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)

Metals such as lead, zinc, copper, aluminum and manganese have been implicated in neuropsychiatric disorders. However, until fairly recently the role of iron in brain function was rather obscure, because little attention was paid to its metabolism in the brain. It is now apparent that maintenance of brain iron homoeostasis is important for the normal functioning of his organ. Most of the studies have been directed towards the cognitive and attentional deficit resulting from nutritional iron deficiency. Evidence so far suggests subsensitivity of striatal dopamine neurotransmission. By contrast the selective increase in free iron in the substantia nigra pars compacta of parkinsonian brains is thought to initiate oxidative stress, from iron-induced liberation of cytotoxic oxygen free radicals. Such radicals are known to promote membrane fluidity, alteration in cellular calcium homoeostasis, lipid peroxidation and finally cell death in systemic organs. Evidence supporting similar processes being responsible for nigrostriatal dopamine neuron degeneration in Parkinson's disease is now becoming available. Such possibilities afford the development of neuroprotective drugs as a means to retard the progression of this disorder. These include other selective monoamine oxidase B inhibitors, iron chelators with the ability to cross the blood-brain barrier, selective calcium channel antagonists and mitochondrial electron transport system protectors.
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PMID:Iron in brain function and dysfunction with emphasis on Parkinson's disease. 164 57

In the last decade it has become quite clear that oxygen free radicals are involved in a vast amount of diseases such as cataract, atherosclerosis, rheumatism, arthritis, Parkinson's disease, reperfusion injuries and many others. The induction of defence systems against certain stresses (heat shock, inflammation) is also mediated by activated oxygen species. Oxygen-activation and -desactivation has to be regulated and well attenuated in aerobic cells and tissues. The biochemical basis of the biological efficacy of oxidants is thus based on a sophisticated balance between catalysis of production and reactivity of oxygen radicals by certain cofactors and transition metals on the one hand and on a reliable detoxification by antioxidants or metabolic chains on the other hand. In this communication, different oxygen activating principles are compared and the biochemical basis for the induction of repair processes by a synthetic heme oxidant, (Tetrachlorodecaoxide, TCDO) is presented.
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PMID:Oxygen radicals--biochemical basis for their efficacy. 166 86

The near IR emission at 1270 nm following pulsed laser excitation of methylene blue in deuterium oxide, was used to study the interaction of a singlet molecular oxygen (1O2) with (i) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidation products, and (ii) biosubstrates of relevance in Parkinson's disease. Steady state irradiation of methylene blue and MPTP led to a product with an absorption profile consistent with that of 1-methyl-4-phenyl-2,3-dihydropyridinium ion. This may suggest that even if monoamine oxidase enzyme activity is inhibited by the use of drugs such as Deprenyl and Paragyline the underlying conversion of MPTP to its neurotoxic oxidation product via 1O2 may still take place.
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PMID:Chemically induced Parkinson's disease. III: A study of a possible role of singlet molecular oxygen in Parkinson's disease. 181 61

A number of neurological disorders including Alzheimer and Parkinson disease have been suggested to be caused by processes leading to lipid peroxidation. Other theories implicate the accumulation of damaged DNA, resulting from a defect in DNA repair, in the pathogenesis of these disorders. I suggest that these theories might be related, since the hydroxy free radical is known to attack DNA and inactivate enzymes so that oxygen metabolism has the potential to interfere with the maintenance of genomic integrity. Since psychometric intelligence correlates highly with erythrocyte glutathione peroxidase activity, a free radical scavenger, perhaps this might explain the marked intellectual impairment caused by chemotherapeutic agents such as cytosine arabinoside, as well as in Alzheimer disease.
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PMID:Dementia in cancer patients undergoing chemotherapy: implication of free radical injury and relevance to Alzheimer disease. 189 Sep 72

Insights into the etiology and pathophysiology of Parkinson's disease may derive from elucidation of the neurotoxic mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite, 1-methyl-4-phenylpyridinium (MPP+). In previous studies, MPP+ provoked oxidation of cytochrome b and K+ leakage into the extracellular space of rat striatal slices. Magnitudes of these time-dependent responses were far greater than expected had the MPP+ effects been limited to dopaminergic terminals. To determine whether cytochromes become oxidized from K(+)-induced increases in ion transport activity or from electron transport inhibition at complex I, oxygen consumption was measured because this should be increased by the former and decreased by the latter mechanism. Low MPP+ concentrations (1 microM) decreased O2 consumption (approximately 40% in 3 h) in striatal slices. This decrease was diminished by mazindol and did not occur in hippocampal slices. High toxin concentrations (100 microM) inhibited oxygen consumption to a greater extent (approximately 60%) in striatal slices; this inhibition was still greater in hippocampal slices. These results support the hypothesis that acute effects of low ("selective") MPP+ concentrations require the presence of dopaminergic terminals to trigger a sequence of destructive metabolic events but that the metabolic consequences of MPP+ spread to neighboring cells. In contrast, high MPP+ concentrations nonselectively inhibit metabolic and ion transport activity without requiring the presence of dopaminergic terminals. These results also suggest that physiological effects of "selective" MPP+ concentrations extend to nondopaminergic cells.
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PMID:Selective and nonselective effects of 1-methyl-4-phenylpyridinium on oxygen consumption in rat striatal and hippocampal slices. 189 8

