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)

Much evidence supports a role of nitric oxide (.NO) and peroxynitrite (ONOO(-)) in experimental and idiopathic Parkinson's disease (PD); moreover, an overexpression of neuronal nitric oxide synthase (nNOS) was recently reported in the basal ganglia of PD patients. In accord, we previously found a 50% increased.NO production rate during the respiratory burst of circulating neutrophils (PMN) from PD patients. As PMN express the nNOS isoform, the objective of the present study was to ascertain whether this increased.NO production is representative of nNOS gene upregulation. PMN were isolated from blood samples obtained from seven PD patients and seven age- and sex-matched healthy donors; nNOS mRNA was amplified by reverse transcriptase-polymerase chain reaction and the products were hybridized with a probe for nNOS. Nitrotyrosine-containing proteins and nNOS were detected by Western blot and NO production rate was measured spectrophotometrically by the conversion of oxymyoglobin to metmyoglobin. The results showed that both.NO production and protein tyrosine nitration were significantly increased in PMN isolated from PD patients (PD 0.09 +/- 0.01 vs 0.06 +/- 0.008 nmol min(-1) 10(6) cells(-1); P < 0.05). In addition, five of the seven PD patients showed about 10-fold nNOS mRNA overexpression; while two of the seven PD patients showed an expression level similar to that of the controls; detection of nNOS protein was more evident in the former group. In summary, it is likely that overexpression of nNOS and formation of ONOO(-) in PMN cells from PD patients emphasizes a potential causal role of.NO in the physiopathology of the illness.
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PMID:Overexpression of neutrophil neuronal nitric oxide synthase in Parkinson's disease. 1102 Mar 42

Oxidative stress, reactive oxygen (ROS), and nitrogen (RNS) species have been known to be involved in a multitude of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Both ROS and RNS have very short half-lives, thereby making their identification very difficult as a specific cause of neurodegeneration. Recently, we have developed a high performance liquid chromatography/electrochemical detection (HPLC/EC) method to identify 3-nitrotyrosine (3-NT), an in vitro and in vivo biomarker of peroxynitrite production, in cell cultures and brain to evaluate if an agent-driven neurotoxicity is produced by the generation of peroxynitrite. We show that a single or multiple injections of methamphetamine (METH) produced a significant increase in the formation of 3-NT in the striatum. This formation of 3-NT correlated with the striatal dopamine depletion caused by METH administration. We also show that PC12 cells treated with METH has significantly increased formation of 3-NT and dopamine depletion. Furthermore, we report that pretreatment with antioxidants such as selenium and melatonin can completely protect against the formation of 3-NT and depletion of striatal dopamine. We also report that pretreatment with peroxynitrite decomposition catalysts such as 5, 10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron III (FeTMPyP) and 5, 10, 15, 20-tetrakis (2,4,6-trimethyl-3,5-sulfonatophenyl) porphinato iron III (FETPPS) significantly protect against METH-induced 3-NT formation and striatal dopamine depletion. We used two different approaches, pharmacological manipulation and transgenic animal models, in order to further investigate the role of peroxynitrite. We show that a selective neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI), significantly protect against the formation of 3-NT as well as striatal dopamine depletion. Similar results were observed with nNOS knockout and copper zinc superoxide dismutase (CuZnSOD)-overexpressed transgenic mice models. Finally, using the protein data bank crystal structure of tyrosine hydroxylase, we postulate the possible nitration of specific tyrosine moiety in the enzyme that can be responsible for dopaminergic neurotoxicity. Together, these data clearly support the hypothesis that the reactive nitrogen species, peroxynitrite, plays a major role in METH-induced dopaminergic neurotoxicity and that selective antioxidants and peroxynitrite decomposition catalysts can protect against METH-induced neurotoxicity. These antioxidants and decomposition catalysts may have therapeutic potential in the treatment of psychostimulant addictions.
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PMID:Methamphetamine-induced dopaminergic neurotoxicity: role of peroxynitrite and neuroprotective role of antioxidants and peroxynitrite decomposition catalysts. 1146 92

