Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug-related autoimmune hemolytic anemia appearing with warm-reacting antibodies can be classified according to the offending substances. One of the subtypes can be induced by alpha-methyldopa. However, the pathophysiology of the underlying mechanism is not yet known. In parallel, patients with Parkinson's disease and other extrapyramidal disorders, who are under administration of dopaminergic drugs, often present with abnormal findings with respect to immune parameters. In order to reveal further mechanisms within the immune response, the capability of patients under dopaminergic medication to release cytokines after a stimulatory signal was examined. Therefore, 18 patients who were treated with the dopamine analogue lisuride were compared with an aged-matched control group of 21 healthy volunteers. After stimulation with phytohemagglutinin (PHA), mitogen-induced concentrations of interferon-gamma were significantly higher in the patients treated with lisuride than in the control group. Interferon-gamma leads to an upregulation of MHC class-I and especially class-II molecules on antigen-presenting cells and to an induction of antibody production in B cells. This condition can result in the induction of an autoimmune process. It might be supposed that alpha-methyldopa-type autoimmune hemolytic anemia is mediated by elevated levels of interferon-gamma produced in T cells after a stimulatory signal.
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PMID:Is alpha-methyldopa-type autoimmune hemolytic anemia mediated by interferon-gamma? 794 14

Perhaps as many as 25-50% of adult patients and children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. How can human immunodeficiency virus type 1 (HIV-1) result in neuronal damage if neurons themselves are for all intents and purposes not infected by the virus? This article reviews a series of experiments leading to a hypothesis that accounts at least in part for the neurotoxicity observed in the brains of AIDS patients. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions among macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia, or monocytes), after interacting with astrocytes, secrete eicosanoids, i.e., arachidonic acid and its metabolites, including platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. In addition, interferon-gamma (IFN-gamma) stimulation of macrophages induces release of the glutamate-like agonist, quinolinate. Furthermore, HIV-infected macrophage production of cytokines, including TNF-alpha and IL1-beta, contributes to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and, therefore, offers hope for future pharmacological intervention. This article focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:HIV-related neuronal injury. Potential therapeutic intervention with calcium channel antagonists and NMDA antagonists. 799 15

We examined the immunohistochemical localization of the proinflammatory cytokines tumor necrosis factor-alpha, lymphotoxin and interferon-gamma in 22 autopsy brains of patients with either cerebrovascular disease (CVD) or other neurological diseases as well as 2 non-neurological control brains. These cytokines were coexpressed mostly in the microglia/macrophages and in a few astroglia in the brains with acute cerebral infarction and cerebral hemorrhage. In cases with cerebral infarction, they were observed as early as 33 h after the onset of the illness and persisted for up to 40 days after the onset. In one patient with cerebral hemorrhage who survived for 4 h, the cytokine-immunoreactive glial cells were confined to the margins of the hematoma. In contrast, the cytokine-immunoreactive glia were distributed diffusely in one patient with cerebral hemorrhage who died 12 days after the onset of the illness. Labeling for these cytokines was weak in the glial cells of control brains and those with neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and multiple system atrophy, in so far as there were no concomitant acute CVD foci. The present results indicate that proinflammatory cytokines are up-regulated in the brains of patients with acute stroke, and suggest an early inflammatory response in human CVD.
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PMID:Glial expression of cytokines in the brains of cerebrovascular disease patients. 887 Aug 30

Oxidative stress is thought to be involved in the mechanism of nerve cell death in Parkinson's disease (PD). Among several toxic oxidative species, nitric oxide (NO) has been proposed as a key element on the basis of the increased density of glial cells expressing inducible nitric oxide synthase (iNOS) in the substantia nigra (SN) of patients with PD. However, the mechanism of iNOS induction in the CNS is poorly understood, especially under pathological conditions. Because cytokines and FcepsilonRII/CD23 antigen have been implicated in the induction of iNOS in the immune system, we investigated their role in glial cells in vitro and in the SN of patients with PD and matched control subjects. We show that, in vitro, interferon-gamma (IFN-gamma) together with interleukin-1beta (Il-1beta) and tumor necrosis factor-alpha (TNF-alpha) can induce the expression of CD23 in glial cells. Ligation of CD23 with specific antibodies resulted in the induction of iNOS and the subsequent release of NO. The activation of CD23 also led to an upregulation of TNF-alpha production, which was dependent on NO release. In the SN of PD patients, a significant increase in the density of glial cells expressing TNF-alpha, Il-1beta, and IFN-gamma was observed. Furthermore, although CD23 was not detectable in the SN of control subjects, it was found in both astroglial and microglial cells in parkinsonian patients. Altogether, these data demonstrate the existence of a cytokine/CD23-dependent activation pathway of iNOS and of proinflammatory mediators in glial cells and their involvement in the pathophysiology of PD.
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PMID:FcepsilonRII/CD23 is expressed in Parkinson's disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells. 1021 4

