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)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Although the exact mechanisms responsible for this cell loss are unclear, emerging evidence suggests the involvement of inflammatory events. In the present study, we characterized the effects of the proinflammatory bacteriotoxin lipopolysaccharide (LPS) on the number of tyrosine hydroxylase immunoreactive (THir) cells (used as an index for DA neurons) in primary mesencephalic cultures. LPS (10-80 microg/ml) selectively decreased THir cells and increased culture media levels of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) as well as nitrite (an index of nitric oxide (NO) production). Cultures exposed to both LPS and neutralizing antibodies to IL-1beta or TNF-alpha showed an attenuation of the LPS-induced THir cell loss by at least 50% in both cases. Inhibition of the inducible form of nitric oxide synthase (iNOS) by L-NIL did not affect LPS toxicity, but increased the LPS-induced levels of both TNF-alpha and IL-1beta. These findings suggest that neuroinflammatory stimuli which lead to elevations in cytokines may induce DA neuron cell loss in a NO-independent manner and contribute to PD pathogenesis.
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PMID:Lipopolysaccharide (LPS)-induced dopamine cell loss in culture: roles of tumor necrosis factor-alpha, interleukin-1beta, and nitric oxide. 1185 61

The prominent pathological feature of the brain in Parkinson's disease is selective degeneration of dopaminergic neurons in the substantia nigra of the midbrain. Glutamate and nitric oxide (NO) are the major effectors of the radical stress that may induce selective loss of dopaminergic neurons. It has been postulated that neurotoxicity induced by glutamate and NO in dopaminergic neurons is regulated by certain endogenous factors. We have reported that estradiol protects dopaminergic neurons against NO-mediated glutamate neurotoxicity by reducing intracellular reactive oxygen species (ROS) levels. We further searched for a candidate for neuroprotective substances with unique structure. From the ether extract of fetal calf serum (FCS), we isolated a novel substance possessing protective activity against neurotoxicity induced by glutamate NO. The compound was a sulfur-containing diterpenoid and showed hydroxyl radical scavenging activity. We further analyzed the change of resistance to excitotoxicity in midbrain dopaminergic neurons in co-culture with the striatum by using a slice culture technique. The results suggested that the generation of NO is involved in NMDA cytotoxicity on dopaminergic neurons and that increased activity of SOD in co-culture renders dopaminergic neurons resistant to NMDA cytotoxicity by preventing peroxynitrite formation. Those findings suggest that regulation of intracellular ROS levels plays a critical role in protecting neurons against NO-mediated radical stress in neurodegenerative disorders.
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PMID:[Role of nitric oxide in survival and death of neurons]. 1186 52

The loss of dopaminergic neurones in the substantia nigra with Parkinson's disease may result from inflammation-induced proliferation of microglia and reactive macrophages expressing inducible nitric oxide synthase (iNOS). We have investigated the effects of the supranigral administration of lipopolysaccharide on iNOS-immunoreactivity, 3-nitrotyrosine formation and tyrosine hydroxylase-immunoreactive neuronal number, and retrogradely labelled fluorogold-positive neurones in the ventral mesencephalon in male Wistar rats. Following supranigral lipopolysaccharide injection, 16-18 h previously, there was intense expression of NADPH-diaphorase and iNOS-immunoreactivity in non-neuronal, macrophage-like cells. This was accompanied by intense expression of glial fibrillary acidic protein-immunoreactive astrocytosis in the substantia nigra. There were also significant reductions in the number of tyrosine hydroxylase(50-60%)- and fluorogold (65-75%)-positive neurones in the substantia nigra. In contrast, tyrosine hydroxylase-immunoreactivity in the ventral tegmental area was not altered. Pre-treatment of animals with the iNOS inhibitor, S-methylisothiourea (10 mg kg(-1), i.p.), led to a significant reduction of lipopolysaccharide-induced cell death. Similar reduction of tyrosine hydroxylase-immunoreactivity and fluorogold-labelled neurones in the substantia nigra following lipopolysaccharide administration suggests dopaminergic cell death rather than down-regulation of tyrosine hydroxylase. We conclude that the expression of iNOS- and 3-nitrotyrosine-immunoreactivity and reduction of cell death by S-methylisothiourea suggest the effects of lipopolysaccharide may be nitric oxide-mediated, although other actions of lipopolysaccharide (independent of iNOS induction) cannot be ruled out.
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PMID:Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration. 1188 72

