Roflupram (ROF) improves cognition and limits neuroinflammation in the brain. However, the beneficial effects of ROF in ameliorating 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 utilized SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium iodide (MPP ) as an in vitro PD model. Cell viability and apoptosis were analyzed via the MTT assay and flow cytometry. Mitochondrial morphology, mitochondrial respiratory capacity and ROS were measured by a mitochondrial tracker, a Seahorse analyzer and a MitoSOX-Red dye. For in vivo PD model, behavioral tests, Nissl staining and immunohistochemistry were used to evaluate the protection of ROF. The levels of tyrosine hydroxylase (TH), cAMP response element-binding protein (CREB) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) were analyzed by Western blotting.
ROF decreased MPP -induced apoptosis in SH-SY5Y cells and human dopaminergic neurons. ROF also increased mitochondrial respiratory capacity, decreased ROS production and restored mitochondrial morphology. ROF reversed the MPP -induced reductions of phosphorylated CREB, PGC-1α, and TH, while the protective effects were blocked by the PKA inhibitor H-89 and via PGC-1α siRNA. In mice treated with MPTP, ROF significantly improved motor functions. Importantly, ROF prevented both dopaminergic neuronal loss and the reduction of phosphorylated CREB and PGC-1α in the substantia nigra and striatum.
ROF protects dopaminergic neurons from apoptosis via the CREB/PGC-1α pathway in PD models. Hence, ROF has potential as a protective drug for the treatment of PD.
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