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)

Apomorphine is a potent radical scavenger and iron chelator. In vitro apomorphine acts as a potent iron chelator and radical scavenger with IC50 of 0.3 microM for iron (2.5 microM) induced lipid peroxidation in rat brain mitochondrial preparation, and it inhibits mice striatal MAO-A and MAO-B activities with IC50 values of 93 microM and 241 microM. Apomorphine (1-10 microM) protects rat pheochromocytoma (PC12) cells from 6-hydroxydopamine (150 microM) and H2O2 (0.6 mM) induced cytotoxicity and cell death. The neuroprotective property of (R)-apomorphine, a dopamine D1-D2 receptor agonist, has been studied in the MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. (R)-apomorphine (5-10 mg/kg, s.c.) pretreatment in C57BL mice, protects against MPTP (24 mg/kg, i.p.) induced loss of nigro-striatal dopamine neurons, as indicated by striatal dopamine content, tyrosine hydroxylase content and tyrosine hydroxylase activity. It is suggested that the neuroprotective effect of (R)-apomorphine against MPTP neurotoxicity derives from its radical scavenging and MAO inhibitory actions and not from its agonistic activity, since the mechanism of MPTP dopaminergic neurotoxicity involves the generation of oxygen radical species induced-oxidative stress.
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PMID:Potent neuroprotective and antioxidant activity of apomorphine in MPTP and 6-hydroxydopamine induced neurotoxicity. 1033 93

Free radicals are involved in the pathology of many CNS disorders, like Parkinson's disease, Alzheimer's disease, or stroke. This discovery lead to the development of many radical scavengers for the clinical treatment of neurodegenerative diseases. In this review, the different chemical concepts for free radical scavenging will be discussed: nitrons, thiols, iron chelators, phenols, and catechols. Especially catechols, like the naturally occurring flavonols, the synthetic drug nitecapone, or the endogenous catacholamines and their metabolites, are of great interest, as they combine iron chelating with radical scavenging activity. We present data on the radical scvenging activity of dopamine and apomorphine, which prevent lipid peroxidation in rat brain mitochondria and protect PC12 cells against H2O2-toxicity.
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PMID:Free radical scavengers: chemical concepts and clinical relevance. 1037 Sep 13

An inverse relationship appears to exist between cigarette smoking and the risk of Parkinson's and Alzheimer's diseases. Since both diseases are characterized by enhanced oxidative stress, we investigated the antioxidant potential of nicotine, a primary component of cigarette smoke. Initial chromatographic studies suggest that nicotine can affect the formation of the neurotoxin 6-hydroxydopamine resulting from the addition of dopamine to Fenton's reagent (i.e., Fe2+ and H2O2). Thus, under certain circumstances, nicotine can strongly affect the course of the Fenton reaction. In in vivo studies, adult male rats being treated with nicotine showed greater memory retention than controls in a water maze task. However, neurochemical analysis of neocortex, hippocampus, and neostriatum from these same animals revealed that nicotine treatment had no effect on the formation of reactive oxygen species or on lipid peroxidation for any brain region studied. In an in vitro study, addition of various concentrations of nicotine to rat neocortical homogenates had no effect on lipid peroxidation compared to saline controls. The results of these studies suggest that the beneficial/protective effects of nicotine in both Parkinson's disease and Alzheimer's disease may be, at least partly, due to antioxidant mechanisms.
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PMID:In vitro and in vivo studies investigating possible antioxidant actions of nicotine: relevance to Parkinson's and Alzheimer's diseases. 1038 59

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

Nitric oxide (*NO)-mediated toxicity has been involved in neurodegenerative diseases, including Parkinson's disease (PD). We have recently reported an increase of about 50% in *NO production rate in PMA-activated polymorphonuclear leukocytes (PMN) from either newly diagnosed or chronically treated PD patients. As humoral factors in sera from PD patients could inhibit cell dopaminergic activity, the aim of this study was to determine whether a plasma circulating factor from PD patients could modify *NO metabolism in PMN from healthy control subjects. To this purpose, we determined simultaneously the maximal production rate of *NO and hydrogen peroxide (H2O2) of PMA-activated PMN isolated from healthy control subjects in the presence of aliquots of plasma of PD patients. The results showed that, after 30 min incubation, plasma from newly diagnosed (n=4) or from L-Dopa chronically treated (n=7) PD patients enhanced *NO release in neutrophils isolated from healthy controls by about 50% and 47% respectively, with respect to non-parkinsonian control plasma (n = 10); in the same condition, H2O2 production did not differ among the groups. These data suggest that an overproduction of *NO related to plasma circulating factors, already detected at initial stages of the disease, participates in the pathophysiology of Parkinson's disease.
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PMID:Circulating plasma factors in Parkinson's disease enhance nitric oxide release of normal human neutrophils. 1042 50

