Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 24, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/ijms24032642
Keywords
Parkinson's disease; therapeutics; NLRP3 inflammasome; neuroinflammation; oxidative stress; MPP+ HMC3 cell model; MPTP mouse model
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Neuroinflammation and oxidative stress are important contributors to Parkinson's disease (PD) pathogenesis. The indole derivative NC009-1 shows potential against neuroinflammation, oxidative stress, and neurodegeneration in PD. In vitro, NC009-1 reduces cytotoxicity and inflammatory factor production, and suppresses inflammasome activation. In vivo, NC009-1 improves motor deficits and depression, increases dopamine levels, and reduces oxidative stress and glial cell reactivity. These effects are achieved by regulating inflammatory and antioxidant factors.
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)-beta, IL-6, tumor necrosis factor (TNF)-alpha, 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-1 beta, IL-6, and TNF-alpha 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-1 beta, IL-6, and TNF-alpha, 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.
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