Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that injection of bacterial lipopolysaccharide (LPS) into gravid female rats at embryonic day 10.5 resulted in a birth of offspring with fewer than normal dopamine (DA) neurons along with innate immunity dysfunction and many characteristics seen in Parkinson's disease (PD) patients. The LPS-exposed animals were also more susceptible to secondary toxin exposure as indicated by an accelerated DA neuron loss. Glutathione (GSH) is an important antioxidant in the brain. A disturbance in glutathione homeostasis has been proposed for the pathogenesis of PD. In this study, animals prenatally exposed to LPS were studied along with an acute intranigral LPS injection model for the status of glutathione homeostasis, lipid peroxidation, and related enzyme activities. Both prenatal LPS exposure and acute LPS injection produced a significant GSH reduction and increase in oxidized GSH (GSSG) and lipid peroxide (LPO) production. Activity of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in de novo GSH synthesis, was up-regulated in acute supranigral LPS model but was reduced in the prenatal LPS model. The GCS light subunit protein expression was also down-regulated in prenatal LPS model. GSH redox recycling enzyme activities (glutathione peroxidase, GPx and glutathione reducdase, GR) and glutathione-S-transferase (GST), gamma-glutamyl transpeptidase (gamma-GT) activities were all increased in prenatal LPS model. Prenatal LPS exposure and aging synergized in GSH level and GSH-related enzyme activities except for those (GR, GST, and gamma-GT) with significant regional variations. Additionally, prenatal LPS exposure produced a reduction of DA neuron count in the substantia nigra (SN). These results suggest that prenatal LPS exposure may cause glutathione homeostasis disturbance in offspring brain and render DA neurons susceptible to the secondary neurotoxin insult.
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PMID:Altered glutathione homeostasis in animals prenatally exposed to lipopolysaccharide. 1729 29

Oxidative stress and lower levels of trophic factors involved in nigrostriatal dopaminergic neurodegeneration are a hallmark of Parkinson disease. Our previous studies found that fibroblast growth factor 9 (FGF9) prevented 1-methyl-4-phenylpyridinium (MPP(+))-induced nigral dopaminergic neuron death and was involved in the neuroprotection of the antioxidant melatonin. However, the protective mechanisms mediated by FGF9 remain unclear. Herein, we explored whether FGF9 regulated the cellular antioxidant defense protecting dopaminergic neurons against MPP(+) intoxication. We found that FGF9 treatment alone induced a decrease in hydrogen peroxide (H(2)O(2)) level, an increase in glutathione content, and an upregulation of gamma-glutamylcysteine synthetase (gamma-GCS) and heme oxygenase 1 (HO-1) expression in primary cortical neurons but not in astrocytes. Simultaneous treatment with FGF9 and MPP(+) prevented MPP(+)-induced neuron death and H(2)O(2) overproduction but did not affect the FGF9-increased gamma-GCS and HO-1 protein expression. Inhibition of gamma-GCS or HO-1 prevented the inhibitory effect of FGF9 on MPP(+)-induced H(2)O(2) production and death in mesencephalic dopaminergic and cortical neurons. However, in the absence of MPP(+), the FGF9-induced H(2)O(2) reduction was blocked by HO-1 inhibitors, but not by gamma-GCS inhibitors. These results indicate that FGF9 upregulates gamma-GCS and HO-1 expression to protect cortical and dopaminergic neurons from MPP(+)-induced oxidative insult.
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PMID:Fibroblast growth factor 9 upregulates heme oxygenase-1 and gamma-glutamylcysteine synthetase expression to protect neurons from 1-methyl-4-phenylpyridinium toxicity. 2061 62

Oxidative stress has been implicated in a range of neurodegenerative diseases, in particular, Parkinson's disease (PD). However, the pathogenic mechanism of its influence on PD progression remains unclear. In order to clarify this, PD models are generated by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intramuscular injection in eight rhesus monkeys. During the of progress PD pathogenesis, the activities of some major antioxidant enzymes, such as serum superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione-s-transferase (GST), were measured, which show continuously decrease. While, the GSH and MDA content, as well as the expression of gamma-glutamylcysteine synthetase (GCS) and glutathione-s-transferase pi (GST-pi) exhibit robust increase. Taken together, this study shows the dynamic changes of antioxidant enzymes and lipid peroxidation in blood of PD monkeys during its progress, which will be important for the diagnosis and treatment of PD.
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PMID:Changes in blood anti-oxidation enzyme levels in MPTP-treated monkeys. 2838 Mar 29


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