Targeting the Rho/ROCK Signaling Pathway Mitigates Mitochondrial Dysfunction in 6-OHDA-Induced Models of Parkinson's...

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and has been attracting increasing attention due to its rising incidence worldwide. Given that modulating the Rho/ROCK signaling pathway presents a potential therapeutic avenue for PD, this investigation sought to elucidate the molecular mechanisms of Y-27632, a potent ROCK inhibitor, building upon prior findings. To achieve this, both in vivo and in vitro PD models were employed. We assessed mitochondrial function through mtDNA copy number, mitochondrial complex-I activity, and membrane potential. Additionally, molecular analyses examined the expression of PD-related and mitochondrial genes at both mRNA and protein levels. Biochemical assays quantified antioxidant enzyme activities, reactive oxygen species (ROS), and ATP levels. The results demonstrated that intracranial Y-27632 microinjections ameliorated 6-OHDA-induced motor deficits in rats. Notably, Y-27632 enhanced mitochondrial complex-I enzyme activity and attenuated ROS production in both in vitro and in vivo models, compared to 6-OHDA-treated groups. Furthermore, Y-27632 administration elevated antioxidant enzyme activities and increased the protein levels of TH, PINK1, UCP2, and UCP3. Consequently, these findings suggest that inhibiting the Rho/ROCK signaling cascade may exert antiparkinsonian effects by modulating mitochondrial functions.