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)

We examined the cytotoxicity of dopa and dopamine for cultured neurons by using a newly developed enzyme immunoassay for neurofilament protein to determine surviving neuronal numbers. Each of the two catechols caused neuronal death in the presence of iron with or without superoxide dismutase and catalase, while deferoxamine mesylate prevented neuronal loss. Lipid peroxidation of phospholipid liposomes was confirmed to be produced by the combination of the catechols and iron (Fe3(+)-ADP complex). Thus, it was strongly suggested that cultured neurons were killed via the peroxidative cleavage of cell membrane components provoked by the catechols and iron. This mechanism of neuronal loss may play an important role in the degeneration in the substantia nigra of Parkinson's disease, because the catechols and iron are abundant in this region.
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PMID:Dopa and dopamine cause cultured neuronal death in the presence of iron. 190 38

Degenerative diseases of the nervous system which are considered to be related to free radicals are Parkinson's disease and Alzheimer-type dementia (ATD). Parkinson's disease is characterized by appearance of Leyw's body and degeneration of nigrostriatal dopaminergic system. But the most fundamental cause of this disease remains still unknown. The fact that H2O2 is formed in the process of oxidative deamination of catecholamines and some substances which can cause Parkinsonism in animal experiments also produce active oxygen in the metabolic processes suggest the important role of free radicals in the pathogenesis of Parkinson's disease. We recently observed that addition of DOPA and Fe3(+)-ADP complex to the microsomal phospholipid system produced lipid peroxides without participation of active oxygen. Neurons cultured in vitro also decreased significantly with addition of DOPA and Fe3(+)-ADP complex and this harmful effect was prevented by desferoxamine (potent Fe chelating agent) or alpha-tocopherol (antioxidant). These results may suggest that lipid peroxidation can occur by interaction of naturally existing substances in the dopaminergic system and induce cell damage. As regards ATD, there is still no definite evidence to support the implication of free radicals in its pathogenesis. However, there are reports that lipid peroxides increase significantly in the brains of patients with ATD. Moreover, recent advances in the study of amyloid in the senile plaque revealed close relationship of ATD to chromosome 21.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Free radicals and degenerative diseases of the nervous system]. 220 Sep 16

Progress in the research on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is reviewed, and the impact given by MPTP to the studies on Parkinson's disease is discussed. Our data on the mechanism of the neuronal degeneration in MPTP-induced experimental parkinsonism are also presented. We studied the effects of the 1-methyl-4-phenylpyridinium ion (MPP+) on mitochondrial respiration. Mitochondria were prepared from mouse brains, and oxygen consumption was measured polarographically. Activity of Complex I was measured after the incubation of the mitochondria with NAD(+)-utilizing substrates in the TCA cycle and ADP. MPP+ significantly inhibited the state 3 respiration supported by glutamate. Amount of ATP synthesized was also significantly reduced by MPP+. Activity of Complex I was significantly inhibited by MPP+. This inhibition was observed with 0.05 mM of MPP+ when intact mitochondria were used. These observations suggest mitochondria as the most probable site of the action for MPP+. It appears to be important to search for endogenous or exogenous toxic substances with similar pharmacological properties as MPTP to elucidate pathogenesis of Parkinson's disease. In addition, studies on mitochondrial functions in Parkinson's disease seem to be also important. Some preliminary data are shown.
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PMID:[Contribution of MPTP to studies on the pathogenesis of Parkinson's disease]. 269 96

Recent reports have stressed an accumulation of iron and enhanced levels of lipid peroxides in the substantia nigra as essential factors in the pathogenesis of Parkinson's disease. Many investigators believe that tissue antioxidants, such as ascorbate, play a protective role. On the other hand, L-DOPA, which is used extensively to treat Parkinson's disease, undergoes autoxidation (as does dopamine), thus generating reactive oxygen species. We studied lipid peroxidation (LPO) in mouse brain homogenates and evaluated the effects of iron (5 microM ferric-ADP), L-DOPA, dopamine and ascorbic acid, added either alone or in mixtures. Ascorbic acid was used at levels of 0.5 mM or 2.0 mM, approximating those present normally in brain. LPO in brain homogenates was stimulated by the addition of either ascorbic acid or iron, as well as by a combination of the two, in agreement with other reports. The effects of L-DOPA were complex: L-DOPA strongly suppressed LPO both with and without added iron-ADP. In sharp contrast, however, when ascorbic acid was also added, L-DOPA no longer suppressed LPO; indeed, L-DOPA stimulated LPO in the presence of added iron and ascorbic acid. Dopamine behaved similarly to L-DOPA. When ascorbic acid was studied over a concentration range, LPO was stimulated at 0.5, 1, 2 or 3 mM, with or without added iron and/or dopamine; 5 and 10 mM ascorbic acid were either not as effective or suppressed LPO below control levels. Deferoxamine, a powerful iron chelator, greatly suppressed LPO under all conditions, as did diethylenetriaminepentaacetate (DTPA). Added superoxide dismutase had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipid peroxidation in brain: interactions of L-DOPA/dopamine with ascorbate and iron. 758 78

