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

As superoxide (.O2-) and hydroxyl radical (.OH) have been implicated in the pathogenesis of Parkinson disease, free radical scavenging and antioxidants have attracted attention as way to prevent progression of this disease. We examined the effects of eugenol, an essential oil extracted from cloves, on 6-hydroxydopamine (6-OHDA)-induced dopamine (DA) reduction in the mouse striatum. Eugenol administration 3 d before and 7 more days following one intracerebroventricular 6-OHDA injection prevented the reduction of striatal DA and its metabolites. Eugenol administration for 3 d reduced the increase of thiobarbituric acid-reactive substances (an indicator of lipid peroxidation) induced by ferric ion and increased glutathione (GSH) and L-ascorbate (Asc) in the striatum. Eugenol did not change the levels of catalase, glutathione peroxidase, or superoxide dismutase-like activities. Eugenol is known to have .O2- and .OH scavenging activities in vitro. These results suggest that eugenol prevents 6-OHDA-induced DA depression by preventing lipid peroxidation directly and indirectly (via stimulation of GSH and Asc generating systems). Furthermore, increased GSH may protect cell death by conjugating with p-quinone produced in 6-OHDA auto-oxidation. The effects of eugenol treatment in this model suggest its possible usefulness for the treatment of Parkinson disease.
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PMID:Eugenol [2-methoxy-4-(2-propenyl)phenol] prevents 6-hydroxydopamine-induced dopamine depression and lipid peroxidation inductivity in mouse striatum. 1732 31

We evaluated an alternative method to investigate a possible involvement of environmental toxins in the pathology of Parkinson's disease (PD). There is considerable evidence supporting the role of oxidative stress in the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin largely used to modeling PD in primates and rodents. We have recently demonstrated that rats treated with intranasal (i.n.) infusion of MPTP suffer from progressive signs of PD that are correlated with time-dependent degeneration in dopaminergic neurons. In the present study, we investigated the time-dependent (2 h to 7 days) effect of a single i.n. administration of MPTP (0.1 mg/nostril) on the glutathione-related antioxidant status and lipid peroxidation (TBARS) in the adult Wistar rat brain. The effects were more pronounced in the olfactory bulb at 6 h after i.n. MPTP administration, as indicated by an increase in TBARS and total glutathione (GSH-t) levels, and also in the gamma-glutamyl transpeptidase (GGT) activity. Increased levels of TBARS, GSH-t and GGT activity were also observed at 6 h post-MPTP infusion in some structures (e.g. striatum, hippocampus and prefrontal cortex). No difference regarding glutathione reductase activity was observed in any of the brain structures analyzed, while a marked decrease in glutathione peroxidase activity was specifically observed in the substantia nigra 7 days after MPTP treatment. These results demonstrate that a single i.n. infusion of MPTP in rats induces significant alterations in the brain antioxidant status and lipid peroxidation, reinforcing the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD.
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PMID:Antioxidant responses and lipid peroxidation following intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats: increased susceptibility of olfactory bulb. 1738 53

Decreased glutathione levels associated with increased oxidative stress are a hallmark of numerous neurodegenerative diseases, including Parkinson's disease. GSH is an important molecule that serves as an anti-oxidant and is also a major determinant of cellular redox environment. Previous studies have demonstrated that neurotoxins can cause changes in reduced and oxidized GSH levels; however, information regarding steady state levels remains unexplored. The goal of this study was to characterize changes in cellular GSH levels and its regulatory enzymes in a dopaminergic cell line (N27) following treatment with the Parkinsonian toxin, 1-methyl-4-phenylpyridinium (MPP(+)). Cellular GSH levels were initially significantly decreased 12 h after treatment, but subsequently recovered to values greater than controls by 24 h. However, oxidized glutathione (GSSG) levels were increased 24 h following treatment, concomitant with a decrease in GSH/GSSG ratio prior to cell death. In accordance with these changes, ROS levels were also increased, confirming the presence of oxidative stress. Decreased enzymatic activities of glutathione reductase and glutamate-cysteine ligase by 20-25% were observed at early time points and partly account for changes in GSH levels after MPP(+) exposure. Additionally, glutathione peroxidase activity was increased 24 h following treatment. MPP(+) treatment was not associated with increased efflux of glutathione to the medium. These data further elucidate the mechanisms underlying GSH depletion in response to the Parkinsonian toxin, MPP(+).
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PMID:1-methyl-4-phenylpyridinium-induced alterations of glutathione status in immortalized rat dopaminergic neurons. 1739 26

