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

Oxidative stress and protein aggregation are biochemical hallmarks of Parkinson's disease (PD), a frequent sporadic late-onset degenerative disorder particularly of dopaminergic neurons in the substantia nigra, resulting in impaired spontaneous movement. PARK6 is a rare autosomal-recessively inherited disorder, mimicking the clinical picture of PD with earlier onset and slower progression. Genetic data demonstrated PARK6 to be caused by mutations in the protein PINK1, which is localized to mitochondria and has a serine-threonine kinase domain. To study the effect of PINK1 mutations on oxidative stress, we used primary fibroblasts and immortalized lymphoblasts from three patients homozygous for G309D-PINK1. Oxidative stress was evident from increases in lipid peroxidation and in antioxidant defenses by mitochondrial superoxide dismutase and glutathione. Elevated levels of glutathione reductase and glutathione-S-transferase were also observed. As a putative cause of oxidation, a mild decrease in complex I activity and a trend to superoxide elevation were detectable. These data indicate that PINK1 function is critical to prevent oxidative damage and that peripheral cells may be useful for studies of progression and therapy of PARK6.
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PMID:Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. 1714 10

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

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

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

It has been proposed that ROS production, including H(2)O(2), may lead to neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Catalpol, an iridoid glycoside, presents in the root of Rehmannia glutinosa, protects cells and mice from damage caused by a variety of toxic stimuli. In this study, we investigated whether catalpol could protect astrocytes from oxidant stress induced by H(2)O(2) because of the critical role of astrocytes in the brain and found the possible mechanism of protection. The results showed that catalpol could significantly increase the cell viability and reduce the intracellular ROS formation. Furthermore, catalpol attenuated H(2)O(2)-induced oxidative stress via preventing the decrease in the activities of antioxidant enzymes in glutathione redox cycling such as glutathione peroxidase, glutathione reductase and glutathione content. However, the catalase activity did not appear to be elevated by catalpol adequately. Together, the main mechanism underlying the protective effects of catalpol in H(2)O(2)-injured astrocytes might be related to the maintenance of glutathione metabolism balance and the decrease of ROS formation. Therefore, catalpol may be developed as a potential preventive or therapeutic drug for neurodegenerative diseases associated with oxidative stress.
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PMID:Protective effects of catalpol against H2O2-induced oxidative stress in astrocytes primary cultures. 1865 78

Oxidative stress during development may predispose humans to neurodegenerative disorders in old age. Moreover, numerous ailments of brain disproportionately affect one of the genders. We therefore hypothesized that, activities of enzymes regenerating and utilizing glutathione (GSH) show sexual dimorphism and developmental differences in rat brain. To test this hypothesis, we collected cortex tissue from male and female Sprague-Dawley rats at post-natal day (PN) 5, PN 10, PN 20, PN 30, and PN 60. We measured tissue levels of NADP-linked isocitrate dehydrogenase (NADP-ICDH), glucose-6-phosphate dehydrogenase (G6PDH), and, glutathione reductase (GR) by UV spectrophotometry and determined glutathione peroxidase (GPx) expression therein by western blotting. Our results showed that sexual maturation had an impact on activities of enzymes that regenerate and utilize GSH and rat female cortex had more anti-oxidant capacity. Moreover, age-related decline in the activities of these key enzymes were observed. Reduced glutathione and NADPH protects the brain from oxidative stress. Thus, our results may have implications for neurodegenerative disorders like Parkinson's disease and developmental disorders of brain like autism in which oxidative stress plays a key role.
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PMID:Reduced glutathione regenerating enzymes undergo developmental decline and sexual dimorphism in the rat cerebral cortex. 1945 May 67