The activity of complex I of the respiratory chain is decreased in the substantia nigra of patients with Parkinson's disease (PD) but the presence of this defect in skeletal muscle is controversial. Therefore, the mitochondrial function of skeletal muscle in patients with PD was investigated in vivo using 31P magnetic resonance spectroscopy. Results from 7 PD patients, 11 age matched controls and 9 mitochondrial myopathy patients with proven complex I deficiency were obtained from finger flexor muscle at rest, during exercise and in recovery from exercise. In resting muscle, the patients with mitochondrial myopathy showed a low PCr/ATP ratio, a low phosphorylation potential, a high P(i)/PCr ratio and a high calculated free [ADP]. During exercise, stores of high energy phosphate were depleted more rapidly than normal, while in recovery, the concentration of phosphocreatine and free ADP returned to pre-exercise values more slowly than normal. In contrast, the patients with PD were not significantly different from normal for any of these variables, and no abnormality of muscle energetics was detected. Three of the PD patients also had mitochondrial function assessed biochemically in muscle biopsies. No respiratory chain defect was identified in any of these patients by polarography or enzyme analysis when compared with age-matched controls. These results suggest that skeletal muscle is not a suitable tissue for the investigation and identification of the biochemical basis of the nigral complex I deficiency in PD.
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PMID:A 31P magnetic resonance spectroscopy study of mitochondrial function in skeletal muscle of patients with Parkinson's disease. 796 92

The evidence is compelling that free radicals, plus increases in free cytosolic Ca2+ and Na+, figure prominently in neuronal death after exposure to glutamate and dicarboxylic excitotoxins such as NMDA and kainate. However, neither the source of these radicals nor the direct connection between Ca2+ mobilization and radical production has been well defined. Electron paramagnetic resonance studies reported here indicate that intact mitochondria isolated from adult rat cerebral cortex and cerebellum generate extremely reactive hydroxyl (.OH) radicals, plus ascorbyl and other carbon-centered radicals when exposed to 2.5 microM Ca2+, 14 mM Na+, plus elevated ADP under normoxic conditions, circumstances that prevail in the cytoplasm of neurons during excitotoxin-induced neurodegeneration. In a feed-forward cycle, exposure of isolated mitochondria to .OH significantly increases subsequent radical production five- to 16-fold (average = 8.8 +/- 1.6 SE, n = 6, p > 0.01) with succinate as substrate, and also selectively impairs function of NADH-CoQ dehydrogenase activity (electron transport complex 1). These effects are also reflected by respiration rates that are reduced 48% with complex 1 substrates, but increased 27% with complex 2 substrate, after .OH exposure. Comparable complex 1 dysfunction is observed in mitochondria isolated from the substantia nigra of Parkinson's disease patients, from platelets of Huntington's disease patients, and from neocortex of Alzheimer's disease patients. Mitochondrial radical production provides a testable model, based on oxyradical toxicity, oxidative enzyme inactivation, and mitochondrial dysfunction, for the final common pathway of neuronal necrosis during excitotoxicity, and in a host of neurodegenerative disorders.
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PMID:Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated CA2+ and Na+: implications for neurodegeneration. 803 83

The antioxidant and pro-oxidant properties of L-DOPA and dopamine were investigated in vitro. Both compounds inhibited the peroxidation of ox-brain phospholipids, with IC50 values of 8.5 microM for dopamine and 450 microM for L-DOPA. Dopamine and L-DOPA reacted with trichloromethyl peroxyl radicals (CCl3O2.) with rate constants of 2.1 x 10(7)M-1s-1 and 1.3 x 10(7)M-1s-1 respectively. The effects of dopamine and L-DOPA on iron ion-dependent hydroxyl radical generation from H2O2 were complex. In general, low concentrations stimulated OH. formation in the presence of ferric-EDTA and, in the case of L-DOPA, ferric-ADP and ferric citrate chelates. Both compounds also reacted with superoxide radical and hypochlorous acid. The products of the reaction with HOCl could still inhibit alpha 1-antiproteinase and appear to be 'long lived' chloramine-type oxidizing species. Our results suggest that L-DOPA and dopamine might have a complex mixture of pro- and anti- oxidant effects, which could contribute to tissue damage due to oxidative stress in Parkinson's disease and other neurological disorders.
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PMID:Evaluation of the pro-oxidant and antioxidant actions of L-DOPA and dopamine in vitro: implications for Parkinson's disease. 884 17