A selective increase in content of iron in the pars compacta of the substantia nigra has been implicated in the biochemical pathology of Parkinson's disease. Iron is thought to induce oxidative stress by liberation of oxygen free radicals from H2O2. Because 6-hydroxydopamine (6-OHDA) is thought to induce nigrostriatal dopaminergic neuronal lesions via metal-catalyzed free radical formation, the effect of the iron chelator desferrioxamine was investigated on 6-OHDA-induced dopaminergic neuron degeneration in the rat. Intracerebroventricular injection of 6-OHDA (250 micrograms) caused a 88, 79, and 70% reduction in striatal tissue content of dopamine (DA), 3,4-dihydroxyphenylacetic acid, and homovanillic acid (HVA), respectively, and a 2.5-fold increase in DA release as indicated by the HVA/DA ratio. Prior injection of desferrioxamine (130 ng i.c.v.) resulted in a significant protection (approximately 60%) against the 6-OHDA-induced reduction in striatal DA content and a normalization of DA release. Dopaminergic-related behavioral responses, such as spontaneous movements in a novel environment and rearing, were significantly impaired in the 6-OHDA-treated group. By contrast, the desferrioxamine-pretreated rats exhibited almost normal behavioral responses. The ability of iron chelators to retard dopaminergic neurodegeneration in the substantia nigra may indicate a new therapeutic strategy in the treatment of Parkinson's disease.
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PMID:The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. 190 May 27

The vulnerability of substantia nigral (SN) melaninized dopamine neurons to neurodegeneration in Parkinson's disease and the selective increases of iron and basal lipid peroxidation in SN indicate that iron-melanin interaction could be crucial to the pathogenesis of this disease. The present study describes, for the first time, the identification and characterization of a high-affinity (KD = 13 nM) and a lower affinity (KD = 200 nM) binding site for iron on dopamine melanin. The binding of iron to melanin is dependent on pH and the concentration of melanin. Iron chelators, U74500A, desferrioxamine, and to less extent 1,10-phenanthroline and chlorpromazine, but not the Parkinson-inducing neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, can inhibit the binding of iron to melanin and iron-induced lipid peroxidation. Although melanin alone diminishes basal lipid peroxidation in rat cortical homogenates, it can also potentiate that initiated by iron, a reaction inhibited by desferrioxamine. In the absence of an identifiable exogenous or endogenous neurotoxin in idiopathic Parkinson's disease, iron-melanin interaction in pars compacta of SN may be a strong candidate for the cytotoxic component of oxygen radical-induced neurodegeneration of melaninized dopamine neurons.
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PMID:Iron-melanin interaction and lipid peroxidation: implications for Parkinson's disease. 191 77

Oxygen free radicals, any chemical moiety containing an oxygen atom with an unpaired electron in the outer orbital shell, are generated during many normal biochemical reactions in living tissue. The unpaired electron makes these compounds highly reactive and they can initiate disruptive peroxidation reactions with various substrates important to the survival of cells such as proteins, lipids and nucleic acids. A fairly complex defense system has evolved to protect living tissue from free radicals and to minimize the damage they might cause. Neurons are especially vulnerable to free radical attack and impaired defenses or exposure to excess free radicals can lead to neuronal death. Free radicals contribute to neuronal loss in cerebral ischemia and hemorrhage and may be involved in the degeneration of neurons in epilepsy, schizophrenia, tardive dyskinesia, normal aging, Parkinson's Disease and Alzheimer's Disease. The development of drugs that limit or prevent the attack of free radicals on neurons would be an important advance in the treatment of these conditions.
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PMID:Oxygen free radicals and brain dysfunction. 134 20

The involvement of oxygen radicals in the pathogenesis of Parkinson's disease has been suggested for some time. This article reviews the evidence supporting the involvement of oxygen radicals in the disease process in the brain. This includes a discussion of iron, lipid peroxidation, peroxidase, catalase, superoxide dismutase, and glutathione levels in the brain. In addition, various theories of induction of Parkinson's disease are discussed in relation to the possible involvement of oxygen radicals. These theories include the environmental toxin theory, the dopamine turnover theory, and the cerebral blood flow theory.
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PMID:Oxygen free radicals and Parkinson's disease. 201 74

Recent evidence suggests that iron accumulates in substantia nigra pars compacta of patients with Parkinson's disease (PD). This finding is compatible with changes in the respiratory chain activity, increase of malondialdehyde concentration (a measure of lipid peroxidation), decrease of enzyme activity of enzymes involved in detoxication of hydrogen peroxide and oxygen radical species, increased MAO-B-activity in this brain area etc. All these data suggest that oxidative stress may play a certain role in the pathobiochemistry of PD. In addition to the description of the neuroprotective mechanism of the MAO-B-inhibitor L-deprenyl a new aspect focuses the role of the endogenous MAO-B substrates "polyamines" which occur both in neurons and glia. A further aspect of this review deals with the role of calcium as cellular toxin. Although of major importance it is not decided yet whether these biochemical changes are primary or secondary importance to the pathogenesis of PD.
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PMID:The role of monoamine oxidase, iron-melanin interaction, and intracellular calcium in Parkinson's disease. 208 94


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