Increased catechol thioether formation is associated with Parkinson's disease. In this study, we examined whether catechol thioethers, having a lower oxidation potential than their parent catechols, would cause greater oxidative damage than their parent catechols. We synthesized 5'-S-glutathionyl, cysteinyl, and N-acetylcysteinyl derivatives of dopamine and dopac, encompassing the known catechol thioethers of the mercapturate pathway. Cyclic voltametry studies showed that catechol thioethers had higher reduction potentials than their parent catechols. A higher reduction potential did not correlate with an increase in oxidative damage, measured by metal-catalyzed DNA strand breakage. 5'-S-Glutathionyldopamine and the cysteinyl adducts of dopamine and dopac mediated less oxidative damage than their parent catechols. In contrast, both N-acetylcysteinyl analogs were equipotent to dopamine. Oxygen consumption corresponded to DNA damage except for 5'-S-glutathionyldopamine. The glutathionyl and cysteinyl adducts of dopamine inhibited dopamine-mediated DNA damage indicating that these adducts may have antioxidant properties. 5'-S-Glutathionyldopamine potentiated H2O2-mediated damage whereas 5-S-cysteinyldopamine was inhibitory. Our results show that the ability of catechol thioethers to cause oxidative damage in vitro is not based simply upon the reduction potential but rather, reflects a complex relationship among structures of the parent catechol and thiol adduct, metal catalyst, and oxidant.
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PMID:Endogenous catechol thioethers may be pro-oxidant or antioxidant. 1046 98

Much of the excess iron reported in the substantia nigra of subjects with Parkinson's disease (PD) implicates nonneuronal (glial) cellular compartments. Yet, the significance of these glial iron deposits vis-a-vis toxicity to indigent nigrostriatal dopaminergic neurons remains unclear. Cysteamine (CSH) induces the appearance of iron-rich (peroxidase-positive) cytoplasmic inclusions in cultured rat astroglia, which are identical to glial inclusions that progressively accumulate in substantia nigra and other subcortical brain regions with advancing age. We previously demonstrated that the iron-mediated peroxidase activity in these cells oxidizes dopamine and other catechols to potentially neurotoxic semiquinone radicals. In the present study, we cocultured catecholamine-secreting PC12 cells (as low-density dispersed cells or high-density colonies) atop monolayers of either CSH-pretreated (iron-enriched) or control rat astroglial substrata. In some experiments, the PC12 cells were differentiated with nerve growth factor (NGF). The nature of the glial substratum did not appreciably affect the growth characteristics of the PC12 cells. However, undifferentiated PC12 cells grown atop CSH-pretreated astrocytes (a senescent glial phenotype) were far more susceptible to dopamine(1 microM)-H2O2(1 microM)-related killing than PC12 cells cultured on control astroglia. Differentiated PC12 cells behaved similarly although the fraction killed was about half that seen with the undifferentiated PC12 cells. In the latter experiments, PC12 cell death was abrogated by coadministration of the antioxidants, ascorbate (200 microM), melatonin (100 microM), or resveratrol (50 microM) or the iron chelator, deferoxamine (400 microM), attesting to the role of oxidative stress and catalytic iron in the mechanism of PC12 cell death in this system. The aging-associated accumulation of redox-active iron in subcortical astrocytes may facilitate the bioactivation of dopamine to neuronotoxic free radical intermediates and thereby predispose the senescent nervous system to PD and other neurodegenerative disorders.
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PMID:Cysteamine pretreatment of the astroglial substratum (mitochondrial iron sequestration) enhances PC12 cell vulnerability to oxidative injury. 1061 54

