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

Abundant reactive gliosis and neuroinflammation are typical pathogenetic hallmarks of brains in Parkinson's disease (PD) patients, but regulation mechanisms are poorly understood. We are interested in role of programmed death-1 (PD-1) in glial reaction, neuroinflammation 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-1-positive cells, dopaminergic neuronal injury, glial activation and generation of inflammatory 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 deficiency showed exacerbation in motor dysfunction of animals, decreased expression of TH protein and TH-positive neuronal protrusions. PD-1 deficiency enhanced microglial activation, production of proinflammatory 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 deficiency could aggravate motor dysfunction of MPTP mouse model by inducing microglial activation and neuroinflammation in midbrains, suggesting that PD-1 signaling abnormality might be possibly involved in PD pathogenesis.

Cheng YY ，Chen BY ，Bian GL ，Ding YX ，Chen LW ... -  《-》

MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration.

Lee E ，Hwang I ，Park S ，Hong S ，Hwang B ，Cho Y ，Son J ，Yu JW ... -  《-》

A role for glia maturation factor dependent activation of mast cells and microglia in MPTP induced dopamine loss and behavioural deficits in mice.

The molecular mechanism mediating degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) is not yet fully understood. Previously, we have shown the contribution of glia maturation factor (GMF), a proinflammatory protein in dopaminergic neurodegeneration mediated by activation of mast cells (MCs). In this study, methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal neurodegeneration and astro-glial activations were determined by western blot and immunofluorescence techniques in wild type (WT) mice, MC-deficient (MC-KO) mice and GMF-deficient (GMF-KO) mice, with or without MC reconstitution before MPTP administration. We show that GMF-KO in the MCs reduces the synergistic effects of MC and Calpain1 (calcium-activated cysteine protease enzyme)-dependent dopaminergic neuronal loss that reduces motor behavioral impairments in MPTP-treated mouse. Administration of MPTP increase in calpain-mediated proteolysis in nigral dopaminergic neurons further resulting in motor decline in mice. We found that MPTP administered WT mice exhibits oxidative stress due to significant increases in the levels of malondialdehyde, superoxide dismutase and reduction in the levels of reduced glutathione and glutathione peroxidase activity as compared with both MC-KO and GMF-KO mice. The number of TH-positive neurons in the ventral tegmental area, substantia nigra and the fibers in the striatum were significantly reduced while granulocyte macrophage colony-stimulating factor (GM-CSF), MC-Tryptase, GFAP, IBA1, Calpain1 and intracellular adhesion molecule 1 expression were significantly increased in WT mice. Similarly, tyrosine hydroxylase, dopamine transporters and vesicular monoamine transporters 2 proteins expression were significantly reduced in the SN of MPTP treated WT mice. The motor behavior as analyzed by rotarod and hang test was significantly reduced in WT mice as compared with both the MC-KO and GMF-KO mice. We conclude that GMF-dependent MC activation enhances the detrimental effect of astro-glial activation-mediated oxidative stress and neuroinflammation in the midbrain, and its inhibition may slowdown the progression of PD.

Selvakumar GP ，Ahmed ME ，Thangavel R ，Kempuraj D ，Dubova I ，Raikwar SP ，Zaheer S ，Iyer SS ，Zaheer A ... -  《-》

Imperatorin inhibits oxidative stress injury and neuroinflammation via the PI3K/AKT signaling pathway in the MPTP-induced Parkinson's disease mouse.

Parkinson's disease (PD) is a disorder of neurodegeneration. Imperatorin is an active natural furocoumarin characterized by antioxidant, anti-inflammatory, and potent vasodilatory properties. Therefore, we aimed to investigate the biological functions of imperatorin and its mechanisms against PD progression. C57BL/6 mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30 mg/kg) daily for 5 consecutive days to mimic PD conditions in vivo. The MPTP-induced PD model mice were intraperitoneally injected with imperatorin (5 mg/kg) for 25 consecutive days after MPTP administration. The motor and cognitive functions of mice were examined by rotarod test, hanging test, narrow beam test and Morris water maze test. After analysis of MWM test, the expression levels of tyrosine hydroxylase and Iba-1 in the substantia nigra pars compacta were measured by immunohistochemistry staining, immunofluorescence staining and western blotting. The expression levels of striatal dopamine and its metabolite 3,4-dihydroxyphenylacetic acid were also measured. The protein levels of inducible nitric-oxide synthase, cyclooxygenase-2, phosphorylated phosphatidylinositol 3-kinase (PI3K) and phosphorylated protein kinase B (Akt) in the mouse striatum were estimated by western blotting. The expression levels of proinflammatory cytokines including tumor necrosis factor, interleukin (IL)-1β and IL-6 in the mouse striatum were measured by ELISA kits. The expression levels of superoxide dismutase, malondialdehyde and glutathione in the mouse midbrains were measured with commercially available kits. TUNEL staining was performed to identify the apoptosis of midbrain cells. Histopathologic changes in the mouse striata were assessed by hematoxylin-eosin staining. Imperatorin treatment markedly improved spatial learning and memory abilities of MPTP-induced PD mice. The MPTP-induced dopaminergic neuron loss in the mouse striata was inhibited by imperatorin. Imperatorin also suppressed neuroinflammation and neuronal oxidative stress in the midbrains of MPTP-induced PD mice. Mechanistically, imperatorin treatment inhibited the MPTP-induced reduction in the PI3K/Akt pathway. Imperatorin treatment can prevent dopaminergic neuron degeneration and improve cognitive functions via its potent antioxidant and anti-inflammatory properties in an MPTP-induced PD model in mice by regulating the PI3K/Akt pathway.

Liu L ，Jiang L ，Zhang J ，Ma Y ，Wan M ，Hu X ，Yang L ... -  《-》

Alpha-lipoic acid improved motor function in MPTP-induced Parkinsonian mice by reducing neuroinflammation in the nigral and spinal cord.

Parkinson's disease (PD) is a chronic neurodegenerative movement disorder, resulting in dopaminergic (DA) neuronal loss in the substantia nigra (SN) and injury of extranigral spinal cord neurons. This study was to investigate the effect of α-lipoic acid (ALA) on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induced neuroinflammation in the substantia nigra and spinal cord as well as motor function of the mice with PD. After MPTP induced mouse model with PD, the effect of ALA on motor defects was evaluated by measurement of fore and hind limb step length and suspension test. The effects of ALA on microglia in the SN and spinal cord of MPTP-induced Parkinsonian mice were detected by immunofluorescence. The effect of ALA on the protein level nuclear factor-κB (NF-κB) in MPTP-induced mice with PD were examined by Western blot. RT-qPCR was used to detect the effect of ALA on gene expression of tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) in the SN and spinal cord of MPTP-induced mice. The behavioral results showed that ALA treatment significantly increased the step length and suspension time of MPTP-induced mice (P < 0.05). Immunofluorescence results showed that ALA significantly reduced MPTP-induced activation of microglia both in the SN and spinal cord (P < 0.05). Western blot and RT-qPCR showed that ALA significantly reduced the expression of NF-κB, TNF-α and iNOS in the nigra and spinal cord (P < 0.05). ALA can play a neuroprotective role through alleviating the activation of microglia, reducing neuroinflammation in the nigra and extranigra of mice induced by MPTP and therefore improving their motor dysfunction.

Zhang J ，Wang M ，Zhao Y ，Zhang Y ，Gao Y ，Zhang X ，Yang G ... -  《-》