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)

The cause of the degeneration of dopamine-containing cells in the zona compacta of the substantia nigra in Parkinson's disease remains unknown. The ability of the selective nigral toxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) (via its metabolite MPP+) to destroy nigral dopamine cells selectively by inhibiting complex I of the mitochondrial energy chain may provide a clue. Indeed, recent studies of post-mortem brain tissue have suggested the presence of an on-going toxic process in the substantia nigra in Parkinson's disease leading to excess lipid peroxidation. This appears also to involve a disruption of mitochondrial function since mitochondrial superoxide dismutase activity is increased and there is impairment of complex I. These changes may in turn relate to a selective increase in the total iron content of substantia nigra coupled to a generalised decrease in brain ferritin content. Piribedil is used in the symptomatic treatment of Parkinson's disease and is particularly effective against tremor. Piribedil (and its metabolites) acts as a dopamine D-2 receptor agonist. However, in our studies in contrast to other dopamine agonists, in vivo piribedil interacts with dopamine receptors in the substantia nigra and nucleus accumbens but not those in the striatum. In patients with Parkinson's disease the beneficial effects of piribedil may be limited by nausea and drowsiness. Indeed, in MPTP-treated primates piribedil reverses motor deficits but marked side-effects occur. However, pre-treatment with the peripheral dopamine receptor antagonist domperidone prevents the unwanted effects and piribedil produces a profound and longer-lasting reversal of all components of the motor syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Parkinson's disease: pathological mechanisms and actions of piribedil. 163 7

Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone. Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity to MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons. Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline. Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article.
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PMID:A review of the pharmacology of selegiline. 168 54

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

As an animal model of human Parkinson's disease 250 micrograms of 6-Hydroxydopamine was injected intraventricularly in the rats. At 24 h, 48 h, 7th and 14th day after injection, the levels of dopamine, norepinephrine, Cu, Zn- and Mn- superoxide dismutase (SOD), catalase as well as the lipid peroxidative products in the striatum, midbrain and hypothalamus were determined. Our data showed that catecholamines decreased persistently, catalase and Mn-SOD decreased concomitantly, Cu, Zn-SOD, however, remained, unchanged. Lipid peroxidative products increased shortly after injection, then subsided. Our result suggests that lipid peroxidation might be involved in the degenerative process of neurons in Parkinson's disease.
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PMID:[Effect of 6-hydroxydopamine on cerebral catecholamines, lipid peroxidation and antioxidant enzymes in rats-concerned with pathogenesis of Parkinson's disease]. 195 95

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

Although many authors have suggested that dopamine and its metabolites producing free radicals have an harmful effect in the substantia nigra, experimental evidence has not been shown. Using a newly established enzyme immunoassay of the neurofilament protein, a reliable index for the number of survived neurons in tissue culture, we evaluate the effects of Dopa on the neurons of dorsal root ganglia from mice. Neurons were destroyed by the exposure of 0.5 mM Dopa with or without superoxide dismutase and catalase, but they were saved by the pretreatment with 1.0 mM deferoxamine mesylate, a powerful iron-chelating agent. Formation of malondialdehyde, an index of lipid peroxidation, was also observed in the reaction of 0.5 mM Dopa and cerebral cortical neurons from new-born rats only when iron was present. These results indicate that Dopa initiates lipid peroxidation of cell membrane in the presence of a small amount of iron in the culture with little or no participation of reactive oxygen species, leading to the destruction of the neurons. In Parkinson's disease, the cytotoxic mechanism of Dopa and iron may involve the neuronal degeneration in the substantia nigra abundant in iron and dopaminergic neurons.
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PMID:[Iron-dependent cytotoxic effects of dopa on cultured neurons of the dorsal root ganglia]. 211 13