Research into methamphetamine-induced neurotoxicity has experienced a resurgence in recent years. This is due to (1) greater understanding of the mechanisms underlying methamphetamine neurotoxicity, (2) its usefulness as a model for Parkinson's disease and (3) an increased abuse of the substance, especially in the American Mid-West and Japan. It is suggested that the commonly used experimental one-day methamphetamine dosing regimen better models the acute overdose pathologies seen in humans, whereas chronic models are needed to accurately model human long-term abuse. Further, we suggest that these two dosing regimens will result in quite different neurochemical, neuropathological and behavioral outcomes. The relative importance of the dopamine transporter and vesicular monoamine transporter knockout is discussed and insights into oxidative mechanisms are described from observations of nNOS knockout and SOD overexpression. This review not only describes the neuropathologies associated with methamphetamine in rodents, non-human primates and human abusers, but also focuses on the more recent literature associated with reactive oxygen and nitrogen species and their contribution to neuronal death via necrosis and/or apoptosis. The effect of methamphetamine on the mitochondrial membrane potential and electron transport chain and subsequent apoptotic cascades are also emphasized. Finally, we describe potential treatments for methamphetamine abusers with reference to the time after withdrawal. We suggest that potential treatments can be divided into three categories; (1) the prevention of neurotoxicity if recidivism occurs, (2) amelioration of apoptotic cascades that may occur even in the withdrawal period and (3) treatment of the atypical depression associated with withdrawal.
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PMID:Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. 1151 69

There is growing evidence that suggests that brain injury after amphetamine and methamphetamine (METH) administration is due to an increase in free radical formation and mitochondrial damage, which leads to a failure of cellular energy metabolism followed by a secondary excitotoxicity. Neuronal degeneration caused by drugs of abuse is also associated with decreased ATP synthesis. Defective mitochondrial oxidative phosphorylation and metabolic compromise also play an important role in atherogenesis, in the pathogenesis of Alzheimer's disease, Parkinson's disease, diabetes, and aging. The energy deficits in the central nervous system can lead to the generation of reactive oxygen and nitrogen species as indicated by increased activity of the free radical scavenging enzymes like catalase and superoxide dismutase. The METH-induced dopaminergic neurotoxicity may be mediated by the generation of peroxynitrite and can be protected by antioxidants selenium, melatonin, and selective nNOS inhibitor, 7-nitroindazole. L-Carnitine (LC) is well known to carry long-chain fatty acyl groups into mitochondria for beta-oxidation. It also plays a protective role in 3-nitropropioinc acid (3-NPA)-induced neurotoxicity as demonstrated in vitro and in vivo. LC has also been utilized in detoxification efforts in fatty acid-related metabolic disorders. In this study we have tested the hypothesis that enhancement of mitochondrial energy metabolism by LC could prevent the generation of peroxynitrite and free radicals produced by METH. Adult male C57BL/6N mice were divided into four groups. Group I served as control. Groups III and IV received LC (100 mg/kg, orally) for one week. Groups II and IV received 4 x 10 mg/kg METH i.p. at 2-h intervals after one week of LC administration. LC treatment continued for one more week to groups III and IV. One week after METH administration, mice were sacrificed by decapitation, and striatum was dissected to measure the formation of 3-nitrotyrosine (3-NT) by HPLC/Coularry system. METH treatment produced significant formation of 3-NT, a marker of peroxynitrite generation, in mice striatum. The pre- and post-treatment of mice with LC significantly attenuated the production of 3-NT in the striatum resulting from METH treatment. The protective effects by the compound LC in this study could be related to the prevention of the possible metabolic compromise by METH and the resulting energy deficits that lead to the generation of reactive oxygen and nitrogen species. These data further confirm our hypothesis that METH-induced neurotoxicity is mediated by the production of peroxynitrite, and LC may reduce the peroxynitrite levels and protect against the underlying mechanism of METH toxicity, which are models for several neurodegenerative disorders like Parkinson's disease.
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PMID:The protective role of L-carnitine against neurotoxicity evoked by drug of abuse, methamphetamine, could be related to mitochondrial dysfunction. 1210 98

