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

Abstract

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.

Coumarin-chalcone hybrid LM-021 and indole derivative NC009-1 targeting inflammation and oxidative stress to protect BE(2)-M17 cells against α-synuclein toxicity

“…The reason for the inconsistent effects of addition of fibrils on inflammation may be due to the relative short duration of fibrils addition in vitro . In our previous study, we did find that the studied compound NC009-1 reduces inflammation in a neurotoxin-induced PD cell model without the addition of fibrils [ 35 ], suggesting that the tested compounds may also exert general anti-inflammatory effects. Therefore, in vivo experiments including behavioral tests are needed in the future to know if similar results can be recapitulated in animal models.…”

Impact of NQO1 dysregulation in CNS disorders

“…Furthermore, administration of NC009-1 reduced oxidative stress and decreased microglia and astrocyte activity in the ventral midbrain of mice after exposure to MPTP. These beneficial effects were accompanied by an upregulation of Nrf2 and NQO1 as well as a downregulation of iNOS, TNF-α, IL-6, and IL-1β [ 153 ]. Moreover, isoliquiritigenin, a flavonoid compound, has been shown to improve motor deficits in a PD mice model through the upregulation of Nrf2 and NQO1, while concurrently downregulating proinflammatory mediators [ 154 ].…”

Synthesis and Evaluation of Schiff’s Base Indole Derivatives Against Inflammation Induced by Carrageenan in Rats

“…Raising SOD2, NRF2, and NQO1 and decreasing CASP1, NLRP3, IL-6, iNOS, TNF and IL-1, allowed for the achievement of these protective effects. 20,21,22,23…”