Activation of the
peroxisome proliferator activated receptor-gamma (
PPAR)- γ is proposed as a neuroprotective strategy to treat
neurodegenerative disorders. In this study, we examined if
LSN862 (
LSN), a novel non-thiazoledinedione partial
PPAR- γ agonist, was neuroprotective in a mouse model of
Parkinson's disease (PD) and assessed possible mechanisms of action. LSN (3, 10, or 30 mg/kg) or vehicle was orally administered daily to C57BL/6 and antioxidant response element-human
placental alkaline phosphatase (ARE-hPAP) reporter mice 3 days prior to
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP; 30 mg/kg, i.p. × 5 days) or PBS administration. LSN elicited a dose-dependent preservation of dopaminergic nigrostriatal innervation that was not associated with inhibition of
MPTP metabolism or activation of Nrf2-ARE, although changes in NQO1 and SOD2
mRNA were observed. A significant dose-dependent downregulation in MAC-1 and GFAP positive cells was observed in
MPTP + LSN-treated mice as well as significant downregulation of
mRNA expression levels of these inflammatory markers.
MPTP-induced increases in
PPAR- γ and PGC1 α expression were ameliorated by LSN dosing. Our results demonstrate that
oral administration of LSN is neuroprotective against
MPTP-induced neurodegeneration, and this effect is associated with downregulation of
neuroinflammation, decreased oxidative stress, and modulation of
PPAR- γ and PGC1 α expression. These results suggest that LSN can be a candidate alternative non-thiazoledinedione partial
PPAR- γ agonist for neuroprotective treatment of PD.