UMLS:C0030567 - FACTA Search

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Query: UMLS:C0030567 (Parkinson's disease)
63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The cause of neurodegeneration in Parkinson's disease (PD) remains unknown. However, isoquinoline derivatives structurally related to the selective dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite, 1-methyl-4-phenylpyridinim (MPP+), have emerged as candidate endogenous neurotoxins causing nigral cell death in Parkinson's disease. Isoquinoline derivatives are widely distributed in the environment, being present in many plants and foodstuffs, and readily cross the blood-brain barrier. These compounds occur naturally in human brain where they are synthesized by non-enzymatic condensation of biogenic amines (e.g. catecholamines and phenylethylamine) with aldehydes, and are metabolized by cytochrome P450s and N-methyltransferases. In addition, isoquinoline derivatives are oxidized by monoamine oxidases to produce isoquinolinium cations with the concomitant generation of reactive oxygen species. Neutral and quaternary isoquinoline derivatives accumulate in dopaminergic nerve terminals via the dopamine re-uptake system, for which they have moderate to poor affinity as substrates. Several isoquinoline derivatives are selective and more potent inhibitors of NADH ubiquinone reductase (complex I) and alpha-ketoglutarate dehydrogenase activity in mitochondrial fragments than MPP+, and lipophilicity appears to be important for complex I inhibition by isoquinoline derivatives. However, compared with MPP+, isoquinoline derivatives are selective but less potent inhibitors of NADH-linked respiration in intact mitochondria, and this appears to be a consequence of their rate-limiting ability to cross mitochondrial membranes. Although both active and passive processes are involved in the accumulation of isoquinoline derivatives in mitochondria, inhibition of respiration is determined by steric rather than electrostatic properties. Compared with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or MPP+, isoquinoline derivatives show selective but relatively weak toxicity to dopamine-containing cells in culture and following systemic or intracerebral administration to experimental animals, which appears to be a consequence of poor sequestration of isoquinoline derivatives by mitochondria and by dopamine-containing neurones. In conclusion, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-like cytotoxic characteristics of isoquinoline derivatives and the endogenous/environmental presence of these compounds make it conceivable that high concentrations of and/or prolonged exposure to isoquinoline derivatives might cause neurodegeneration and Parkinson's disease in humans.
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PMID:Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson's disease. 977 2

We have proposed that a very early step in the pathogenesis of idiopathic Parkinson's disease is the elevated translocation of L-cysteine into neuromelanin-pigmented dopaminergic neurons in the substantia nigra. This influx of L-cysteine was proposed to divert the normal neuromelanin pathway by scavenging dopamine-o-quinone, formed by autoxidation of cytoplasmic dopamine, to give initially 5-S-cysteinyldopamine, which is further oxidized to 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1). In a recent report, it was demonstrated that DHBT-1 evokes inhibition of complex I respiration when incubated with intact rat brain mitochondria and a time-dependent irreversible inhibition of NADH-coenzyme Q1 (CoQ1) reductase when incubated with mitochondrial membranes. In this study, it is established that the time dependence of NADH-CoQ1 reductase inhibition reflects the oxidation of DHBT-1, catalyzed by an unknown constituent of the inner mitochondrial membrane, to an o-quinone imine intermediate that rearranges to 7-(2-aminoethyl)-5-hydroxy-1,4-benzothiazine-3-carboxylic acid (BT-1) and decarboxylates to 7-(2-aminoethyl)-5-hydroxy-1,4-benzothiazine (BT-2), which are further catalytically oxidized to o-quinone imine intermediates. The electrophilic o-quinone imine intermediates formed in these mitochondria-catalyzed oxidations of DHBT-1, BT-1, and BT-2 are proposed to bind covalently to key sulfhydryl residues at the complex I site, thus evoking irreversible inhibition of NADH-CoQ1 reductase. Evidence for this mechanism derives from the fact that greater than equimolar concentrations of glutathione completely block inhibition of NADH-CoQ1 reductase by DHBT-1, BT-1, and BT-2 by scavenging their electrophilic o-quinone imine metabolites to form glutathionyl conjugates. The results of this investigation may provide insights into the irreversible loss of glutathione and decreased mitochondrial complex I activity, which are both anatomically specific to the substantia nigra and exclusive to Parkinson's disease.
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PMID:Brain mitochondria catalyze the oxidation of 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxyli c acid (DHBT-1) to intermediates that irreversibly inhibit complex I and scavenge glutathione: potential relevance to the pathogenesis of Parkinson's disease. 979 30

