Pharmacological inhibition of REV-ERBα ameliorates motor deficits in the 6-OHDA-lesioned mouse model of Parkinson's disease

Abstract

Parkinson's disease (PD) is characterized by nigrostriatal dopaminergic (DAergic) degeneration and motor dysfunction. Many PD patients also show circadian rhythm disturbances. Increasing evidence links circadian clock dysfunction to PD pathology. REV-ERB alpha is a circadian nuclear receptor that regulates DAergic genes under physiological conditions. However, its role in nigrostriatal dopamine (DA) homeostasis and motor function in PD remains unclear. In this study, we found elevated Rev-erb alpha mRNA expression in tyrosine hydroxylase (TH)-positive neurons of the substantia nigra (SN) in a 6-hydroxydopamine (6-OHDA) mouse model of PD. To test its functional role, we assessed the acute effects of local SN microinjection of the REV-ERB alpha antagonist SR8278. We found that SR8278 partially recovered motor performance and improved fine motor function. These effects occurred regardless of circadian timing. SR8278 administration did not restore TH expression or tissue DA levels in the striatum and SN. However, in vivo microdialysis showed enhanced extracellular DA turnover in the striatum. Specifically, while extracellular DA metabolites level increased, basal extracellular DA levels showed no change. Together, these findings identify REV-ERB alpha as a potential therapeutic target that modulates extracellular nigrostriatal DA dynamics and improves motor function in PD.