Based on a number of lines of evidence, we have proposed recently that a very early step in the pathogenesis of idiopathic Parkinson's disease might be elevated translocation of L-cysteine into neuromelanin-pigmented dopaminergic cell bodies in the substantia nigra. In vitro studies suggest that such an influx of L-cysteine would divert the neuromelanin pathway by scavenging dopamine-o-quinone, the proximate autoxidation product of dopamine, to give 5-S-cysteinyldopamine, which is oxidized further to 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1) and other cysteinyldopamines and dihydrobenzothiazines. In this study, it is demonstrated that DHBT-1 inhibits ADP-stimulated oxidation of malate and pyruvate (state 3 or complex I respiration) when incubated with intact rat brain mitochondria with an IC50 of approximatelly 0.80 mM. Incubation of DHBT-1 with freeze-thawed rat brain mitochondria in both the presence and absence of KCN and/or NADH causes an irreversible, time-dependent decrease of NADH-coenzyme Q1 reductase activity. Significantly lower concentrations of DHBT-1 are necessary to cause this effect when mitochondrial membranes are incubated in the absence of KCN and NADH. The irreversible inhibition of mitochondrial complex I caused by DHBT-1 under the latter conditions could be blocked only partially by glutathione, ascorbic acid, superoxide dismutase, or catalase. Together, these results suggest that DHBT-1 can cross the outer mitochondrial membrane and irreversibly inhibit complex I by a mechanism that is not primarily related to oxygen radical-mediated damage. Formation of DHBT-1 requires only dopamine, L-cysteine, and an oxidizing environment, conditions that may well exist in the cytoplasm of neuromelanin-pigmented dopaminergic neurons in the parkinsonian substantia nigra. The results of this study raise the possibility that DHBT-1 might be an endotoxin formed specifically in pigmented dopaminergic neurons that can contribute to irreversible damage to mitochondrial complex I and substantia nigra cell death in Parkinson's disease.
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PMID:Irreversible inhibition of mitochondrial complex I by 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxyli c acid (DHBT-1): a putative nigral endotoxin of relevance to Parkinson's disease. 932 82

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes parkinsonism in humans and nonhuman animals, and its use has led to greater understanding of the pathogenesis of Parkinson's disease. However, its molecular targets have not been defined. We show that mice lacking the gene for poly(ADP-ribose) polymerase (PARP), which catalyzes the attachment of ADP ribose units from NAD to nuclear proteins after DNA damage, are dramatically spared from MPTP neurotoxicity. MPTP potently activates PARP exclusively in vulnerable dopamine containing neurons of the substantia nigra. MPTP elicits a novel pattern of poly(ADP-ribosyl)ation of nuclear proteins that completely depends on neuronally derived nitric oxide. Thus, NO, DNA damage, and PARP activation play a critical role in MPTP-induced parkinsonism and suggest that inhibitors of PARP may have protective benefit in the treatment of Parkinson's disease.
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PMID:Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. 1031 60

Mitochondrial membrane potential (delta psi(m)) was determined in intact isolated nerve terminals using the membrane potential-sensitive probe JC-1. Oxidative stress induced by H2O2 (0.1-1 mM) caused only a minor decrease in delta psi(m). When complex I of the respiratory chain was inhibited by rotenone (2 microM), delta psi(m) was unaltered, but on subsequent addition of H2O2, delta psi(m) started to decrease and collapsed during incubation with 0.5 mM H2O2 for 12 min. The ATP level and [ATP]/[ADP] ratio were greatly reduced in the simultaneous presence of rotenone and H2O2. H2O2 also induced a marked reduction in delta psi(m) when added after oligomycin (10 microM), an inhibitor of F0F1-ATPase. H2O2 (0.1 or 0.5 mM) inhibited alpha-ketoglutarate dehydrogenase and decreased the steady-state NAD(P)H level in nerve terminals. It is concluded that there are at least two factors that determine delta psi(m) in the presence of H2O2: (a) The NADH level reduced owing to inhibition of alpha-ketoglutarate dehydrogenase is insufficient to ensure an optimal rate of respiration, which is reflected in a fall of delta psi(m) when the F0F1-ATPase is not functional. (b) The greatly reduced ATP level in the presence of rotenone and H2O2 prevents maintenance of delta psi(m) by F0F1-ATPase. The results indicate that to maintain delta psi(m) in the nerve terminal during H2O2-induced oxidative stress, both complex I and F0F1-ATPase must be functional. Collapse of delta psi(m) could be a critical event in neuronal injury in ischemia or Parkinson's disease when H2O2 is generated in excess and complex I of the respiratory chain is simultaneously impaired.
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PMID:Depolarization of in situ mitochondria due to hydrogen peroxide-induced oxidative stress in nerve terminals: inhibition of alpha-ketoglutarate dehydrogenase. 1038 74


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