Programmed Death-1 Deficiency Aggravates Motor Dysfunction in MPTP Model of Parkinson's Disease by Inducing Microglial Activation and Neuroinflammation in Mice

Abstract

Abundant reactive gliosis and neuroin ammation are typical pathogenetic hallmarks of brains inParkinson's disease (PD) patients, but regulation mechanisms are poorly understood. We are interested in role of programmed death-1 (PD-1) in glial reaction, neuroin ammation and neuronal injury in PD pathogenesis. Using PD mouse model and PD-1 knockout (KO) mice, we designed wild-type-control (WT-CON), WT-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (WT-MPTP), PD-1-KO-control (KO-CON) and PD-1-KO-MPTP (KO-MPTP), and observed motor dysfunction of animal, morphological distribution of PD-1positive cells, dopaminergic neuronal injury, glial activation and generation of in ammatory cytokines in midbrains by motor behavior detection, immunohistochemistry and western blot. WT-MPTP mouse model exhibited decrease of PD-1/Iba1-positive microglial cells in the substantia nigra compared with WT-CON mice. By comparison of four groups, PD-1 de ciency showed exacerbation in motor dysfunction of animals, decreased expression of TH protein and TH-positive neuronal protrusions. PD-1 de ciency enhanced microglial activation, production of pro-in ammatory cytokines like inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1β and interleukin-6, and expression and phosphorylation of AKT and ERK1/2 in the substantia nigra of MPTP model. We concluded that PD-1 de ciency could aggravate motor dysfunction of MPTP mouse model by inducing microglial activation and neuroin ammation in midbrains, suggesting that PD-1 signaling abnormality might be possibly involved in PD pathogenesis.

Vincamine alleviates brain injury by attenuating neuroinflammation and oxidative damage in a mouse model of Parkinson's disease through the NF‐κB and Nrf2/HO‐1 signaling pathways

“…Moreover, GFAP and Iba‐1 expression in the SN was also enhanced by MPTP treatment, suggesting the activation of microglia and astrocytes as well as the trigger of neuroinflammation in MPTP‐induced PD mouse models, which was consistent with the previous studies. [ 45,46 ] Vincamine was previously demonstrated to exert potent suppression of inflammation in lipopolysaccharide‐induced mouse models of acute lung injury by increasing anti‐inflammatory cytokine expression but reducing pro‐inflammatory cytokine expression. [ 47 ] Vincamine administration can also reduce serum levels of TNF‐α, IL‐1β, and IL‐6 in experimental rat models of renal ischemia/reperfusion injury.…”

Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression

“…Cheng et al. ( 344 ) reported that loss of programmed death-1 (PD-1) exacerbates motor impairment in the MPTP model of PD by triggering microglial activation and neuroinflammation in mice. Utilizing a PD mouse model and PD-1 KO mice, these authors established distinct experimental groups: WT-CON, WT-MPTP, KO-CON, and KO-MPTP, which stand for wild-type-control, wild-type-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, PD-1-KO-control, and PD-1-KO-MPTP, respectively.…”

Characteristic clinical immune phenotypes and molecular mechanisms associated with inflammatory diseases

“…Cheng et al (344) reported that loss of programmed death-1 (PD-1) exacerbates motor impairment in the MPTP model of PD by triggering microglial activation and neuroinflammation in mice. Utilizing a PD mouse model and PD-1 KO mice, these authors established distinct experimental groups: WT-CON, WT-MPTP, KO-CON, and KO-MPTP, which stand for wild-type-control, wildtype-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, PD-1-KOcontrol, and PD-1-KO-MPTP, respectively.…”