The total activity of superoxide dismutase (SOD) and cytosolic and particulate activity of SOD in human substantia nigra and cerebellum were measured by a spectrophotometric method based on the ability of SOD to inhibit the autoxidation of adrenaline. The cytosolic and particulate isoenzymes of SOD were differentiated by the inclusion of potassium cyanide which selectively inhibits cytosolic copper/zinc-dependent SOD activity. In autopsied human brains, there was no difference in total SOD activity, or the activity of SOD in cytosol in substantia nigra of patients dying with Parkinson's disease compared to age-matched controls. However, the activity of the particulate form of SOD was higher in the parkinsonian substantia nigra compared to control tissue. In the cerebellum there was no difference in the total, cytosolic, or particulate activity of SOD between parkinsonian patients and age-matched controls. Increased activity of SOD in particulate fraction may be a protective response to elevated levels of toxic free radicals in the parkinsonian substantia nigra. Alternatively, increased SOD activity may induce cell death through the accumulation of hydrogen peroxide.
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PMID:A selective increase in particulate superoxide dismutase activity in parkinsonian substantia nigra. 276 Jun 16

Oxygen-derived toxicity has been suggested as being involved in the pathogenesis of Parkinson's disease. Superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase provide the enzymatic defence against oxygen toxicity. The activities of these enzymes were measured in peripheral blood leucocytes, cerebrospinal fluid and in different brain regions from patients with idiopathic Parkinson's disease and from controls. There was no indication of a generalized defect in any of these enzymes in Parkinson's disease. The brain activities of catalase, glutathione peroxidase and glutathione reductase were also comparable to those of the controls. An increased superoxide dismutase-like activity was observed in several regions of parkinsonian brains, including the temporal cortex, thalamus and red nucleus. However, the most pronounced increase occurred in the substantia nigra and basal nucleus. This may be due to an increase of the superoxide dismutase activity or be a result of the presence of a compound with superoxide dismutase-like activity, and may reflect the involvement of radical-induced cell damage in the pathogenesis of Parkinson's disease.
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PMID:Oxygen toxicity protecting enzymes in Parkinson's disease. Increase of superoxide dismutase-like activity in the substantia nigra and basal nucleus. 322 Dec 44

Three groups have reported defective antioxidant mechanisms in substantia nigra of patients with Parkinson's disease, namely a decreased catalase and peroxidase activity, a reduction of glutathione and, more recently, a diminished nigral glutathione peroxidase activity. We decided to investigate these mechanisms in erythrocytes to determine whether these brain defects represent generalized or genetic aberrations, in which case they should also be present in blood cells. The glutathione cycle has been investigated (reduced and oxidized glutathione, glutathione reductase and peroxidase) plus the activities of catalase and superoxide dismutase. The basal malonaldehyde content of erythrocytes was used as an index of endogenous lipid peroxidation. None of the above-mentioned parameters were found altered in erythrocytes of parkinsonians, suggesting that no genetic or generalized biochemical abnormalities underly the deficiencies detected in substantia nigra.
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PMID:Erythrocyte antioxidant activity in human patients with Parkinson's disease. 358 38

Aging is a major risk factor for several common neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Huntington's disease (HD). Recent studies have implicated mitochondrial dysfunction and oxidative stress in the aging process and also in the pathogenesis of neurodegenerative diseases. In brain and other tissues, aging is associated with progressive impairment of mitochondrial function and increased oxidative damage. In PD, several studies have demonstrated decreased complex I activity, increased oxidative damage, and altered activities of antioxidant defense systems. Some cases of familial ALS are associated with mutations in the gene for Cu, Zn superoxide dismutase (Cu, Zn SOD) and decreased Cu, Zn SOD activity, while in sporadic ALS oxidative damage may be increased. Defects in energy metabolism and increased cortical lactate levels have been detected in HD patients. Studies of AD patients have identified decreased complex IV activity, and some patients with AD and PD have mitochondrial DNA mutations. The age-related onset and progressive course of these neurodegenerative diseases may be due to a cycling process between impaired energy metabolism and oxidative stress.
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PMID:Bioenergetic and oxidative stress in neurodegenerative diseases. 747 93


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