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)

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

Parkinson's disease (PD) is characterized mainly by a loss of nigrostriatal dopamine neurons. Thus far, the actual physiopathology of PD remains uncertain, although recent studies have found decreased activity of complex I, one of the enzymatic units of the mitochondrial respiratory chain, in various tissues of PD patients. Because most, if not all, of PD patients are treated chronically with levodopa, the precursor of dopamine, and because we have shown previously that catecholamines may alter mitochondrial respiration, we assessed the effects of chronic administration of levodopa on complex I activity in rat brain. We found that chronic administration of levodopa, at a dose used in PD patients, caused a significant reduction in complex I activity while it did not affect the activities of complex II, complex IV, and citrate synthase. Reduction in complex I activity correlated well with catecholamine innervation as the reduction was observed mainly in the striatum and substantia nigra and to a lesser extent in the frontal cortex but not in the cerebellum. Moreover, the levodopa-induced decrease of complex I activity was reversible since activities at 1, 3, and 7 days after the last injection showed a progressive return to control values. Incubation of whole brain mitochondria in vitro showed that both levodopa and dopamine inhibit complex I activity in a dose- and time-dependent manner. In contrast, other compounds such as homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 3-O-methyl-dopa were minimally effective. Reduced glutathione, ascorbate, superoxide dismutase, and catalase prevented the effect of levodopa and dopamine on complex I. Various inhibitors of monoamine oxidase also prevented the effect of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Chronic levodopa administration alters cerebral mitochondrial respiratory chain activity. 823 66

(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), structurally closely related to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. It is a highly potent and selective irreversible inhibitor of B-type monoamine oxidase (MAO) and interferes with the uptake of catecholamines and indirectly acting symphathomimetics. In striking contrast to PEA and its relatives, which displace the transmitter from the storage places, (-)deprenyl inhibits the releasing effect of tyramine and is up to the present the only safe MAO inhibitor which can be administered without dietary restrictions. Maintenance on (-)deprenyl enhances selectively superoxide dismutase (SOD) and catalase activities in the striatum. This effect is unrelated to the MAO and uptake inhibitory effects of the drug. Maintenance on (-)deprenyl facilitates the activity of the nigrostriatal dopaminergic neurons with remarkable selectivity and this effect too, is unrelated to either the MAO or the uptake inhibitory effects of the drug. Maintenance on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. As a consequence of its complex spectrum of activity male rats maintained on (-)deprenyl live longer, lose their capacity to ejaculate later, show improved performance in learning tests and maintain this activity for a longer period than their untreated peers. Patients with Parkinson's disease maintained on levodopa plus (-)deprenyl (10 mg daily) live significantly longer than those on levodopa alone. Freshly diagnosed patients treated with (-)deprenyl need levodopa later than their placebo-treated peers. Continuous administration of (-)deprenyl improves the performance of patients with Alzheimer's disease.
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PMID:The pharmacological basis of the beneficial effects of (-)deprenyl (selegiline) in Parkinson's and Alzheimer's diseases. 829 2

Central nervous system has a low antioxidative capacity, which is formed mainly by ascorbic acid. Therefore the cerebral tissue is threatened by the increased formation of free radicals and their metabolites (ROS--reactive oxygen species). ROS are formed such as in reperfusion phase after ischemia and in catecholamine metabolism, in oxidative stress due to hyperglycaemia. Polyunsaturated fatty acids (PUFA) are peroxidased by ROS; proteins and DNK are damaged as well. Free radicals are involved in etiology and pathogenesis of many CNS diseases, such as neuritis, Alzheimer disease, Parkinson disease, Huntington disease, aging and atherosclerosis of the brain, epilepsy, etc. During the antioxidant therapy it is necessary to consider the types of ROS, their origin and their mode of action, whether to administer hydrophilic or lipophilic antioxidants, eventually chelate agents, etc. Hydrophylic antioxidants are acting very soon after the administration, whereas the lipophilic ones reach their target tissues with a great delay. Therefore it is better to apply them preferentially like a prevention, if possible. Enzymatic antioxidants (SOD, GSPHx and catalase and others) are usually acting only for a short time. The methods of estimation of free radicals attacks are discussed as well their possible pathophysiological effects.
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PMID:[Free radicals in the central nervous system]. 866 12

We studied nitrogen radical nitric oxide (.NO) release and reactive oxygen species (ROS) production by isolated neutrophils after phorbol myristate acetate (PMA) stimulation in 12 newly diagnosed and nine treated Parkinson's disease (PD) patients and 10 age-matched healthy controls. Neutrophils of both groups of PD patients had an elevated PMA-activated release of .NO [61 and 57%, respectively, higher than that of controls (p < 0.05)]. In contrast, H2O2 release was only significantly increased by 56% in chronically treated patients. In agreement, the maximum rate of luminol-dependent chemiluminescence, which partly represents O2- H2O2- .NO interactions, was increased only in the treated group. When other blood markers of oxidative stress were compared, only erythrocyte catalase activity was decreased in both PD patient series by 33 and 39%, respectively (p < 0.05), whereas plasma antioxidant capacity and erythrocyte superoxide dismutase activity levels were decreased only in treated PD patients. This study suggests that neutrophils express a primary alteration of .NO release in PD patients, whereas H2O2 and oxidative-stress parameters are more probably related to the evolution of PD or to effects of treatment with L-dopa.
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PMID:Neutrophil function, nitric oxide, and blood oxidative stress in Parkinson's disease. 872 42

