Investigating Therapeutic Effects of Indole Derivatives Targeting Inflammation and Oxidative Stress in Neurotoxin-Induced Cell and Mouse Models of Parkinson's Disease

• Published in: International journal of molecular sciences 2023-01, Vol.24 (3), p.2642
• Main Authors: Chiu, Ya-Jen, Lin, Chih-Hsin, Lin, Chung-Yin, Yang, Pei-Ning, Lo, Yen-Shi, Chen, Yu-Chieh, Chen, Chiung-Mei, Wu, Yih-Ru, Yao, Ching-Fa, Chang, Kuo-Hsuan, Lee-Chen, Guey-Jen
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - adverse effects; 1-Methyl-4-phenylpyridinium - toxicity; Alzheimer's disease; Animal models; Animals; Biocompatibility; Cell culture; Cytotoxicity; Disease Models, Animal; Dopamine; Dopamine transporter; Drug development; Humans; Hydrogen bonds; IL-1β; Indoles; Inflammasomes; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Interleukin 6; Interleukin-6 - metabolism; Kinases; Mesencephalon; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; MPP; MPTP; Neostriatum; Neurodegeneration; Neuroinflammatory Diseases; Neurotoxins - pharmacology; Nitric oxide; Nitric-oxide synthase; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Oxidative Stress; Parkinson Disease - drug therapy; Parkinson Disease - etiology; Parkinson Disease - metabolism; Parkinson's disease; Proteins; Pyrin protein; Toxins; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24032642

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.