Antioxidative properties of alpha-lipoic acid (LA) are widely investigated in different in vivo and in vitro models. The aim of this study was to examine whether LA attenuates oxidative stress induced in rats by reserpine, a model substance frequently used to produce Parkinsonism in animals. Male Wistar rats were treated with reserpine (5 mg/kg) and LA (50 mg/kg) separately or in combination. The levels of reduced glutathione (GSH), glutathione disulfide (GSSG), nitric oxide (NO) and S-nitrosothiols as well as activities of glutathione peroxidase (GPx), glutathione-S-transferase (GST) and L-gamma-glutamyl transpeptidase (gamma-GT) were determined in the striatum and prefrontal cortex homogenates. In the striatum and prefrontal cortex a single dose of reserpine significantly enhanced levels of GSSG and NO but not that of S-nitrosothiols when compared with control. In the striatum, LA administered jointly with reserpine markedly increased the concentration of GSH and decreased GSSG level. In the prefrontal cortex, such treatment produced only an increasing tendency in GSH level but caused no changes in GSSG content. In both structures LA injected jointly with reserpine markedly decreased NO concentrations but did not cause significant changes in S-nitrosothiol levels when compared with control. Enzymatic activities of GPx and GST were intensified by LA in the striatum. In the prefrontal cortex, GPx activity was not altered, while that of GST was decreased. Gamma-GT activity was attenuated by reserpine in the striatum while LA reversed this effect. Such changes were not observed in the prefrontal cortex. The mode of LA action in the striatum during the reserpine-evoked oxidative stress strongly suggests that this compound may be of therapeutic value in the treatment of Parkinson's disease.
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PMID:Alpha-lipoic acid differently affects the reserpine-induced oxidative stress in the striatum and prefrontal cortex of rat brain. 1747 54

Young parkin null (pk-/-) mice have subtle abnormalities of behaviour, dopamine (DA) neurotransmission and free radical production, but no massive loss of DA neurons. We investigated whether these findings are maintained while ageing. Pk-/- mice have reduced life span and age-related reduced exploratory behaviour, abnormal walking and posture, and behaviours similar to those of early Parkinson's disease (PD), reduced number of nigrostriatal DA neurons and proapoptotic shifts in the survival/death proteins in midbrain and striatum. Contrary to young pk-/- animals 24-month-old pk-/- mice do not have compensatory elevation of GSH in striatum, glutathione reductase (GR) and glutathione peroxidase (GPx) activities are increased and catalase unchanged. Aged pk-/- mice accumulate high levels of tau and fail to up-regulate CHIP and HSP70. Our results suggest that aged pk-/- mice lack of the compensatory mechanisms that maintain a relatively normal DA function in early adulthood. This study could help to explain the effects of ageing in patients with genetic risks for Parkinson's disease.
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PMID:Mortality, oxidative stress and tau accumulation during ageing in parkin null mice. 1762 40

Organophosphate pesticides (OP) belong to the class of xenobiotics that are intentionally released to the environment. Toxicity of these compounds is mainly due to inhibition of acetylcholinesterase (AChE), but many authors postulate that OP in acute as well as in chronic intoxication disturb the redox processes, changing the activities of antioxidative enzymes and causing enhancement of lipid peroxidation in many organs. Epidemiological studies have demonstrated a relationship of certain human diseases with pesticide exposure and with changes in antioxidative enzymes. There is also evidence that oxidative stress is an important pathomechanism of neurological disorders such as Alzheimer disease and Parkinson disease, cardiovascular disorders and many others. The study objective was to investigate the activities of brain antioxidative enzymes and reduced glutathione level in rats subchronically intoxicated with chlorfenvinphos. In the rat brain the activities of such enzymes as superoxide dismutase, catalase, glutathione peroxidase and reductase were found to increase, while reduced glutathione level decreased in chlorfenvinphos intoxication. Based on experimental findings of this study, it can be suggested that subchronic administration of chlorfenvinphos leads to a change in the brain oxidative status and that the change occurs at a dose of 0.3 mg/kg/day, i.e., twice smaller than LOAEL level for rats.
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PMID:Subchronic intoxication with chlorfenvinphos, an organophosphate insecticide, affects rat brain antioxidative enzymes and glutathione level. 1770 53