In order to investigate the role of two free radical detoxificant enzymes in patients with aging brain disorders, superoxide dismutase (SOD) and catalase (CAT) activities have been measured in blood from male and female human patients of different ages with several types of aging brain disorders. When compared with activities in the normal population, we have detected: 1) SOD and CAT activities are decreased in patients with Parkinson disease. 2) SOD activity seems to be normal and CAT activity is decreased in patients with dementia. 3) In the patients with stroke, SOD activity is normal, while CAT activity is decreased. SOD activity was measured in red blood cells using the Minami and Yoshikawa method. CAT activity was measured in hemolysates by the method of Aebi. We can conclude that SOD and CAT activities in patients with Parkinson disease are decreased.
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PMID:Human aging brain disorders: role of antioxidant enzymes. 889 40

Current concepts of the pathogenesis of Parkinson's disease (PD) center on the formation of reactive oxygen species and the onset of oxidative stress leading to oxidative damage to substantia nigra pars compacta. Extensive postmortem studies have provided evidence to support the involvement of oxidative stress in the pathogenesis of PD; in particular, these include alterations in brain iron content, impaired mitochondrial function, alterations in the antioxidant protective systems (most notably superoxide dismutase [SOD] and reduced glutathione [GSH]), and evidence of oxidative damage to lipids, proteins, and DNA. Iron can induce oxidative stress, and intranigral injections have been shown to induce a model of progressive parkinsonism. A loss of GSH is associated with incidental Lewy body disease and may represent the earliest biochemical marker of nigral cell loss. GSH depletion alone may not result in damage to nigral neurons but may increase susceptibility to subsequent toxic or free radical exposure. The nature of the free radical species responsible for cell death in PD remains unknown, but there is evidence of involvement of hydroxyl radical (OH.), peroxynitrite, and nitric oxide. Indeed, OH. and peroxynitrite formation may be critically dependent on nitric oxide formation. Central to many of the processes involved in oxidative stress and oxidative damage in PD are the actions of monoamine oxidase-B (MAO-B). MAO-B is essential for the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion, for a component of the enzymatic conversion of dopamine to hydrogen peroxide (H2O2), and for the activation of other potential toxins such as isoquinolines and beta-carbolines. Thus, the inhibition of MAO-B by drugs such as selegiline may protect against activation of some toxins and free radicals formed from the MAO-B oxidation of dopamine. In addition, selegiline may act through a mechanism unrelated to MAO-B to increase neurotrophic factor activity and upregulate molecules such as glutathione, SOD, catalase, and BCL-2 protein, which protect against oxidant stress and apoptosis. Consequently, selegiline may be advantageous in the long-term treatment of PD.
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PMID:Oxidative stress and the pathogenesis of Parkinson's disease. 895 85

Enhanced oxidative stress has been suggested to be involved in the degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease. The high turnover rate of dopamine and/or unsequestered dopamine may cause an increase of formation of hydrogen peroxide via either oxidative deamination of dopamine by monoamine oxidase or autoxidation. Hydrogen peroxide would be converted to more toxic hydroxyl free radicals. L-beta-3,4-Dihydroxyphenylalanine hydrochloride (L-DOPA), the most useful drug in the symptomatic treatment of Parkinson's disease, has been considered to possess deteriorating degenerative side-effects. The catecholaminergic neuroblastoma SH-SY5Y cells were chosen to investigate the cytotoxic effect of dopamine and L-DOPA. Both dopamine and L-DOPA were found to be cytotoxic towards SH-SY5Y cells. Such toxic effects were accompanied by an increase of oxidative stress in the cell cultures and could be reversed effectively by catalase and to a lesser extent by superoxide dismutase. The non-enzymatic antioxidants L-ascorbic acid, glutathione, N-acetyl-L-cysteine, but not (+)-alpha-tocopherol, also completely protected SH-SY5Y cells against the cytotoxic effects induced by dopamine and L-DOPA. Antioxidative factors, namely free radical scavengers (including N-tert-butyl-alpha-phenylnitrone, salicylic acid, and D-mannitol) and a strong iron chelator, deferoxamine, however, did not protect the SH-SY5Y cells against dopamine and L-DOPA. The generation of reactive oxygen species and the resulting enhanced oxidative stress was clearly involved in the dopamine- and L-DOPA-induced cytotoxic effects. Hydrogen peroxide played the most important role related to cytotoxicity of dopamine and L-DOPA.
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PMID:Dopamine- and L-beta-3,4-dihydroxyphenylalanine hydrochloride (L-Dopa)-induced cytotoxicity towards catecholaminergic neuroblastoma SH-SY5Y cells. Effects of oxidative stress and antioxidative factors. 906 40


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