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)

Three groups have reported defective antioxidant mechanisms in substantia nigra of patients with Parkinson's disease, namely a decreased catalase and peroxidase activity, a reduction of glutathione and, more recently, a diminished nigral glutathione peroxidase activity. We decided to investigate these mechanisms in erythrocytes to determine whether these brain defects represent generalized or genetic aberrations, in which case they should also be present in blood cells. The glutathione cycle has been investigated (reduced and oxidized glutathione, glutathione reductase and peroxidase) plus the activities of catalase and superoxide dismutase. The basal malonaldehyde content of erythrocytes was used as an index of endogenous lipid peroxidation. None of the above-mentioned parameters were found altered in erythrocytes of parkinsonians, suggesting that no genetic or generalized biochemical abnormalities underly the deficiencies detected in substantia nigra.
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PMID:Erythrocyte antioxidant activity in human patients with Parkinson's disease. 358 38

Glutathione peroxidase is an enzyme of major importance in the detoxification of peroxides in brain. Using the spectrophotometric procedure of Paglia and Valentine [8] and Beutler [2] we measured the activity of this enzyme in autopsied brain from 12 patients dying with idiopathic Parkinson's disease and 11 neurologically normal adults matched with respect to age and postmortem interval. In the Parkinson's disease patients glutathione peroxidase activity was slightly but significantly reduced in several brain areas including substantia nigra. Although the magnitude of the glutathione peroxidase deficiency in Parkinson's disease substantia nigra was small (19% reduction), coupled with the reported marked deficiency of reduced glutathione [9] it may represent one of the contributing factors leading to nigral dopamine neurone loss.
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PMID:Glutathione peroxidase activity in Parkinson's disease brain. 404 94

Excessive free radical formation or antioxidant enzyme deficiency can result in oxidative stress, a mechanism proposed in the toxicity of MPTP and in the etiology of Parkinson's disease (PD). However, it is unclear if altered antioxidant enzyme activity is sufficient to increase lipid peroxidation in PD. We therefore investigated if MPTP can alter the activity of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) and the level of lipid peroxidation. L-Deprenyl, prior to MPTP administration, is used to inhibit MPP+ formation and its subsequent effect on antioxidant enzymes. MPTP induced a threefold increase in SOD activity in the striatum of C57BL/6 mice. No parallel increase in GSH-PX or CAT activities was observed, while striatal lipid peroxidation decreased. At the level of the substantia nigra (SN), even though increases in CAT activity and reduction in SOD and GSH-PX activities were detected, lipid peroxidation was not altered. Interestingly, L-deprenyl induced similar changes in antioxidant enzymes and lipid peroxidation levels, as did MPTP. Taken together, these results suggest that an alteration in SOD activity, without compensatory increases in CAT or GSH-PX activities, is not sufficient to induce lipid peroxidation.
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PMID:Effect of MPTP and L-deprenyl on antioxidant enzymes and lipid peroxidation levels in mouse brain. 759 71

Oxidative stress has been linked to the destruction of dopaminergic neurons in the substantia nigra and may be a significant factor in both Parkinson's disease and MPTP toxicity. Using primary cultures of embryonic rat mesencephalon and standard immunocytochemical techniques, we have examined the survival of tyrosine hydroxylase-containing (TH+) neurons cultured in the presence of antioxidants and/or in an environment of low oxygen partial pressure. The number of TH+ neurons increased approximately twofold if superoxide dismutase, glutathione peroxidase (GP), or N-acetyl cysteine (NAC) were added to the culture media. Exposure of the neurons to a 5% oxygen environment (38 torr, i.e., 38 mm Hg) also increased the survival of TH+ neurons by about twofold. A dramatic enhancement of survival, however, was seen when NAC was used in combination with the 5% oxygen environment. In this case, the number of TH+ neurons increased fourfold from nontreated controls. Morphological changes were also noted. GP increased the average neurite length while NAC increased the average area of the cell body in the TH+ neuron. These results suggest that manipulation of oxidative conditions by changing the ambient O2 tension or the level of antioxidants promotes survival of TH+ neurons in culture and may have implications for transplantation therapies in Parkinson's disease.
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PMID:Protection from oxidation enhances the survival of cultured mesencephalic neurons. 772 Aug 26

Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherited parkinsonism affecting multiple members in three generations. Affected individuals exhibited the cardinal signs and symptoms of Parkinson's disease, with a mean age of onset of 51, 62, and 61 years in Families A, B, and C, respectively. Parkinsonian symptoms responded to L-dopa treatment, and an [18F]6-fluoro-L-dopa positron emission tomography scan in 1 affected member of Family B showed decreased striatal uptake typical of Parkinson's disease. Ancestors of all three families were traced to a small region in northern Germany and southern Denmark, suggesting the possibility of a common mutation. Linkage studies were performed with polymorphic markers associated with the following candidate genes: the genes for glutathione peroxidase (GPX1, 3q11), tyrosine hydroxylase (TH, 11p15.5), brain-derived neurotrophic factor (BDNF, 11p14), catalase (CAT, 11p13), amyloid precursor protein (APP, 21q21), copper-zinc superoxide dismutase (SOD1, 21q21), and debrisoquin 4-hydroxylase (CYP2D6, 22q13.1). Summed lod scores for all families excluded linkage to the genes GPX1, TH, APP, SOD1, and CYP2D6, as well as to the chromosomal region containing the genes CAT and BDNF. If families were analyzed individually, exclusion was possible for two (Family A), six (Family B), and five (Family C) of the seven candidate genes. There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave slightly positive pairwise lod scores in Family A. Our results indicate that the candidate genes investigated are not involved in the etiology of parkinsonism in these families.
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PMID:Genetic linkage studies in autosomal dominant parkinsonism: evaluation of seven candidate genes. 791 97

Oxidants are ubiquitous in our aerobic environment and could play an etiological role in aging and neurodegenerative diseases such as Alzheimer's disease. All cells contain several antioxidant enzymes, most importantly, superoxide dismutases (MnSOD and CuZnSOD), glutathione peroxidase (GSH-Px), glutathione reductase and catalase. The individual contribution of these antioxidant enzymes in neuronal protection during aging and under in vivo conditions remains unknown. We feel that the use of genetic manipulations to construct cells and/or transgenic mice that specifically overexpress or lack a single function represent a way to an understanding of the role of the individual antioxidant enzymes in neuronal aging. Copper-zinc superoxide dismutase (CuZnSOD) is one of the genes encoded by chromosome 21. As a consequence of gene dosage excess, CuZnSOD activity and protein are increased by 50% in all tissues of Down syndrome (DS) patients. It has been suggested that this increment, by accelerating hydrogen peroxide formation, might promote oxidative damage within DS cells and might be involved in the various neurobiological abnormalities found in DS such as premature aging and Alzheimer-type neurological lesions. Moreover, the level of CuZnSOD protein and mRNA is particularly high in pyramidal hippocampal neurons susceptible to degenerative processes in Alzheimer's disease, and in dopaminergic melanized-neurons vulnerable in Parkinson's disease. In order to test this hypothesis, we have created transfected cells and transgenic mice which express human CuZnSOD gene. An oversupply of this enzyme is not beneficial to the brain of transgenic mice and causes increased thiobarbituric-reactive substances (TBARS), an index of lipid peroxidation, and may be due to peroxides generated by an imbalance between enzymatic activities of CuZnSOD and GSH-Px. Unlike what has been observed in transfected cells with the human CuZnSOD gene, but similar to what was found in the DS fetal brain, the GSH-Px activity was not increased in the brain of transgenic mice. One possibility to explain this discrepancy could be the differential cellular localization of these two enzymes in the brain (CuZnSOD in neurons and GSH-Px in glial cells). This heterogeneous cellular distribution of the enzymes implicated in oxygen-free radicals detoxification could participate to a selective neuronal degeneration. Interestingly, overexpression of CuZnSOD in the brain of transgenic mice is associated with an increased MnSOD activity, the mitochondrial form of the enzyme. This increased MnSOD might be a defense response to protect mitochondria from oxidative damage.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Transgenic mice overexpressing copper-zinc superoxide dismutase: a model for the study of radical mechanisms and aging]. 801 10

(-)Deprenyl, a MAO-B inhibitor that is also known to be effective for symptoms of Parkinson's disease, when injected subcutaneously (sc) in male Fischer-344 rats at a dose of 0.5 mg/kg per day (3 times a week) from 18 months of age, significantly increased the remaining life expectancy. The average life span after 24 months was 34% greater in treated rats than in saline-treated control animals. Furthermore, a short-term (3 wk) continuous sc infusion of deprenyl significantly increased activities of superoxide dismutase and catalase but not of glutathione peroxidase in selective brain regions such as s. nigra, striatum, and cerebral cortex, but not in hippocampus or cerebellum, or the liver. The optimal dose for increasing these activities, however, differed greatly depending on the sex and age of animals, with a 10-fold lower value for young female than male rats. Interestingly, aging caused an increase and a decrease in the optimal dose in female and male rats, respectively. In addition, treatment for a longer term tended to reduce the optimal dosage in the same animal group. The results clearly demonstrate that deprenyl increases antioxidant enzyme activities in selective brain regions. If this effect of deprenyl is causally related to its life-prolonging effect, the dosage to be used for any life span study would be a critical factor, with the dosage differing widely depending on sex, age of animal, and mode and duration of drug administration.
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PMID:(-)Deprenyl increases the life span as well as activities of superoxide dismutase and catalase but not of glutathione peroxidase in selective brain regions in Fischer rats. 803 Aug 52