Incidence of Parkinson's disease (PD) is lower in women compared to men (1:1.46), which is reflected in animal models. However, precise mechanisms are unclear. Administration of MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) to female mice does not lead to mitochondrial complex I inhibition as seen in males and the progressive dopaminergic cell loss in substantia nigra (SNpc) is significantly attenuated. Redox driven apoptotic signaling pathways regulated by thiol disulfide oxidoreductase(s) have been implicated in the neurodegeneration seen in PD. Oxidation of thioredoxin leads to activation of apoptosis signal regulating kinase 1 (ASK1; MAPKKK) initiating cell death cascade through MAP kinase(s). Higher constitutive expression of enzymes involved in cellular redox maintenance, such as glutathione reductase, thioredoxin, and thioredoxin reductase is observed in female brain. Exposure to MPTP activates ASK1 in male but not in female mice. Higher expression of Trx in females potentially prevents ASK1 activation. Downstream of ASK1, phosphorylation of p38 MAP kinase is seen in male but not female mice. Expression of DJ-1, the redox sensing protein is higher in females and the loss of nuclear DJ-1, followed by translocation of Daxx (death associated protein) from the nucleus to the cytosol, which promotes ASK1 mediated death cascade is not seen in females. The enzymes involved in redox maintenance potentially could play a crucial role in preventing the activation of redox driven death signaling cascade and offer neuroprotection. Theraupeutic strategies that help maintain redox homeostasis may help prevent the progressive neurodegeneration seen in PD.
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PMID:Redox activated MAP kinase death signaling cascade initiated by ASK1 is not activated in female mice following MPTP: novel mechanism of neuroprotection. 1952 88

The degeneration of dopaminergic neurons in the substantia nigra has been linked to the formation of the endogenous neurotoxin 5-S-cysteinyl-dopamine. Sulforaphane (SFN), an isothiocyanate derived from the corresponding precursor glucosinolate found in cruciferous vegetables has been observed to exert a range of biological activities in various cell populations. In this study, we show that SFN protects primary cortical neurons against 5-S-cysteinyl-dopamine induced neuronal injury. Pre-treatment of cortical neurons with SFN (0.01-1 microM) resulted in protection against 5-S-cysteinyl-dopamine-induced neurotoxicity, which peaked at 100 nM. This protection was observed to be mediated by the ability of SFN to modulate the extracellular signal-regulated kinase 1 and 2 and the activation of Kelch-like ECH-associated protein 1/NF-E2-related factor-2 leading to the increased expression and activity of glutathione-S-transferase (M1, M3 and M5), glutathione reductase, thioredoxin reductase and NAD(P)H oxidoreductase 1. These data suggest that SFN stimulates the NF-E2-related factor-2 pathway of antioxidant gene expression in neurons and may protect against neuronal injury relevant to the aetiology of Parkinson's disease.
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PMID:Sulforaphane protects cortical neurons against 5-S-cysteinyl-dopamine-induced toxicity through the activation of ERK1/2, Nrf-2 and the upregulation of detoxification enzymes. 2016 44

The present study was undertaken to investigate the neuroprotective effects of resveratrol (RES) on 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) in rats. PD is an age-related neurodegenerative disorder in which the role of reactive oxygen species (ROS) is strongly implicated. RES, a polyphenolic antioxidant compound enriched in grapes, has been shown to have antioxidant and anti-inflammatory actions and thus was tested for its beneficial effects using 6-OHDA-induced PD rat model. Male Wistar rats were pretreated with RES (20mg/kg body weight i.p.) once daily for 15 days and subjected to unilateral intrastriatal injection of 6-OHDA (10 microg in 0.1% ascorbic acid in normal saline). Three weeks after 6-OHDA infusion, rats were tested for neurobehavioral activity and were killed after 4 weeks of 6-OHDA infusion for the estimation of lipid peroxidation, glutathione content, and activity of antioxidant enzymes (glutathione peroxidase [GPx], glutathione reductase [GR], catalase [CAT], and superoxide dismutase [SOD]. RES was found to be successful in upregulating the antioxidant status and lowering the dopamine loss. Conversely, the elevated level of thiobarbituric acid reactive substances (TBARS), protein carbonyl (PC), and activity of phospholipase A2 in 6-OHDA group was attenuated significantly in RES-pretreated group when compared with 6-OHDA-lesioned group. These results were supported by the immunohistochemical findings in the substantia nigra that has shown the protection of neurons by RES from deleterious effects of 6-OHDA. Thus, RES may be used to reduce the deterioration caused by free radicals thereby preventing subsequent behavioral, biochemical, and histopathological changes that occur during PD.
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PMID:Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson's disease. 2016 6


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