Neuroinflammation and oxidative stress have been emerging as important pathways contributing to
Parkinson's disease (PD) pathogenesis. In PD brains, the activated microglia release inflammatory factors such as
interleukin (IL)-β,
IL-6,
tumor necrosis factor (TNF)-α, and
nitric oxide (NO), which increase oxidative stress and mediate neurodegeneration. Using
1-methyl-4-phenylpyridinium (MPP+)-activated human microglial HMC3 cells and the sub-chronic
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP)-induced mouse model of PD, we found the potential of
indole derivative
NC009-1 against
neuroinflammation, oxidative stress, and neurodegeneration for PD. In vitro,
NC009-1 alleviated MPP+-induced cytotoxicity, reduced NO, IL-1β,
IL-6, and TNF-α production, and suppressed NLR family pyrin domain containing 3 (NLRP3)
inflammasome activation in MPP+-activated HMC3 cells. In vivo,
NC009-1 ameliorated motor deficits and non-motor depression, increased
dopamine and
dopamine transporter levels in the striatum, and reduced oxidative stress as well as microglia and astrocyte reactivity in the ventral midbrain of
MPTP-treated mice. These protective effects were achieved by down-regulating NLRP3, CASP1, iNOS, IL-1β,
IL-6, and TNF-α, and up-regulating SOD2, NRF2, and NQO1. These results strengthen the involvement of
neuroinflammation and oxidative stress in PD pathogenic mechanism, and indicate
NC009-1 as a potential drug candidate for PD treatment.