DOPA seems to be a neuromodulator in striata and hippocampal CA1 and a neurotransmitter of the primary baroreceptor afferents terminating in the nucleus tractus solitarii (NTS) and baroreflex pathways in the caudal ventrolateral medulla and rostral ventrolateral medulla in the brainstem of rats. DOPA recognition sites differ from dopamine (DA) D(1) and D(2) and ionotropic glutamate receptors. Via DOPA sites, DOPA stereoselectively releases by itself neuronal glutamate from in vitro and in vivo striata. In the cultured neurons, DOPA and DA cause neuron death via autoxidation. In addition, DOPA causes autoxidation-irrelevant neuron death via glutamate release. Furthermore, DOPA released by four-vessel occlusion seems to be an upstream causal factor for glutamate release and resultant delayed neuron death by brain ischemia in striata and hippocampal CA1. Glutamate has been regarded as a neurotransmitter of baroreflex pathways. Herein, we propose a new pathway that DOPA is a neurotransmitter of the primary aortic depressor nerve and glutamate is that of secondary neurons in neuronal microcircuits of depressor sites in the NTS. DOPA seems to release unmeasurable, but functioning, endogenous glutamate from the secondary neurons via DOPA sites. A common following pathway may be ionotropic glutamate receptors-nNOS activation-NO production-baroreflex neurotransmission and delayed neuron death. However, we are concerned that DOPA therapy may accelerate neuronal degeneration process especially at progressive stages of Parkinson's disease.
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PMID:DOPA causes glutamate release and delayed neuron death by brain ischemia in rats. 1220 Jan 94

Effects of neuronal nitric oxide synthase (nNOS) inhibitor (7-nitroindazole), nonselective NOS inhibitor (N(G)-nitro-L-arginine methyl ester; L-NAME), and monoamine oxidase inhibitor (pargyline) were studied on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. The mice received four intraperitoneal injections of MPTP at 1-h intervals. A significant depletion in dopamine and DOPAC concentration was observed in the striatum from 1 day after MPTP treatment. The pretreatment of 7-nitroindazole and pargyline, but not L-NAME, dose-dependently protected against MPTP-induced depletion in dopamine content 3 days after MPTP treatment. Our histochemical study also showed that 7-nitroindazole and pargyline can prevent a marked decrease in the nigral cells and a marked increase in astrocytes in striatum 7 days after MPTP treatment. The protective effect of 7-nitroindazole against MPTP-induced dopamine and DOPAC depletion in the striatum was not attenuated by intraperitoneal pretreatment with L-arginine. Furthermore, the posttreatment of 7-nitroindazole or pargyline protected against MPTP-induced depletion of dopamine content. These results demonstrate that the protective mechanism by which 7-nitroindazole counteracts MPTP neurotoxicity in mice may be due not only to inhibition of nNOS, but also to MAO-B inhibition. Furthermore, our study suggests that the posttreatment of 7-nitroindazole and pargyline can prevent a significant decrease in dopamine levels in the striatum of MPTP-treated mice. These findings have important implications for the therapeutic time window and choice of nNOS or MAO inhibitors in patients with Parkinson's disease.
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PMID:Therapeutic effect of neuronal nitric oxide synthase inhibitor (7-nitroindazole) against MPTP neurotoxicity in mice. 1232 87

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway injury similar to that observed in Parkinson's disease. Many hypotheses have been proposed to explain the mechanisms underlying MPTP neurotoxicity. Previous work showed that the inhibitor of neuronal nitric oxide synthase (nNOS) might produce protection against MPTP-induced dopaminergic toxicity. To exactly test the role of NO in MPTP neurotoxicity, we examined the effect of nNOS inhibitor 7-nitroindazole, in comparison with that of nonselective NOS inhibitor (L-NAME), immunosuppressant (FK-506), monoamine oxidase (MAO) inhibitors (clorgyline and pargyline), N-methyl-D-aspartate receptor antagonist (MK-801) and Ca2+ antagonist (amlodipine). Among seven compounds, 7-nitroindazole produced dose-dependent protection against MPTP-induced depletion of striatal dopamine and its metabolite 3,4-dihydroxyphenyl acetic acid (DOPAC) in mice. Clorgyline and pargyline also showed a significant effect on MPTP-induced dopamine depletion in the mouse striatum. However, both compounds did not protect against MPTP-induced depletion of striatal DOPAC Our immunohistological study with tyrosine hydroxylase (TH) and microtuble-associated protein 2 (MAP 2) showed that 7-nitroindazole or pargyline can protect against MPTP-induced depletion of TH and MAP 2 immunostained neurons in the substantia nigra. Furthermore, these compounds reduced a marked increase in GFAP-positive astrocytes of the mouse striatum after MPTP treatments. The present study demonstrates that nNOS inhibitor 7-nitroindazole as well as MAO inhibitors clorgyline and pargyline can produce dose-dependent neuroprotection against the dopaminergic neurotoxicity of MPTP. However, nonselective NOS inhibitor L-NAME, immunosuppressant FK-506, NMDA receptor antagonist MK-801 and Ca2+ antagonist amlodipine did not show a beneficial effect on MPTP neurotoxicity.
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PMID:Role of nitric oxide synthase against MPTP neurotoxicity in mice. 1239 1