An involvement of immunological events in the process of neurodegeneration has frequently been reported. We investigated the cytokine producing capacity for interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) in whole blood cultures of de-novo patients with idiopathic Parkinson's disease (PD) at the time of first diagnosis and after oral amantadine treatment. Before treatment, productions of IL-2 and IFN-gamma were markedly decreased in PD patients compared to patients with major depressive disorder and healthy controls. After amantadine treatment, the in vitro IL-2 secretion defect was corrected to normal levels in half of the patients, and the increase in IL-2 production was correlated with an increase in IFN-gamma secretion. Our findings suggest that immunological abnormalities occur in the course of PD and that a formerly unappreciated therapeutic potential of amantadine may arise from its immunomodulatory effects on altered T cell function in patients with PD.
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PMID:Effects of amantadine treatment on in vitro production of interleukin-2 in de-novo patients with idiopathic Parkinson's disease. 1043 55

Past studies including our own have confirmed that chronic administration of deprenyl can prolong life spans of at least four different animal species. Pretreatment with the drug for several weeks increases activities of superoxide dismutase (SOD) and catalase (CAT) in selective brain regions. An up-regulation of antioxidant enzyme activities can also be induced in organs such as the heart, kidney, spleen, and adrenal gland, and all are accompanied by an increase in mRNA levels for SODs in these organs. The effect of deprenyl on enzyme activities has a dose-effect relationship of a typical inverted U shape. A similar inverted U shape also has emerged for the drug's effect on survival of animals. An apparent parallelism observed between these two effects of the drug seems to support our contention that the up-regulation of antioxidant enzymes is at least partially responsible for the life-prolonging effect on animals. Further, when a clinically applied dose of the drug for patients with Parkinson's disease was given to monkeys, SOD and CAT activities were increased in striatum of these monkeys, which suggests potential for the drug's applicability to humans. The drug was also found to increase concentrations of cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in the above rat organs. Together with past reports demonstrating that deprenyl increases natural killer (NK) cell functions and interferon-gamma, and prevents the occurrence of malignant tumors in rodents and dogs, the mobilization of these humoral factors may therefore be included as possible mechanisms of action of deprenyl for its diverse antiaging and life-prolonging effects. The potentials of propargylamines, (-)deprenyl in particular, for human use as antiaging drugs remain worthy of exploration in the future.
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PMID:Pharmacological interventions in aging and age-associated disorders: potentials of propargylamines for human use. 1197 4

Neurological injury and Parkinson disease (PD) are often associated with the increase of nitric oxide (NO) and free radicals from resident glial cells in the brain. In vitro, exposure to L-3-4-dihydroxyphenylalanine (L-DOPA), one of the main therapeutic agents for the treatment of PD, can lead to neurotoxicity. In this study, lipopolysaccharide (LPS) and interferon-gamma (IFN-g) were used to stimulate C6 glioma cells in the presence of varying concentrations of L-DOPA (1 microM-1 mM). The results indicated a slight augmentation of NO(2)(-) production at low concentrations of L-DOPA (<100 microM) and complete inhibition of NO(2)(-) at higher concentrations (500 microM, 1 mM), (p < 0.001). Western blot analysis corroborated that L-DOPA effects on iNOS was at the level of its protein expression. Total reactive oxygen species (ROS) were detected using 2', 7'-dichlorofluorescein diacetate fluorescence dye (2', 7'-DCFC) and there was an increase of intensity with the increasing concentrations of L-DOPA. Furthermore, large amounts of superoxide (O(2)(-)) and hydrogen peroxide (H(2)O(2)) were generated from the autoxidation of L-DOPA. C6 cells contain high levels of catalase, with inadequate levels of superoxide dismutase (SOD); therefore, there was an accumulation of O(2)(-), tantamount to elevation in 2'7'-DCFC intensity. Simultaneous accumulation of O(2)(-) and NO(2)(-) would propel formation of peroxynitrite (ONOO-). SOD completely attenuated the autoxidation of L-DOPA and significantly reversed the inhibitory effects on iNOS at high concentrations. The data obtained confirmed that the observed effects on iNOS were not due to the activation of the D(1) or beta1 adrenergic receptors by L-DOPA. It was concluded from this study that L-DOPA contributed to the modulation of iNOS and to the increase of O(2)(-) production in the stimulated glioma cells in vitro.
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PMID:Levodopa modulating effects of inducible nitric oxide synthase and reactive oxygen species in glioma cells. 1241 52

