探究新穎香豆素-查耳酮雜合物LM-021和吲哚衍生物NC009-1的抗發炎和抗氧化作用對巴金森氏症細胞和小鼠模型的療效(II)(2/2)

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)-1β, IL-6 and tumor necrosis factor (TNF)-α, which increase oxidative stress and mediate neurodegeneration. Using 1-methyl-4-phenylpyridinium (MPP+)-activated human microglial HMC3/neuroblastoma BE(2)-M17 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 in-house synthetic indole derivative NC009-1 and coumarin-chalcone derivatives LM-021 and LM-036 against neuroinflammation, oxidative stress and neurodegeneration. NC009-1, LM-021 and LM-036 suppressed the inflammatory action of MPP+ in HMC3 cells, including reduced expression of microglial activation markers CD68, CD11B and/or MHCII, and decreased NLRP3, CASP1, iNOS, IL-1β, IL-6 and TNF-α protein levels. In addition, LM-021 and LM-036 increased cell viability, reduced lactate dehydrogenase (LDH) release, ameliorated cellular reactive oxygen species (ROS) production, decreased caspase-1, caspase-3 and caspase-6 activities, and promoted neurite outgrowth in MPP+-treated BE(2)-M17 cells. These protective effects were mediated by down-regulating inflammatory NLRP1, IL-1β, IL-6 and TNF-α, and up-regulating antioxidative NRF2, NQO1, GCLC, PGC-1α and neuroprotective CREB, BDNF, BCL2. In MPTP-induced PD mice, NC009-1 increased dopamine transporter level in the striatum, down-regulated NLRP3, CASP1, iNOS, IL-1β, IL-6 and TNF-α, and up-regulated SOD2, NRF2 and NQO1. These results strengthen the involvement of neuroinflammation and oxidative stress in PD pathogenic mechanism, and indicate NC009-1, LM-021 and LM-036 as a potential drug candidates for PD treatment.