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)

A significant body of evidence has been provided to support the hypothesis that oxidant stress may be responsible for the degeneration of dopaminergic neurons in the substantia nigra pars compacta in Parkinson's disease. Apomorphine, a dopamine D1/D2-receptor agonist in the clinical therapy of Parkinson's disease, has been found to be a potent antioxidant and to prevent free radical reaction in rat brain mitochondrial fraction. In this article we show that 1-10 microM of apomorphine protects rat pheochromocytoma (PC12) cells from the toxic effects of H2O2 (0.6 mM) and the neurotoxin 6-hydroxydopamine (150 microM). These effects were not exhibited by ascorbic acid, desferal, lisuride, or bromocriptine. Although pergolide exhibited some protection of PC12 cells against H2O2 toxicity, it was not as potent as apomorphine. In light of the present findings and the clinical reports that parkinsonian patients on long-term apomorphine stabilize clinically and can be weaned off L-dopa, one may assume that apomorphine can exert a neuroprotective activity via its potent antioxidant properties.
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PMID:Apomorphine enantiomers protect cultured pheochromocytoma (PC12) cells from oxidative stress induced by H2O2 and 6-hydroxydopamine. 953 36

It is now well established that the formation of free radicals and oxidative stress-induced neuronal cell death can be involved in various neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. The pineal hormone melatonin has been suggested to be a neuroprotective antioxidant. To better understand the molecular mechanism of this activity, we compared the ability of melatonin and its precursor, N-acetyl-serotonin (normelatonin), to protect human neuroblastoma SK-N-MC cells and primary cerebellar granular neurons against oxidative stress. We found that normelatonin and melatonin have differential neuroprotective effects depending on the neuronal cell type. Normelatonin was more protective against hydrogen peroxide (H2O2) and glutamate-induced cell death in SK-N-MC cells compared to melatonin which was more effective to protect primary cerebellar granular neurons against the toxicity of H2O2, glutamate and N-methyl-D-aspartate when compared to normelatonin. At the molecular level, we tested the capacity of normelatonin and melatonin to inhibit the oxidative stress-induced NF-kappaB activation in both neuronal systems. Whereas normelatonin was more potent in the suppression of the activation of NF-kappaB by H2O2 in SK-N-MC cells compared to melatonin, no apparent differences in the extent of suppression could be detected in primary neurons. Normelatonin's and melatonin's neuroprotective activity in SK-N-MC neuroblastoma cells may be mediated by the suppression of NF-kappaB activation.
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PMID:N-acetyl-serotonin (normelatonin) and melatonin protect neurons against oxidative challenges and suppress the activity of the transcription factor NF-kappaB. 955 54

The free radical hypothesis for the pathogenesis and/or progression of Parkinson's disease (PD) has gained wide acceptance in recent years. Although it is clear that dopamine (DA) agonists cannot completely replace levodopa therapy, they can be beneficial early in the course of PD by reducing the accumulation of DA which undergoes auto-oxidation and generates cytotoxic free radicals. In the present study we demonstrate that pergolide, a widely used DA agonist, has free radical scavenging and antioxidant activities. Using a direct detection system for nitric oxide radical (NO.) by electron spin resonance (ESR) spectrometry in an in vitro .NO-generating system, we examined the quenching effects of pergolide on the amount of NO. generated. Pergolide dose-dependently scavenged NO.. In the competition assay, the IC50 value for pergolide was estimated to be about 30 microM. Pergolide also dose-dependently attenuated the hydroxyl radical (.OH) signal in an in vitro FeSO4-H2O2 ESR system with an approximate IC50 value of 300 microM. Furthermore, this agent significantly inhibited phospholipid peroxidation of rat brain homogenates in in vitro experiments and after repeated administration (0.5 mg/kg/24 h, i.p. for 7 days). Our findings suggest a neuroprotective role for pergolide on dopaminergic neurons due to its free radical scavenging and antioxidant properties.
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PMID:Pergolide scavenges both hydroxyl and nitric oxide free radicals in vitro and inhibits lipid peroxidation in different regions of the rat brain. 959 94

A significant body of evidence has been provided to support the hypothesis that oxidant stress may be responsible for the degeneration of dopaminergic neurons in the substantia nigra pars compacta in Parkinson's disease. Apomorphine, a dopamine D1/D2-receptor agonist in the clinical therapy of Parkinson's disease, has been found to be a potent antioxidant and to prevent free radical reaction in rat brain mitochondrial fraction. In this article we show that 1-10 microM of apomorphine protects rat pheochromocytoma (PC12) cells from the toxic effects of H2O2 (0.6 mM) and the neurotoxin 6-hydroxydopamine (150 microM). Neither of these effects were exhibited by ascorbic acid, desferal, lisuride, or bromocriptine. Although pergolide exhibited some protection of PC12 cells against H2O2 toxicity, it was not as potent as apomorphine. In light of the present findings and the clinical reports that parkinsonian patients on long-term apomorphine therapy stabilize clinically and can be weaned off L-dopa, one may assume that apomorphine can exert a neuroprotective activity by way of its potent antioxidant properties.
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PMID:Apomorphine enantiomers protect cultured pheochromocytoma (PC12) cells from oxidative stress induced by H2O2 and 6-hydroxydopamine. 968 71