We recently showed that trisialoganglioside (GT1b) induces cell death of dopaminergic neurons in rat mesencephalic cultures (Chung et al., Neuroreport 12:611-614, 2001). The present study examines the in vivo neurotoxic effects of GT1b on dopaminergic neurons in the substantia nigra (SN) of Sprague-Dawley rats. Seven days after GT1b injection into the SN, immunocytochemical staining of SN tissue revealed death of nigral neurons, including dopaminergic neurons. Additional immunostaining using OX-42 and OX-6 antibodies showed that GT1b-activated microglia were present in the SN where degeneration of nigral neurons was found. Western blot analysis and double-labeled immunohistochemistry showed that inducible nitric oxide synthase (iNOS) was expressed in the SN, where its levels were maximal at 8 h post-GT1b injection, and that iNOS was localized exclusively within microglia. GT1b-induced loss of dopaminergic neurons in the SN was partially inhibited by N(G)-nitro-L-arginine methyl ester hydrochloride, an NOS inhibitor. Our results indicate that in vivo neurotoxicity of GT1b against nigral dopaminergic neurons is at least in part mediated by nitric oxide released from activated microglia. Because GT1b exists abundantly in central nervous system neuronal membranes, our data support the hypothesis that immune-mediated events triggered by endogenous compounds such as GT1b could contribute to the initiation and/or the progression of dopaminergic neuronal cell death that occurs in Parkinson's disease.
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PMID:Trisialoganglioside GT1b induces in vivo degeneration of nigral dopaminergic neurons: role of microglia. 1192 Dec

Reactive oxygen species have been implicated in dopaminergic toxicity caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and iron. Although MPTP produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP(+)) by type B monoamine oxidase (MAO-B) in the brain, the etiology of this disease remains obscure. MPP(+) is a highly potent dopaminbergic-releasing agents and dopamine (DA) autoxidation catalyzed by iron and oxidative stress may be involved in the pathogenesis of Parkinson's disease. Neuromelanine synthesis from DA produce highly reactive free radicals. Although the controversy possible neurotoxin and/or neuroprotective roles of nitric oxide (NO) was discussed, NO contributes to oxidative injury to brain neurons in vivo. An environmental estrogen-like chemical also related to MPP(+)-induced *OH generation. This review describes actual mechanism of the free radicals formation by dialysis studies of in vivo free radical trapping in the pathogenesis of neurodegenerative disorders, including in the Parkinson's disease, Alzheimer disease and traumatic brain injuries.
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PMID:Role of hydroxyl radical formation in neurotoxicity as revealed by in vivo free radical trapping. 1204 41

Increasing evidence has suggested that inflammation in the brain is closely associated with the pathogenesis of several degenerative neurologic disorders, including Parkinson's disease, Alzheimer's diseases, multiple sclerosis, amyotrophic lateral sclerosis, and AIDS dementia. The hallmark of brain inflammation is the activation of glial cells, especially that of microglia that produce a variety of proinflammatory and neurotoxic factors, including cytokines, fatty acid metabolites, free radicals--such as nitric oxide (NO) and superoxide. Excessive production of NO, as a consequence of nitric oxide synthase induction in activated glia, has been attributed to participate in neurodegeneration. Using primary mixed neuron-glia cultures and glia-enriched cultures prepared from embryonic rodent brain tissues, we have systemically studied the relationship between the production of NO and neurodegeneration in response to stimulation by the inflammagen lipopolysaccharide. This review summarizes our recent findings on the kinetics of NO generation, the relative contribution of microglia and astrocytes to NO accumulation, the relationship between NO production and neurodegeneration, and points of intervention along the pathways associated with NO generation to achieve neuroprotection. We also describe our results relating to the effect of several opioid-related agents on microglial activation and neuroprotection. Among these agents, the opioid receptor antagonist naloxone, especially its non-opioid enantiomer (+)-naloxone, promises to be of potential therapeutic value for the treatment of inflammation-related diseases.
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PMID:Role of nitric oxide in inflammation-mediated neurodegeneration. 1207 84

