downregulating P62 expression. Importantly, intervention with the autophagy inhibitor chloroquine (CQ) reversed IDE-mediated improvement of motor deficits, indicating that autophagy activation is a key mechanism. Collectively, IDE exerts neuroprotection in MPTP-induced PD zebrafish by activating autophagy, alongside anti-oxidative and anti-apoptotic actions, providing experimental evidence for its therapeutic potential in PD.