A new mechanism of oxygen radical formation in dopaminergic neurons is proposed, based on the oxidative mechanism of tyrosine hydroxylase. The cofactor (6R,6S)-5,6,7,8-tetrahydrobiopterin can rearrange in solution which allows an autoxidation reaction producing O2.-, H2O2 and HO.. The combination of tyrosine hydroxylase and the cofactor produces more oxygen radicals than does the autoxidation of the cofactor. This production of oxygen radicals could be damaging to dopaminergic neurons. In the presence of tyrosine, the enzyme produces less radicals than it does in the absence of tyrosine. Mechanisms are proposed for the generation of reactive oxygen species during the autoxidation of the cofactor and during enzymatic catalysis. The generation, by tyrosine hydroxylase, of very small amounts of oxygen radicals over the period of 65 years could contribute to the oxidative stress that causes Parkinson's disease.
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PMID:Tyrosine hydroxylase: mechanisms of oxygen radical formation. 975 25

Parkinson's disease (PD) is one of the most frequent disorders of the basal ganglia. From epidemiological studies there is a controversial discussion on the question whether tobacco smoking is correlated with a decreased incidence of PD. The present study aimed to elucidate the role of nicotine and its potential neuroprotective effects in a rodent model of PD. These effects may be related to an altered hydroxyl radical formation; this possibility was studied in vitro. Nicotine and alpha-phenyl-N-tert-butyl nitrone (PBN) were examined in a cell-free in vitro Fenton system (Fe3+/EDTA + H2O2) for their radical scavenging properties using the salicylate trapping method. Salicylic acid (0.5 mM) was incubated in the presence and absence of nicotine or PBN and the main products of the reaction of hydroxyl radicals with salicylic acid, namely 2,3- and 2,5-dihydroxybenzoic acid, were immediately determined using HPLC in combination with electrochemical detection. Nicotine and PBN were both able to significantly reduce hydroxyl radical levels at concentrations of 1, 2.5 and 5 mM. Interestingly, at 5 mM nicotine was able to reduce hydroxyl radical levels significantly more than the radical scavenger PBN (5 mM). To investigate the in vivo effects of nicotine, male C57BL/6 mice were used in the MPTP mouse model of PD. Nicotine (0.1 or 0.4 mg/kg s.c.) was administered twice daily for a period of 14 days. On day 8 a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg s.c.) was given as well as an enhanced protocol of nicotine treatment (0.1 or 0.4 mg/kg s.c., 30 min before MPTP and 30, 90, 210, 330, 450, 570 min after MPTP) for a total of seven injections of nicotine. High dosage nicotine treatment significantly increased the MPTP-induced loss of body weight and resulted in a significantly decreased striatal dopamine content and an increased dopamine turnover in comparison with the MPTP-treated controls at day 15. However, the lower dosage of nicotine did not significantly alleviate the MPTP-induced effects, although some parameters showed a slight tendency in this direction. These results demonstrate that in vitro nicotine has radical scavenging properties which might suggest neuroprotective effects. In vivo experiments with nicotine, however, showed that a low dosage of nicotine did not alleviate the MPTP-induced dopamine depletion, but a large dosage even enhanced it.
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PMID:Effects of nicotine on hydroxyl free radical formation in vitro and on MPTP-induced neurotoxicity in vivo. 977 23

Oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine (DA) to generate semiquinones/quinones, oxygen radicals, and other reactive oxygen species may play a role in neuronal cell death in Parkinson's disease (PD). In particular, semiquinones/quinones can form conjugates with thiol compounds such as GSH and cysteine. Exposure of L-DOPA, DA, and other catecholamines to a system generating O2.- radical led to O2(.-)-dependent depletion of added GSH (or cysteine), accompanied by the formation of thiol-DA or -DOPA adducts as detected by HPLC. Superoxide could additionally cause destruction of these adducts. Iron or copper ions could also promote conjugate formation between GSH or cysteine and DA and L-DOPA, especially if H2O2 was present. We applied HPLC to measure glutathionyl and cysteinyl conjugates of L-DOPA, DA, and 3,4-dihydroxyphenylacetic acid (DOPAC) in postmortem brain samples from PD patients and normal control subjects. Conjugates were detected in most brain areas examined, but levels were highest in the substantia nigra and putamen. In most regions, adduct levels were lower in PD, but there were significant increases in cysteinyl adducts of L-DOPA, DA, and DOPAC in PD substantia nigra, suggesting that acceleration of L-DOPA/DA oxidation occurs in PD, although we cannot say if this is a primary feature of the disease or if it is related to therapy with L-DOPA. In vitro, conjugate formation could be inhibited by the dithiol dihydrolipoate but not by its oxidised form, lipoic acid.
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PMID:Conjugates of catecholamines with cysteine and GSH in Parkinson's disease: possible mechanisms of formation involving reactive oxygen species. 979 37