Glial cells play a key role in the function of dopamine (DA) neurons and regulate their differentiation, morphology, physiological and pharmacological properties, survival, and resistance to different models of DA lesion. Several studies suggest that glial cells may be important in the pathogenesis of Parkinson's disease (PD), a common neurodegenerative disorder characterized by degeneration of the nigrostriatal DA system. In this disease the role of glia could be due to the excessive production of toxic products such as nitric oxide (NO) or cytokines characteristic of inflammatory process, or related to a defective release of neuroprotective agents, such as small antioxidants with free radical scavenging properties or peptidic neurotrophic factors.
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PMID:The role of astroglia on the survival of dopamine neurons. 1210 74

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP(+)) by B-form monoamine oxidase (MAO) in the brain, which is one of the most potent dopamine (DA)-releasing agents. MPP(+) perfusion into the striatum increases extracellular DA levels and this increase may concomitantly induce the formation of reactive free oxygen radicals, such as hydroxyl radical (.OH). These elevations seem to induce lipid peroxidation of striatum membranes, as detected by increases non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) levels. Sustained increase in striatal DA efflux by MAO inhibition produce.OH generation by products of monoamine. Therefore, reserpine-induced DA depletion clearly decreased MPP(+)-induced.OH formation. Neuromelanine synthesis from DA produce highly reactive free radicals. Nitric oxide (NO) contributes to produce MPP(+)-induced.OH generation via NO synthase (NOS) activation by depolarization. The antioxidation effect of angiotensin converting enzyme (ACE) inhibitor protects against MPP(+)-induced.OH generation due to the suppression of the Ca(2+)-dependent release of DA. These findings may be useful in elucidating the actual mechanism of free radical formation in the pathogenesis of neurodegenerative brain disorders, including Parkinson's disease and traumatic brain injuries. This review describes the free radicals mechanisms involved in MPTP toxicity and their possible involvement in the the pathogenesis of Parkinson's disease.
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PMID:Dopamine efflux by MPTP and hydroxyl radical generation. 1220 43

Multiple chemical sensitivity (MCS) is a condition where previous exposure to hydrophobic organic solvents or pesticides appears to render people hypersensitive to a wide range of chemicals, including organic solvents. The hypersensitivity is often exquisite, with MCS individuals showing sensitivity that appears to be at least two orders of magnitude greater than that of normal individuals. This paper presents a plausible set of interacting mechanisms to explain such heightened sensitivity. It is based on two earlier theories of MCS: the elevated nitric oxide/peroxynitrite theory and the neural sensitization theory. It is also based on evidence implicating excessive NMDA activity in MCS. Four sensitization mechanisms are proposed to act synergistically, each based on known physiological mechanisms: Nitric oxide-mediated stimulation of neurotransmitter (glutamate) release; peroxynitrite-mediated ATP depletion and consequent hypersensitivity of NMDA receptors; peroxynitrite-mediated increased permeability of the blood-brain barrier, producing increased accessibility of organic chemicals to the central nervous system; and nitric oxide inhibition of cytochrome P450 metabolism. Evidence for each of these mechanisms, which may also be involved in Parkinson's disease, is reviewed. These interacting mechanisms provide explanations for diverse aspects of MCS and a framework for hypothesis-driven MCS research.
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PMID:NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and organic solvents as the mechanism of chemical sensitivity in multiple chemical sensitivity. 1220 32

The cause of premature death of dopamine neurons in patients with Parkinson's disease remains unknown. It is speculated that damaging reactive species resulting from the metabolism of dopamine, nitric oxide, and tetrahydrobiopterin (BH(4)) may be involved. GTP cyclohydrolase I (GCH1) is the first and rate-limiting enzyme in the synthesis of BH(4), an essential cofactor for tyrosine hydroxylase and nitric oxide synthase in dopamine and nitric oxide production, respectively. Our studies have explored BH(4) metabolism in the nigrostriatal system following intrastriatal kainic acid lesion. We have demonstrated that 1 week following kainic acid there was an increase in striatal GCH1 mRNA, protein, and activity. There was also an elevation of BH(4) levels in the striatum. Part of the induction of GCH1 was localized in situ to astrocytes. Further, the striatal lesion caused death of both neurons and astrocytes in striatum, as shown by in situ end labeling. These novel observations suggest that the induction of GTP cyclohydrolase and BH(4) in striatal astrocytes may be mediating death of striatal neuronal and non-neuronal cells. This work supports existing and emerging reports that demonstrate the importance of dopamine metabolism in neuronal death of the nigrostriatal system.
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PMID:GTP cyclohydrolase I induction in striatal astrocytes following intrastriatal kainic acid lesion. 1229 63


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