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)

Excitotoxicity, mitochondrial dysfunction and free radical induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease. Much of the interest in the association of neurodegeneration with mitochondrial dysfunction and oxidative damage emerged from animal studies using mitochondrial toxins. Within mitochondria 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), acts to inhibit NADH-coenzyme Q reductase (complex I) of the electron transport chain. MPTP produces Parkinsonism in humans, primates, and mice. Similarly, lesions produced by the reversible inhibitor of succinate dehydrogenase (complex II), malonate, and the irreversible inhibitor, 3-nitropropionic acid (3-NP), closely resemble the histologic, neurochemical and clinical features of HD in both rats and non-human primates. The interruption of oxidative phosphorylation results in decreased levels of ATP. A consequence is partial neuronal depolarization and secondary activation of voltage-dependent NMDA receptors, which may result in excitotoxic neuronal cell death (secondary excitotoxicity). The increase in intracellular Ca2+ concentration leads to an activation of Ca2+ dependent enzymes, including the constitutive neuronal nitric oxide synthase (cnNOS) which produces NO.. NO. may react with the superoxide anion to from peroxynitrite. We show that systemic administration of 7-nitroindazole (7-NI), a relatively specific inhibitor of cnNOS in vivo. attenuates lesions produced by striatal malonate injections or systemic treatment with 3-NP or MPTP. Furthermore 7-NI attenuated increases in lactate production and hydroxyl radical and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. Our results suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.
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PMID:The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases. 930 87

Iron(II/III) and manganese(II) both catalyze the autoxidation of the neurotransmitter dopamine (DA) in the presence of L-cysteine (CySH) in buffered aqueous solution at pH 7.4. Fe2+/Fe3+ and CySH together generate the hydroxyl (HO.) and cysteinyl thiyl (CyS.) radicals. DA is oxidized by HO. to DA semiquinone radical species that either react with CyS. to give 5-S-cysteinyldopamine (5-S-CyS-DA), 2-S-CyS-DA, and 6-S-CyS-DA or disproportionate to DA-o-quinone that reacts with CySH to give the same cysteinyl conjugates of DA. The major product of this initial reaction is 5-S-CyS-DA. However, 5-S-CyS-DA can be further oxidized by HO. to an o-quinone (2) that undergoes intramolecular cyclization to an o-quinone imine (3). The latter intermediate is the precursor of the dihydrobenzothiazine (DHBT) 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1, 4-benzothiazine-3-carboxylic acid (DHBT-1) and several other cyclized products. However, cysteinyl conjugates of DA can also be oxidized by HO. in a one-electron abstraction reaction that leads to DA thiyl radicals. Reactions of these radicals with CyS. or DA semiquinone radicals lead to some novel DA disulfides and thioethers, respectively. The Mn(II)-catalyzed oxidation of DA generates DA-o-quinone that is scavenged by CySH to give 5-S-CyS-DA (major initial product) with lower yields of other cysteinyldopamines. Subsequent Mn(II)-catalyzed oxidation of 5-S-CyS-DA gives o-quinone 2 and thence o-quinone imine 3 that serve as the precursors of DHBT-1 and several other DHBTs. Organic or oxygen radicals do not play significant roles in the Mn(II)-catalyzed oxidation of DA in the presence of CySH. Recent studies have demonstrated that DHBT-1 can be accumulated by brain mitochondria and evoke irreversible inhibition of NADH-coenzyme Q reductase (complex I). Furthermore, iron, manganese, and alterations in glutathione and CySH metabolism have been implicated in the selective degeneration of nigrostriatal dopaminergic neurons in idiopathic and chemically induced Parkinson's disease (PD). Because DHBT-1 is formed in both the iron- and manganese-catalyzed oxidation of DA in the presence of CySH and a defect in mitochondrial complex I respiration contributes to dopaminergic neuronal cell death in PD, the results of this investigation are discussed in terms of their possible implications to an understanding of the neuropathological processes in idiopathic and chemically induced parkinsonism.
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PMID:Iron- and manganese-catalyzed autoxidation of dopamine in the presence of L-cysteine: possible insights into iron- and manganese-mediated dopaminergic neurotoxicity. 967 46