Most Parkinson's disease (PD) treatments palliate symptoms by increasing nigrostriatal dopaminergic tone. A unique strategy for accomplishing this pharmacological end-point proposes using reduced nicotinamide adenine dinucleotide (NADH) to boost endogenous dopamine production, since NADH indirectly supplies reducing equivalents to the rate-limiting, tyrosine hydroxylase-catalysed step of dopamine synthesis. Support for using NADH in PD treatment includes claims that NADH stimulates tyrosine hydroxylase and dopamine biosynthesis in tissue culture and humans, as well as case series associating intravenous and oral NADH administration with PD rating scale improvements. Theoretical and practical arguments against NADH include underlying NADH disposal impairment in PD and failure of a placebo-controlled trial to show any clear benefit. While NADH may yet prove to ameliorate parkinsonism, recommendations for its use in PD are premature.
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PMID:Is NADH effective in the treatment of Parkinson's disease? 980 7

We report effect of various tetrahydroisoquinoline derivatives on mitochondrial respiration and the electron transfer complexes. Generally these compounds were potent inhibitors of NADH-linked mitochondrial state 3 respiration and complex I. Presence of a phenyl group at the C1 position or oxidation of N-methylated isoquinones into N-methylisoquinolinium ion augmented the potency to inhibit mitochondrial respiration and complex I. Many of these compounds have been identified in human brains. In view of the mitochondrial and oxidative stress hypothesis, our results suggest involvement of these neurotoxins as potential causes of mitochondrial failure in Parkinson's disease.
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PMID:Effects of various tetrahydroisoquinoline derivatives on mitochondrial respiration and the electron transfer complexes. 982 10

In 1983, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a contaminant of "synthetic heroin", has been reported to induce parkinsonian symptoms in humans, who were responsive to L-DOPA therapy, as a result of the degeneration of nigrostriatal neurons. The "MPTP story" hypothesizes that Parkinson's disease may be initiated or percipitated by environmental and/or endogenous toxins by a mechanism similar to that of MPTP in genetically-predisposed individuals. Several classes of heterocyclic molecules structurally related to MPTP have been advanced as possible neurotoxicant precursors underlying the nigrostriatal degeneration in Parkinson's disease. Indoleamine-related beta-carbolines (beta Cs), a class of heterocyclics which are basically plant alkaloids, are proposed as the most promising natural MPTP-like toxicants or protoxicants. In this article, beta Cs and N-methylated beta C cations are reviewed with regards to their formation, bioactivation, toxicity and presence in the human central nervous system. The enzymes in mammalian brain particulate fractions methylate beta Cs, sequentially forming 2-mono-[N]-methylated (2-Me beta C+s) and neurotoxic 2,9-di-[N, N']-methylated (2,9-Me2 beta C+s) beta-carbolinium cations. These beta C+s are structural analogs of 1-methyl-4-phenylpyridinium ion (MPP+), an active metabolite of MPTP, with a nitrogen bridge. The beta C+s not only inhibit DA reuptake and tyrosine hydroxylase, but also function as NADH-linked respiratory inhibitors in isolated mitochondria. The quarternization of beta C strikingly increased the affinity for dopamine transporter with 2-10 times greater Km and 10 times smaller Vmax values than MPP+. Furthermore, we have found higher concentrations of beta C+s localized in the nigra than in the cortex, and observed the S-adenosyl-L-methionine-dependent methylation of 2[beta]- and 9[indole]-nitrogens of beta Cs in non-parkinsonian human brains. Moreover, the cerebrospinal fluid levels of these beta C+s are higher in parkinsonian than non-parkinsonian patients. Simple beta-carboline induced parkinsonian-like symptoms in mice via N-methylation. These results indicated that beta C is a selective dopaminergic toxin precursor, that is sequentially methylated to form 2,9-Me2 beta C+ that could be an underlying factor in idiopathic Parkinson's disease.
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PMID:[Metabolic activation of azaheterocyclics induced dopaminergic toxicity: possible candidate neurotoxins underlying idiopathic Parkinson's disease]. 1007 75