Experimental intoxication models are used to study the more common sporadic form of Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) animal models of PD provide a valuable and predictive tool to probe the molecular mechanisms of dopamine neuronal cell death in PD. MPTP is a powerful neurotoxin that induces neuronal degeneration in the substantia nigra pars compacta and produces PD-like symptoms in several mammalian species tested, a feat not yet accomplished in genetically engineered mice expressing human genetic mutations. The mechanisms of MPTP-induced neurotoxicity are not yet fully understood but involve activation of N-methyl-D-aspartate (NMDA) receptors by glutamate, production of NO by nNOS and iNOS, oxidative injury to DNA, and activation of the DNA damage-sensing enzyme poly (ADP-ribose) polymerase (PARP). Recent experiments indicate that translocation of a mitochondrial protein apoptosis inducing factor (AIF) from mitochondria to the nucleus depends on PARP activation and plays an important role in excitotoxicity-induced cell death. This article briefly reviews the experimental findings regarding excitotoxicity, PARP activation, and AIF translocation in MPTP toxicity and dopaminergic neuronal cell death.
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PMID:Apoptosis inducing factor and PARP-mediated injury in the MPTP mouse model of Parkinson's disease. 1284 82

Parkinson's disease is a neurodegenerative disorder of unknown pathogenesis. Oxidative stress has been proposed as one of several pathogenic hypotheses. Evidence for the participation of oxidative processes in the pathogenesis of Parkinson's disease have been obtained in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model by the use of genetically altered mice. MPTP administration has been shown to increase levels of superoxide both intracellularly, via the inhibition of mitochondrial respiration and other mechanisms and extracellularly, via the activation of NADPH-oxidase in microglia. In addition to superoxide, nitric oxide production by nNOS or by microglial iNOS also contributes to the MPTP neurotoxocity. Mice with endowed defences against superoxide or with deficiency in the nNOS and iNOS are protected from MPTP toxicity suggesting that formation of reactive oxygen and nitrogen intermediates both intracellularly and extracellularly contributes to the demise of dopaminergic neurons. Similar contribution of reactive nitrogen and oxygen species may well underlie the neurodegenerative processes in Parkinson's disease.
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PMID:Nitric oxide and reactive oxygen species in Parkinson's disease. 1293 35

We recently reported that neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole, can protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. It protected against both dopamine depletions and tyrosine hydroxylase (TH) positive neuron decreases in the mouse brain. In the present study, we further examined whether 7-nitroindazole can also protect against the alterations of TH-, microtubule-associated protein 2a,b (MAP2)-, glial fibrillary acidic protein (GFAP)-, parvalbumin (PV)-, dopamine transporter (DAT)-, nNOS- or endothelial NOS (eNOS)-positive cells, in comparison with pargyline as a relatively selective inhibitor of the monoamine oxidase-B (MAO-B). The present study showed that nNOS inhibitor as well as MAO-B inhibitor has a dose-dependent protective effect against MPTP-induced striatal dopamine and DOPAC depletion in mice. Furthermore, the present study revealed that 7-nitroindazole and pargyline can protect the alterations of immunohistochemical changes in the striatum and substantia nigra after MPTP treatment. These protective effects may be, at least in part, produced by the reduction of neuronally derived NO and peroxynitrite caused by MPTP. Our results also demonstrate that MPTP can cause functional damage of interneurons in the substantia nigra. These results suggest the possibility that nNOS inhibitors as well as MAO-B inhibitors may be therapeutically useful in neurodegenerative diseases such as Parkinson's disease. Thus our present results provide valuable information for the pathogenesis of degeneration of the nigrostriatal dopaminergic neuronal pathway.
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PMID:Protective effects of neuronal nitric oxide synthase inhibitor in mouse brain against MPTP neurotoxicity: an immunohistological study. 1501 24


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