Microglial Activation and Dopaminergic Cell Injury: An<i>In Vitro</i>Model Relevant to Parkinson's Disease

Le, Weidong; Rowe, Dominic B.; Xie, Wenjie; Ortiz, Irving; He, Yi; Appel, Stanley H.

doi:10.1523/jneurosci.21-21-08447.2001

Cited by 239 publications

(197 citation statements)

References 44 publications

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“…Primary ventral mesencephalic cultures were prepared from embryonic day 14 (E14) Sprague Dawley rats (Harlan, Indianapolis, IN) (Le et al, 2001). The ventral mesencephalon was dissected in PBS, pH 7.2 (Invitrogen), and cells were mechanically dissociated in DMEM (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Basic Fibroblast Growth Factor Protects against Rotenone-Induced Dopaminergic Cell Death through Activation of Extracellular Signal-Regulated Kinases 1/2 and Phosphatidylinositol-3 Kinase Pathways

Hsuan¹,

Klintworth²,

Xia³

2006

J. Neurosci.

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Administration of rotenone to rats reproduces many features of Parkinson's disease, including dopaminergic neuron degeneration, and provides a useful model to study the pathogenesis of Parkinson's disease. However, the cell death mechanisms induced by rotenone and potential neuroprotective mechanisms against rotenone are not well defined. Here we report that rotenone-induced apoptosis in human dopaminergic SH-SY5Y cells is attenuated by pretreatment with several growth factors, most notably basic fibroblast growth factor (bFGF). bFGF activated both extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase (PI3-kinase) pathways in SH-SY5Y cells. Ectopic activation of ERK1/2 or PI3-kinase protected against rotenone, whereas inhibition of either pathway attenuated bFGF protection. Reducing the expression of the proapoptotic protein Bcl-2-associated death protein (BAD) by small interfering RNA rendered SH-SY5Y cells resistant to rotenone, implicating BAD in rotenone-induced cell death. Interestingly, bFGF induced a long-lasting phosphorylation of BAD at serine 112, suggesting BAD inactivation through the ERK1/2 signaling pathway. Moreover, primary cultured dopaminergic neurons from mesencephalon were more sensitive to rotenone-induced cell death than nondopaminergic neurons in the same culture. The loss of dopaminergic neurons was blocked by bFGF, an inhibition dependent on ERK1/2 and PI3-kinase signaling. These data suggest that rotenone-induced dopaminergic cell death requires BAD and identify bFGF and its activation of ERK1/2 and PI3-kinase signaling pathways as novel intervention strategies to block cell death in the rotenone model of Parkinson's disease.

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Section: Methodsmentioning

confidence: 99%

Basic Fibroblast Growth Factor Protects against Rotenone-Induced Dopaminergic Cell Death through Activation of Extracellular Signal-Regulated Kinases 1/2 and Phosphatidylinositol-3 Kinase Pathways

Hsuan¹,

Klintworth²,

Xia³

2006

J. Neurosci.

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“…This cell line displays properties of substantia nigra zona compacta neurons and is considered a dopaminergic cell that expresses tyrosine hydroxylase and synthesizes dopamine [19]. Mes 23.5 cells exhibit a unique susceptibility to oxidative stressinduced toxicity and have been use as a cell model to study free-radical-mediated cell damage [20].…”

Section: Introductionmentioning

confidence: 99%

HIF-1α activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death

Zhang

Liu

et al. 2007

Free Radical Biology and Medicine

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Cyanide produces degeneration of the nervous system in which different modes of cell death are activated in the vulnerable brain areas. In brain, the mechanism underlying the cell death is not clear. In this study, an immortalized dopaminergic cell line was used to characterize the cell death signaling cascade activated by cyanide. Cyanide-treated cells exhibited a time-and concentration-dependent apoptosis that was caspase-independent. Cyanide induced a rapid surge of intracellular reactive oxygen species (ROS) generation, followed by p38 mitogen-activated protein kinase (MAPK) activation and nuclear accumulation of hypoxia-inducible factor-1α (HIF-1α). Activation of p38 MAPK and HIF-1α accumulation were attenuated by N-acetyl-L-cysteine (antioxidant), catalase (hydrogen peroxide scavenger) or a selective p38 MAPK inhibitor (SB203580). Cyanide activated the hypoxia response element (HRE) promoter, which was also blocked by the antioxidants and SB203580. HRE activation was followed by increased BNIP3 gene transcription, as reflected by elevated BNIP3 mRNA and protein levels. BNIP3 upregulation was reduced by selective RNAi knockdown of HIF-1α. Overexpression of BNIP3 produced mitochondrial dysfunction (reduced membrane potential), caspase-independent apoptosis, and sensitization of the cells to cyanideinduced toxicity. Expression of a dominant negative mutant or RNAi knockdown of BNIP3 protected the cells from cyanide. It was concluded that cyanide activated the HIF-1α-mediated pathway of BNIP3 induction through a redox-sensitive process. Increased BNIP3 expression then served as an initiator of mitochondrial-mediated death.

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“…4,5 M1 microglia polarization is associated with the production and release of multiple proinflammatory cytokines. [6][7][8][9][10] The released factors generally act in tissue defense and promote the destruction of pathogens. 11,12 However, overactivated or dysregulated microglia are constantly involved in the pathogenesis of PD and serve to amplify neuronal damage caused by pathological stimuli and toxins, which in turn, induces more widespread damage to the neighboring neurons.…”

mentioning

confidence: 99%

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

et al. 2013

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Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either detrimental or beneficial effects in the central nervous system (CNS). Harnessing the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of Parkinson's disease (PD). However, the epigenetic mechanism that regulates microglia polarization remains elusive. Here, we reported that histone H3K27me3 demethylase Jumonji domain containing 3 (Jmjd3) was essential for M2 microglia polarization. Suppression of Jmjd3 in N9 microglia inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, which led to extensive neuron death in vitro. We also observed that the suppression of Jmjd3 in the substantia nigra (SN) in vivo dramatically caused microglial overactivation and exacerbated dopamine (DA) neuron death in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD. Moreover, we showed that the Jmjd3 level was lower in the midbrain of aged mice, which was accompanied by an elevated level of H3K27me3 and an increased ratio of M1 to M2 markers, suggesting that aging is an important factor in switching the microglia phenotypes. Overall, our studies indicate that Jmjd3 is able to enhance the polarization of M2 microglia by modifying histone H3K27me3, and therefore it has a pivotal role in the switch of microglia phenotypes that may contribute to the immune pathogenesis of PD.

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Microglial Activation and Dopaminergic Cell Injury: AnIn VitroModel Relevant to Parkinson's Disease

Cited by 239 publications

References 44 publications

Basic Fibroblast Growth Factor Protects against Rotenone-Induced Dopaminergic Cell Death through Activation of Extracellular Signal-Regulated Kinases 1/2 and Phosphatidylinositol-3 Kinase Pathways

Basic Fibroblast Growth Factor Protects against Rotenone-Induced Dopaminergic Cell Death through Activation of Extracellular Signal-Regulated Kinases 1/2 and Phosphatidylinositol-3 Kinase Pathways

HIF-1α activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

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