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

The present study was conducted to characterize the possible interaction of Al3+ and Fe2+ with synthetic melanin in the potentiation of lipid peroxidation in liposomes and rat caudate-putamen homogenates. Al3+ stimulated melanin-initiated lipid peroxidation as measured by the production of 2-thiobarbituric acid-reactive substances (TBARS) and conjugated dienes. The effect of A13+ was dependent on melanin (10-100 microg/ml) and A13+ (2.5-250 microM) concentrations and no synergism between Fe2+ and Al3+ was observed. The prooxidant effect of Al3+ was partially inhibited by superoxide dismutase indicating the involvement of O2*- . Ga3+ and Be2+ which can increase NADH oxidation in the presence of O2*-, also were shown to stimulate melanin-initiated TBARS production. Based on the effect of Al3+ and other non redox metals, we suggest that Al3+ does not act through either the induction of melanin free radicals, or the induction of changes in membrane physical properties. Results show that Al3+ enhances melanin-initiated lipid peroxidation in part through an interaction with O2*- generated from the autoxidation of melanin. We speculate that Al3+ contributes to neuromelanin-mediated oxidative damage in dopaminergic neurons and subsequent neuronal degeneration and death in Parkinson's disease.
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PMID:Aluminum enhances melanin-induced lipid peroxidation. 1047 39

Nicotinamide adenine dinucleotide (NADH) may be utilized for the synthesis and regeneration of tetrahydrobiopterin (BH(4)), which in turn is an essential cofactor for tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine (DA). NADH has been reported to relieve some of the symptoms of Parkinson's disease, presumably by altering dopaminergic function. The present study examines the efficacy of NADH in influencing DA activity in the rat striatum. In striatal slices, NADH (350 microM) significantly increased basal DA and DOPAC efflux and caused a 2-fold increase in the DA overflow evoked by high KCl (25 mM). Tissue levels of BH(4), basal BH(4) efflux, and KCl-evoked BH(4) overflow were unaffected by NADH, as was [(3)H]DA uptake into striatal synaptosomes. In contrast to the effects of NADH on DA function in vitro, no effects were observed when NADH was administered systemically. NADH (10 or 100 mg/kg, s.c.) did not influence the tissue content of DA, 5-HT, or their metabolites in the midbrain or striatum, nor did it alter DA extracellular concentrations. These results indicate that NADH can increase DA release from striatal slices, although we are as yet unable to detect this effect in vivo.
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PMID:Effects of NADH on dopamine release in rat striatum. 1076 56

The major initial product of the oxidation of norepinephrine (NE) in the presence of L-cysteine is 5-S-cysteinylnorepinephrine which is then further easily oxidized to the dihydrobenzothiazine (DHBT) 7-(1-hydroxy-2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1, 4-benzothiazine-3-carboxylic acid (DHBT-NE-1). When incubated with intact rat brain mitochondria, DHBT-NE-1 evokes rapid inhibition of complex I respiration without affecting complex II respiration. DHBT-NE-1 also evokes time- and concentration-dependent irreversible inhibition of NADH-coenzyme Q(1) (CoQ(1)) reductase, the pyruvate dehydrogenase complex (PDHC), and alpha-ketoglutarate dehydrogenase (alpha-KGDH) when incubated with frozen and thawed rat brain mitochondria (mitochondrial membranes). The time dependence of the inhibition of NADH-CoQ(1) reductase, PDHC, and alpha-KGDH by DHBT-NE-1 appears to be related to its oxidation, catalyzed by an unknown component of the inner mitochondrial membrane, to electrophilic intermediates which bind covalently to active site cysteinyl residues of these enzyme complexes. The latter conclusion is based on the ability of glutathione to block inhibition of NADH-CoQ(1) reductase, PDHC, and alpha-KGDH by scavenging electrophilic intermediates, generated by the mitochondrial membrane-catalyzed oxidation of DHBT-NE-1, forming glutathionyl conjugates, several of which have been isolated and spectroscopically identified. The possible implications of these results to the degeneration of neuromelanin-pigmented noradrenergic neurons in the locus ceruleus in Parkinson's disease are discussed.
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PMID:Oxidative metabolites of 5-S-cysteinylnorepinephrine are irreversible inhibitors of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes: possible implications for neurodegenerative brain disorders. 1095 63

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