The pathophysiology of organ system failure in sepsis, in particular the effects of septic shock on the central nervous system, are still incompletely understood. Lipopolysaccharide (LPS) from Gram-negative bacteria affects the permeability of the blood-brain barrier and causes the activation of brain microglia. A growing body of research supports involvement of activated brain microglia in brain pathologies caused by infectious diseases, trauma, tumors, ischemia, Alzheimer's disease, Parkinson's disease, Down's syndrome, multiple sclerosis and AIDS. Those seminal studies that have contributed to the characterization of the in vivo and in vitro effects of LPS on microglia function, mediator generation and receptor expression are presented within a historical perspective. In particular, all those in vitro studies on O2-, H2O2 and NO. generation by either unprimed or primed microglia have been extensively reviewed. The apparent controversial effect of LPS on microglia O2- is discussed. Because treatment modalities for septic shock have not significantly affected the current high mortality, alternative strategies with antioxidants are currently being investigated. Reduction of microglia O2- generation is proposed as a possible complementary strategy to antioxidative therapy for septic shock and CNS pathologies that involve activated microglia.
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PMID:Therapeutic implications of microglia activation by lipopolysaccharide and reactive oxygen species generation in septic shock and central nervous system pathologies: a review. 981

Reactive oxygen species (ROS) play an important role in the pathogenesis of many human diseases, including the acute respiratory distress syndrome, Parkinson's disease, pulmonary fibrosis, and Alzheimer's disease. In mammalian cells, several genes known to be induced during the immediate early response to growth factors, including the protooncogenes c-fos and c-myc, have also been shown to be induced by ROS. We show that members of the STAT family of transcription factors, including STAT1 and STAT3, are activated in fibroblasts and A-431 carcinoma cells in response to H2O2. This activation occurs within 5 min, can be inhibited by antioxidants, and does not require protein synthesis. STAT activation in these cell lines is oxidant specific and does not occur in response to superoxide- or nitric oxide-generating stimuli. Buthionine sulfoximine, which depletes intracellular glutathione, also activates the STAT pathway. Moreover, H2O2 stimulates the activity of the known STAT kinases JAK2 and TYK2. Activation of STATs by platelet-derived growth factor (PDGF) is significantly inhibited by N-acetyl-L-cysteine and diphenylene iodonium, indicating that ROS production contributes to STAT activation in response to PDGF. These findings indicate that the JAK-STAT pathway responds to intracellular ROS and that PDGF uses ROS as a second messenger to regulate STAT activation.
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PMID:Activation of the JAK-STAT pathway by reactive oxygen species. 984 26

In the CNS, reactive oxygen species (ROS) have been implicated in a wide range of degenerative processes including amyotrophic lateral sclerosis, ischemia-reperfusion injury, Alzheimer disease, Parkinson disease and aging. However, the exact mechanism is unknown, and there is little information on possible roles of ROS in cell injury and the process on recovery of astrocytes, the most abundant glial cells in the brain. We examined hydrogen peroxide (H2O2)-induced DNA fragmentation and thymidine incorporation into cultured astrocytes as an indicator of the process of recovery from astrocytic DNA injury. Astrocytes were isolated from cerebral cortices of 0-day-old rats and treated with 1 mM dibutyryl cyclic AMP for 4 days. H2O2 of 100 microM stimulated thymidine incorporation into astrocytes. Caffeine, ryanodine, cyclic ADP-ribose (endogenous ryanodine receptor agonist) and beta-NAD+ (precursor of cyclic ADP-ribose) suppressed partially the stimulatory effect of H2O2. Ruthenium red (ryanodine receptor antagonist) facilitated further the stimulatory effect of H2O2. The facilitated effect of ruthenium red on H2O2-induced thymidine incorporation was suppressed by caffeine, ryanodine, cyclic ADP-ribose and beta-NAD+. H2O2-induced DNA fragmentation and astrocytic death were suppressed by ruthenium red. These findings suggest that the process of recovery from astrocytic DNA injury by H2O2 may be regulated by Ca2+ efflux from ryanodine-sensitive intracellular Ca2+ stores.
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PMID:[Role of ryanodine receptors in hydrogen peroxide-induced DNA fragmentation and thymidine incorporation in cultured rat astrocytes]. 1019 Jan 45


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