Within the central nervous system uncontrolled production of large amounts of nitric oxide (NO) by activated glial cells might be the common pathogenesis of several neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. In the present investigation, we measured the effect of a novel antioxidant gamma-L-glutamyl-S-[2-[[[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl]oxy]carbonyl]-3-[[2-(1H-indol-3-yl)ethyl]amino]-3-oxopropyl]-L-cysteinyl-glycine sodium salt (ESeroS-GS) on NO production in cultured rat astrocytes. Upon stimulation with 1 microg/mL lipopolysaccharide plus 100 U/mL interferon-gamma which induced the expression of inducible nitric oxide synthase, cultured astrocytes generated large amounts of NO as measured by nitrite assay and ESR technique. The endogenous NO caused oxidative damage in astrocytes, which was confirmed by the accumulation of both cytosolic and extracellular peroxides, the decrease in the cellular glutathione level, and the formation of thiobarbituric acid reactive substrates. Production of endogenous NO resulted in cell death finally. Pretreatment with the novel antioxidant ESeroS-GS effectively decreased the expression of iNOS gene, inhibited the formation of endogenous NO, and prevented NO-induced oxidative damage and cell death in astrocytes. The results suggest that ESeroS-GS might be used as a potential agent for the prevention and therapy of diseases associated with the overproduction of NO by activated astrocytes.
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PMID:The antioxidant ESeroS-GS inhibits NO production and prevents oxidative stress in astrocytes. 1281 68

Nitric oxide (NO), in excess, behaves as a cytotoxic substance mediating the pathological processes that cause neurodegeneration. The NO-induced dopaminergic cell loss causing Parkinson's disease (PD) has been postulated to include the following: an inhibition of cytochrome oxidase, ribonucleotide reductase, mitochondrial complexes I, II, and IV in the respiratory chain, superoxide dismutase, glyceraldehyde-3-phosphate dehydrogenase; activation or initiation of DNA strand breakage, poly(ADP-ribose) synthase, lipid peroxidation, and protein oxidation; release of iron; and increased generation of toxic radicals such as hydroxyl radicals and peroxynitrite. NO is formed by the conversion of L-arginine to L-citrulline by NO synthase (NOS). At least three NOS isoforms have been identified by molecular cloning and biochemical studies: a neuronal NOS or type 1 NOS (nNOS), an immunologic NOS or type 2 NOS (iNOS), and an endothelial NOS or type 3 NOS (eNOS). The enzymatic activities of eNOS or nNOS are induced by phosphorylation triggered by Ca(2+) entering cells and binding to calmodulin. In contrast, the regulation of iNOS seems to depend on de novo synthesis of the enzyme in response to a variety of cytokines, such as interferon-gamma and lipopolysaccharide. The evidence that NO is associated with neurotoxic processes underlying PD comes from studies using experimental models of this disease NOS inhibitors can prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Furthermore, NO fosters dopamine depletion, and the said neurotoxicity is averted by nNOS inhibitors such as 7-nitroindazole working on tyrosine hydroxylase-immunoreactive neurons in substantia nigra pars compacta. Moreover, mutant mice lacking the nNOS gene are more resistant to MPTP neurotoxicity when compared with wild-type littermates. Selegiline, an irreversible inhibitor of monoamine oxidase B, is used in PD as a dopaminergic function-enhancing substance. Selegiline and its metabolite, desmethylselegiline, reduce apoptosis by altering the expression of a number of genes, for instance, superoxide dismutase, Bcl-2, Bcl-xl, NOS, c-Jun, and nicotinamide adenine nucleotide dehydrogenase. The selegiline-induced antiapoptotic activity is associated with prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons. As apoptosis is critical to the progression of neurodegenerative disease, including PD, selegiline or selegiline-like compounds to be discovered in the future may be efficacious in treating PD.
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PMID:Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. 1288 Apr 86

Serum levels of interferon-gamma (IF gamma), tumor necrosis factor alpha (TNF alpha) and autoantibodies (a-AT) to these cytokines were investigated in patients with Parkinson's disease (PD). The increased levels of TNF alpha (50%) and IF gamma (35%) were found in PD patients. There was close correlation between the serum level of TNF alpha and the manifestation of neurological symptoms (r = 0.434; p < 0.05), and between levels of IF gamma and the duration of this disease (r = 0.4511, p < 0.05) and patients age as well (r = 0.4358; p < 0.05). There was increased level of a-AT to TNF alpha in PD patients versus healthy controls (130.3 +/- 11.92 and 105.3 +/- 4.62, respectively, p < 0.05). The combined increase of levels of a-AT to TNF alpha and IF gamma (r = 0.91, p < 0.01) close reverse correlation between duration of PD and levels of a-AT to TNF alpha and IF gamma (r = 0.4644 and r = 0.606, respectively, p < 0.01) were also recognised. The data obtained suggest the involvement of TNF alpha and IF gamma into the pathological process during PD, which requires further investigation in this direction.
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PMID:[Level of interferon-gamma, tumor necrosis factor alpha, and antibodies to them in blood serum from Parkinson disease patients]. 1456 85


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