Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.6.3.1 (
NADPH oxidase
)
11,281
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Parkinson's disease (PD) is a profound
movement disorder
resulting from progressive degeneration of the nigrostriatal dopaminergic pathway. Although its etiology remains unknown, increasing evidence suggests the involvement of multiple factors such as environmental toxins and genetic susceptibilities in the pathogenesis of PD. In this study using mesencephalic neuron-glia cultures as an in vitro PD model, we demonstrated that the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 0.1-0.5 microM) and an inflammogen lipopolysaccharide (LPS, 0.5 ng/ml) synergistically induced a progressive and selective degeneration of dopaminergic neurons. The synergistic neurotoxicity was observed when both agents were applied either simultaneously or in tandem. The synergistic neurotoxicity was more prominent when lower doses of both agents were applied for a longer period of time. Mechanistically, microglial
NADPH oxidase
-mediated generation of reactive oxygen species played a pivotal role in the synergistic neurotoxicity: MPTP and LPS synergistically stimulated the
NADPH oxidase
-mediated release of superoxide free radical; pharmacological inhibition and genetic inactivation of
NADPH oxidase
prevented superoxide production and the synergistic neurotoxicity. Additionally, inhibition of nitric oxide synthase afforded significant neuroprotection, suggesting the involvement of nitric oxide in the synergistic neurotoxicity. This study lends strong support for a multifactorial etiology of PD and provides clues for therapeutic interventions.
...
PMID:Synergistic dopaminergic neurotoxicity of MPTP and inflammogen lipopolysaccharide: relevance to the etiology of Parkinson's disease. 1292 73
Parkinson's disease (PD) is a neurodegenerative
movement disorder
characterized by a progressive loss of dopaminergic neurons in the substantia nigra and depletion of the neurotransmitter dopamine in the striatum. Progress in the search for effective therapeutic strategies that can halt this degenerative process remains limited. Mechanistic studies using animal systems such as the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent PD model have revealed the involvement of the brain's immune cells and free radical-generating processes. We recently reported that dextromethorphan (DM), a widely used anti-tussive agent, attenuated endotoxin-induced dopaminergic neurodegeneration in vitro. In the current study, we investigated the potential neuroprotective effect of DM and the underlying mechanism of action in the MPTP rodent PD model. Mice (C57BL/6J) that received daily MPTP injections (15 mg free base/kg body weight, s.c.) for 6 consecutive days exhibited significant degeneration of the nigrostriatal dopaminergic pathway. However, the MPTP-induced loss of nigral dopaminergic neurons was significantly attenuated in those mice receiving DM (10 mg/kg body weight, s.c.). In mesencephalic neuron-glia cultures, DM significantly reduced the MPTP-induced production of both extracellular superoxide free radicals and intracellular reactive oxygen species (ROS). Because
NADPH oxidase
is the primary source of extracellular superoxide and intracellular ROS, we investigated the involvement of
NADPH oxidase
in the neuroprotective effect of DM. Indeed, the neuroprotective effect of DM was only observed in the wild-type but not in the
NADPH oxidase
-deficient mice, indicating that
NADPH oxidase
is a critical mediator of the neuroprotective activity of DM. More importantly, due to its proven safety record of long-term clinical use in humans, DM may be a promising agent for the treatment of degenerative neurological disorders such as PD.
...
PMID:Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase. 1473 32
Astrogliosis has long been recognized in Parkinson's disease (PD), the most common neurodegenerative
movement disorder
. However, the mechanisms of how astroglia become activated remain unclear. Reciprocal interactions between microglia and astroglia play a pivotal role in regulating the activities of astroglia. The purpose of this study is to investigate the mechanism by which microglia regulate astrogliosis by using lipopolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD models. We found that the activation of microglia preceded astroglia in the substantia nigra of mice treated with either LPS or MPTP. Furthermore, suppression of microglial activation by pharmacological inhibition or genetic deletion of
NADPH oxidase
(NOX2) in mice attenuated astrogliosis. The important role of NOX2 in microglial regulation of astrogliosis was further mirrored in a mixed-glia culture system. Mechanistically, H
2
O
2
, a product of microglial NOX2 activation, serves as a direct signal to regulate astrogliosis. Astrogliosis was induced by H
2
O
2
through a process in which extracellularly generated H
2
O
2
diffused into the cytoplasm and subsequently stimulated activation of transcription factors, STAT1 and STAT3. STAT1/3 activation regulated the immunological functions of H
2
O
2
-induced astrogliosis since AG490, an inhibitor of STAT1/3, attenuated the gene expressions of both proinflammatory and neurotrophic factors in H
2
O
2
-treated astrocyte. Our findings indicate that microglial NOX2-generated H
2
O
2
is able to regulate the immunological functions of astroglia via a STAT1/3-dependent manner, providing additional evidence for the immune pathogenesis and therapeutic studies of PD.
...
PMID:NADPH oxidase-derived H
2
O
2
mediates the regulatory effects of microglia on astrogliosis in experimental models of Parkinson's disease. 2823 79
Environmental exposure to the highly persistent chlorinated pesticides including dieldrin and lindane is postulated to be a risk factor to the development of Parkinson's disease, a devastating
movement disorder
. We have previously reported that the combined treatment with dieldrin and lindane induces a cooperative toxicity in the rat N27 dopaminergic neuronal cells through increased oxidative stress and mitochondrial dysfunction. In this study, we investigated the involvement of
NADPH oxidase
(NOX) proteins in the combined treatment with dieldrin and lindane-induced dopaminergic neurotoxicity. Immunoblot analysis demonstrated the presence of NADPH Oxidase 1 (Nox1) isoform and p67
phox
in N27 neurons. Furthermore, treatment with dieldrin and lindane upregulated the cellular expression of Nox1 but not p67
phox
protein. Functionally, dieldrin and lindane-induced ROS production was attenuated, in a dose-dependent manner, by Nox inhibitors diphenylene iodonium and apocynin. Subcellular localization analysis of Nox1 and p67
phox
proteins indicated colocalization of both subunits with mitochondria in untreated cells. Treatment with dieldrin and lindane further increased mitochondrial colocalization of Nox1 protein, suggesting a potentially prominent role for mitochondrial Nox1 protein in dieldrin and lindane-induced ROS generation in dopaminergic neurons and its contribution to the combined organochlorinated pesticide-induced neurotoxicity.
...
PMID:Role of NADPH oxidase in cooperative reactive oxygen species generation in dopaminergic neurons induced by combined treatment with dieldrin and lindane. 3024 May 90