The activities of enzymes related to glutathione synthesis, degradation, and function were analyzed in various brain regions (cerebral cortex, caudate nucleus, putamen, globus pallidus, and substantia nigra) from patients dying with pathologically proven Parkinson's disease (PD) and multiple system atrophy (MSA), and from matched controls with no neurological disorder. The activity of the glutathione degradative enzyme, gamma-glutamyltranspeptidase, was selectively elevated in substantia nigra (SN) in PD. In contrast, the activity of the synthetic enzyme, gamma-glutamylcysteine synthetase, was unaltered in SN and other brain areas in PD. Similarly, glutathione peroxidase and glutathione transferase activities were unaltered in SN or in other brain regions in PD. gamma-Glutamylcysteine synthetase, gamma-glutamyltranspeptidase, glutathione peroxidase, and glutathione transferase activities were normal in SN and most other brain areas in MSA. However, glutathione peroxidase activity was increased in the lateral globus pallidus and caudate nucleus in MSA. The depletion of reduced glutathione (GSH) in the SN in PD, with no change in oxidized glutathione (GSSG), may be due to efflux of GSH mainly out of glia promoted by gamma-glutamyltranspeptidase, perhaps with additional increased conversion of GSH to GSSG (which itself is transported out of cells by gamma-glutamyltranspeptidase), in response to increased hydrogen peroxide formation.
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PMID:Glutathione-related enzymes in brain in Parkinson's disease. 808 Feb 39

In Parkinson's disease (PD) an elevation of iron with staging of the disease has been observed in the substantia nigra (SN), especially the zona compacta (ZC). The iron is found to be present in glia, active microglia, macrophages, oligodendrocytes, outside the degenerated dopamine neurons and as a mild halo around Lewy bodies and within melanized dopamine neurons of SNZC. Although in control brains iron is absent in melanized dopamine neurons, in PD it is bound to neuromelanin in a fashion similar to the interaction of iron with synthetic dopamine-melanin. The iron in SNZC is thought to induce oxidative stress and thus be associated with the reported decreases of glutathione peroxidase activity, reduced glutathione (GSH), mitochondrial Complex I activity, calcium binding protein and increase of basal lipid peroxidation. An animal (rat) model of PD has been described in which intranigral iron injection induces a relatively specific lesioning of dopamine neurons resulting in behavioural and biochemical Parkinsonism in rats. Support for the neurotoxicity of iron liberated from an endogenous source has come from the 6-hydroxydopamine model of PD. This neurotoxin is thought to owe its toxicity to the liberation of iron from ferritin, which in turn alters the homeostasis of mitochondrial Ca2+ with the subsequent depletion of tissue GSH, resulting in oxidative stress. Pretreatment of rats with intraventricular injection of a relatively selective prototype iron chelator, desferrioxamine (desferal), attenuates the 6-hydroxydopamine lesion of nigrostriatal dopamine. Thus iron can fulfill the role of a neurotoxin. However it remains to be established whether its role in PD is primary or secondary to some other neurotoxic event.
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PMID:The role of iron in senescence of dopaminergic neurons in Parkinson's disease. 829 1

Parkinson's disease is characterized by a massive neuronal loss in several cell groups of the midbrain. However, the most consistent lesions are observed in dopaminergic systems including nigral neurons. Although the cause of this neuronal loss remains unknown, oxidative stress has been suspected to participate in the mechanism of nerve cell death for several reasons. (1) Lipid peroxidation, a consequence of oxygen free radical production, has been found to be elevated in the substantia nigra in Parkinson's disease. (2) Catecholaminergic neurons containing neuromelanin, an autooxidation by-product of catecholamines, are more vulnerable in Parkinson's disease than non-melanized catecholaminergic neurons. (3) Catecholaminergic neurons surrounded by a low density of cells containing glutathione peroxidase, a free radical scavenging enzyme, are more susceptible to degeneration in Parkinson's disease than those well protected against oxidative stress. (4) The content of iron, a compound which exacerbates the production of free radicals in catecholaminergic neurons, is increased in the substantia nigra in Parkinson's disease. It remains, however, to be determined whether oxidative stress participates to the cause of the disease or only represents a consequence of nerve cell death.
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PMID:Does oxidative stress participate in nerve cell death in Parkinson's disease? 837 33


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