Glutathione deficiency has been associated with a number of neurodegenerative diseases including Lou Gehrig's disease, Parkinson's disease, and HIV. A crucial role for glutathione is as a free radical scavenger. Alzheimer's disease (AD) brain is characterized by oxidative stress, manifested by protein oxidation, lipid oxidation, oxidized glutathione, and decreased activity of glutathione S-transferase, among others. Reasoning that elevated levels of endogenous glutathione would offer protection against free radical-induced oxidative stress, rodents were given in vivo injections of N-acetylcysteine (NAC), a known precursor of glutathione, to study the vulnerability of isolated synaptosomal membranes treated with Fe2+/H2O2, a known hydroxyl free radical producer. Protein carbonyls, a marker of protein oxidation, were measured. NAC significantly increased endogenous glutathione levels in cortical synaptosome cytosol (P < 0.01). As reported previously, protein carbonyl levels of the Fe2+/H2O2-treated synaptosomes were significantly higher compared to that of non-treated controls (P < 0.01), consistent with increased oxidative stress. In contrast, protein carbonyl levels in Fe2+/H2O2-treated synaptosomes isolated from NAC-injected animals were not significantly different from saline-injected non-treated controls, demonstrating protection against hydroxyl radical induced oxidative stress. These results are consistent with the notion that methods to increase endogenous glutathione levels in neurodegenerative diseases associated with oxidative stress, including AD, may be promising.
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PMID:In-vivo glutathione elevation protects against hydroxyl free radical-induced protein oxidation in rat brain. 1067 51

An experimental rat model of Parkinson's disease was established by injecting rats directly in the striatum with the neurotoxic agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In order to study the action mechanism of this neurotoxic agent, MPTP and its main metabolite 1-methyl-4-phenylpyridinium (MPP+) were also added to suspensions of pyruvate/malate-supplemented nonsynaptic brain mitochondria, and the rates of hydrogen peroxide and ATP production were measured. Intrastriatal administration of MPTP produced a pronounced decrease in striatal dopamine levels (p < 0.005) and a strong increase in 3,4-hydroxiphenylacetic acid/dopamine ratio (an indicator of dopamine catabolism; p < 0.005) in relation to controls, as evaluated by in situ microdialysis. MPTP addition to rat brain mitochondria increased hydrogen peroxide production by 90%, from 1.37+/-0.35 to 2.59+/-0.48 nanomoles of H2O2/minute . mg of protein (p < 0.01). The metabolite MPP+ produced a marked decrease on the rate of ATP production of brain mitochondria (p < 0.005). These findings support the mitochondria-oxidative stress-energy failure hypothesis of MPTP-induced brain neurotoxicity.
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PMID:Effect of MPTP on brain mitochondrial H2O2 and ATP production and on dopamine and DOPAC in the striatum. 1073 Oct 84

6-Hydroxydopamine (6-OHDA) is a dopaminergic neurotoxin putatively involved in the pathogenesis of Parkinson's disease (PD). Its neurotoxicity has been related to the production of reactive oxygen species. In this study we examine the effects of the antioxidants ascorbic acid (AA), glutathione (GSH), cysteine (CySH), and N-acetyl-CySH (NAC) on the autoxidation and neurotoxicity of 6-OHDA. In vitro, the autoxidation of 6-OHDA proceeds rapidly with the formation of H2O2 and with the participation of the H2O2 produced in the reaction. The presence of AA induced a reduction in the consumption of O2 during the autoxidation of 6-OHDA and a negligible presence of the p-quinone, which demonstrates the efficiency of AA to act as a redox cycling agent. The presence of GSH, CySH, and NAC produced a significant reduction in the autoxidation of 6-OHDA. In vivo, the presence of sulfhydryl antioxidants protected against neuronal degeneration in the striatum, which was particularly remarkable in the case of CySH and was attributed to its capacity to remove the H2O2 produced in the autoxidation of 6-OHDA. These results corroborate the involvement of oxidative stress as the major mechanism in the neurotoxicity of 6-OHDA and the putative role of CySH as a scavenger in relation to PD.
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PMID:Autoxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson's disease. 1073 18


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