Roflupram exerts neuroprotection via activation of CREB/PGC‐1α signalling in experimental models of Parkinson's disease

Abstract

Roflupram improves cognition and limits neuroinflammation in the brain. However, the beneficial effects of roflupram on Parkinson's disease (PD) remain unknown. Therefore, we aimed to elucidate the pharmacological effects and mechanisms of action of ROF in experimental models of PD. We used an in vitro PD model of SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium iodide (MPP+ ). Cell viability and apoptosis were analysed via the MTT assay and flow cytometry. Mitochondrial morphology, mitochondrial respiratory capacity, and ROS were measured by a mitochondrial tracker, Seahorse Analyzer, and a MitoSOX-Red dye. For in vivo PD model, behavioural tests, Nissl staining, and immunohistochemistry were used to evaluate protection by roflupram. The levels of TH, cAMP response element-binding protein (CREB), and PPARγ coactivator-1α (PGC-1α) were analysed by western blotting. Roflupram decreased MPP+ -induced apoptosis in SH-SY5Y cells and human dopaminergic neurons. Roflupram also increased mitochondrial respiratory capacity, decreased ROS production, and restored mitochondrial morphology. Roflupram reversed the MPP+ -induced reductions of phosphorylated CREB, PGC-1α and TH. These protective effects were blocked by the PKA inhibitor H-89 or by PGC-1α siRNA. In mice treated with MPTP, roflupram significantly improved motor functions. Roflupram prevented both dopaminergic neuronal loss and the reduction of phosphorylated CREB and PGC-1α in the substantia nigra and striatum. Roflupram protected dopaminergic neurons from apoptosis via the CREB/PGC-1α pathway in PD models. Hence, roflupram has potential as a protective drug in the treatment of PD.