Neuroprotective effects of MHY908, a PPAR α/γ dual agonist, in a MPTP-induced Parkinson's disease model

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and are considered promising therapeutic targets in several neurodegenerative diseases. A number of PPAR agonists have been shown to have neuroprotective properties in the presence of oxidative stress, neuroinflammatory response, and apoptosis in various neurodegenerative disease. MHY908 is a novel PPAR α/γ dual agonist, which has been shown to suppress inflammatory response and attenuate insulin resistance in aged rats and db/db mice. Here, we evaluated the neuroprotective effects of MHY908 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Pretreatment with MHY908 attenuated MPTP-induced dopaminergic neuronal loss and motor deficit. MPTP-induced glial activations were mitigated by MHY908 in the nigrostriatal pathway, and MHY908 effectively blocked 1-methyl-4-phenylpyridinium (MPP+)-induced cell death and ROS production in SH-SY5Y neuroblastoma cells. Further study revealed MHY908 inhibited MPP+-induced astroglial activation by suppressing NF-κB signaling in primary astrocytes. Taken together, the present study suggests that PPAR α/γ dual agonists be considered potentially useful preventions for PD and other neurodegenerative diseases associated with neuroinflammation.