Parkinson's disease (PD) is a common neurodegenerative movement disorder. Whereas the majority of PD cases are sporadic, rare genetic defects have been linked to this prevalent movement disorder. Mutations in DJ-1 are associated with autosomal recessive early-onset PD. The exact biochemical function of DJ-1 has remained elusive. Here we report the generation of DJ-1 knockout (KO) mice by targeted deletion of exon 2 and exon 3. There is no observable degeneration of the central dopaminergic pathways, and the mice are anatomically and behaviorally similar to WT mice. Fluorescent Amplex red measurements of H(2)O(2) indicate that isolated mitochondria from young and old DJ-1 KO mice have a 2-fold increase in H(2)O(2). DJ-1 KO mice of 2-3 months of age have a 60% reduction in mitochondrial aconitase activity without compromising other mitochondrial processes. At an early age there are no differences in antioxidant enzymes, but in older mice there is an up-regulation of mitochondrial manganese superoxide dismutase and glutathione peroxidase and a 2-fold increase in mitochondrial glutathione peroxidase activity. Mutational analysis and mass spectrometry reveal that DJ-1 is an atypical peroxiredoxin-like peroxidase that scavenges H(2)O(2) through oxidation of Cys-106. In vivo there is an increase of DJ-1 oxidized at Cys-106 after 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine intoxication of WT mice. Taken together these data indicate that the DJ-1 KO mice have a deficit in scavenging mitochondrial H(2)O(2) due to the physiological function of DJ-1 as an atypical peroxiredoxin-like peroxidase.
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PMID:DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. 1776 38

Present study was to assess lipid peroxidation and antioxidant enzymes in the blood of the Parkinson's disease (PD) patients in the Indian population. It may be useful to develop peripheral markers, for the diagnosis and prognosis of Parkinson's disease during lifetime. Malondialdehyde content was increased in patients with PD (2 fold), with respect to the activity of superoxide-dismutase (p<0.001). The levels of glutathione (p<0.001) and blood thiols were decreased. No changes were observed in gamma-GTP, glutathione peroxidase and glutathione reductase. Increased lipid peroxidation, decreased glutathione levels and increased superoxide dismutase activity in the blood of PD patients indicate oxidative stress.
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PMID:Plasma lipid peroxidation and antioxidant status of Parkinson's disease patients in the Indian population. 1803 86

Biological aging is associated with an increased incidence of cerebrovascular disease. Recent findings indicate that oxidative stress promoting age-related changes of cerebral circulation are involved in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease. The aim of this study was to evaluate the contribution of cerebral microvessels to the oxidative stress during brain aging, by: (i) assessment of precursors for advanced glycation end products (AGE) formation, (ii) activities of antioxidant enzymes, namely superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione disulfide reductase (GR), and (iii) the activities of metalloproteinases (MMPs), MMP-2 and MMP-9, involved in synaptogenesis and memory consolidation. The experiments were performed on two groups of male Wistar rats: 15 young (3-6 months old) and 15 aged (18-24 months old) animals. The cerebral microvessels were isolated by mechanical homogenization, the concentration of protein carbonyls and the activity of antioxidant enzymes were evaluated by spectrophotometry, and gelatin SDS-PAGE zymography was employed to evaluate MMP-2 and MMP-9 activities. The results showed that, by comparison with young rats, aged brain microvessels contain: (i) approximately 106 % increase of protein carbonyls production; (ii) approximately 68% higher GPx activity, unmodified activities of SOD and GR; (iii) approximately 30% diminishment in MMP-2 activity, and the specific occurrence of MMP-9 enzyme. The data suggest that the age-related changes of microvessels could increase the propensity for cerebral diseases and might represent, at least in part, a prerequisite for the deterioration of mental and physical status in the elderly.
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PMID:Advanced glycation end products, oxidative stress and metalloproteinases are altered in the cerebral microvasculature during aging. 1804 47


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