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)

6R-L-erythro-5, 6, 7, 8-Tetrahydrobiopterin (6R-BH4) is known as a cofactor for the hydroxylases of phenylalanine, tyrosine and tryptophan and also as a cofactor for nitric oxide synthase. Recently, a novel function of 6R-BH4 has been found: that is, 6R-BH4 acts on specific membrane receptors to directly stimulate the release of monamine neurotransmitters such as dopamine and serotonin, independently of its cofactor activity. In addition, it indirectly stimulates the release of non-monoamine neurotransmitters such as acetylcholine and glutamate, through activation of monoaminergic systems. In this paper, we briefly review recent experimental data, which provide new insights into the role of 6R-BH4 as a regulator of neuronal function. We also discuss the possibility of treatment by 6R-BH4 of neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, depression and infantile autism.
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PMID:[A novel function of tetrahydrobiopterin]. 136 Nov 76

Recent evidence suggests that an excitotoxic mechanism may play a role in the etiology of Parkinson's disease. Previously, we have shown that the nigrostriatal dopaminergic neurons are sensitive to focal infusions of an N-methyl-D-aspartate (NMDA) receptor agonist; this toxicity was potentiated by systemic administration of the nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine methyl ester. The present investigation was undertaken to assess the role of the selective neuronal NOS inhibitor, 7-nitro indazole (7-NI) on the neurotoxicity elicited by NMDA receptor activation in vivo. Single injections of 7-NI (0-125 mg/kg, i.p.) into male Sprague-Dawley rats resulted in a dose-dependent decrease in both nigral and cerebellar NOS activity measured 30 min post-injection. Maximal NOS inhibition was obtained with 20 mg/kg 7-NI (nigra: 90.2 +/- 3.7%, cerebellum: 86.7 +/- 6.3%). In addition, it was found that 7-NI (80 mg/kg, i.p.) did not cause an increase in mean arterial blood pressure over a 48 hr period. Vehicle pretreatment of animals prior to stereotaxic infusion of NMDA (15 nmol) into the substantia nigra compacta resulted in a 56.1 +/- 5.1% decrease in striatal tyrosine hydroxylase (TH) activity from the contralateral side. Pretreatment with 7-NI (5 and 80 mg/kg) produced a 76.9 +/- 3.2% and 49.8 +/- 5.6% decrease, respectively, in striatal TH activity. Thus, a significant increase in NMDA toxicity was observed at the lower but not higher dose of 7-NI. It was also observed that 7-NI (20 and 80 mg/kg) produced a decrease in locomotor activity over a 2 hr period.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potentiation of NMDA-mediated toxicity on nigrostriatal neurons by a low dose of 7-nitro indazole. 753 27

N-Methyl, 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces experimental parkinsonism after oxidation to N-methylpyridinium ion (MPP+), accumulation in dopamine neurons and concentration in mitochondria. Inhibition by MPP+ of mitochondrial electron transport impairs respiratory function, but the molecular mechanisms of cell death are not clear. We tested the hypothesis that locally produced nitric oxide is a key component in MPTP toxicity by providing a necessary intermediate in the production of hydroxyl free radicals. Inhibition of nitric oxide synthase reduced MPP(+)-induced hydroxyl radical formation in striatum and MPTP toxicity to nigrostriatal dopamine terminals, but did not interfere with inhibition of complex-I activity. Nitric oxide appears to be necessary for hydroxyl free radical generation in MPP+ toxicity and may play a role in neuronal degeneration in Parkinson's disease.
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PMID:Reduction of MPP(+)-induced hydroxyl radical formation and nigrostriatal MPTP toxicity by inhibiting nitric oxide synthase. 753 21

Nitric oxide (NO) is thought to be involved in neurodegenerative processes. Concerning Parkinson's disease (PD) it remains to be elucidated, if NO contributes to pathological alterations in the striatum. The present study evaluates the post-mortem putamen of PD patients and control subjects for distribution patterns of NO-synthase containing neurons, using the NADPH-diaphorase technique. The ratio of positively stained neurons and the total number of cells (control: 1,120 +/- 69 per mm2, n = 5; PD: 575 +/- 164mm2, n = 5) shows striking differences between controls and PD patients. Our findings give reason to conclude that NADPH-diaphorase positive structures may have pathogenetic importance in degenerative processes in PD putamen.
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PMID:NADPH-diaphorase/nitric oxide synthase containing neurons in normal and Parkinson's disease putamen. 753 4

Nitric oxide (NO) is a recently discovered endogenous mediator of vasodilatation, neurotransmission, and macrophage cytotoxicity. NO is thought to have a function in memory and in long-term potentiation. At high concentrations NO is neurotoxic and may play a role in neurodegeneration. NO is formed from L-arginine by the enzyme NO synthase (NOS), for which tetrahydrobiopterin (BH4) is a necessary co-factor. Alzheimer's disease (AD) and, to a lesser degree, Parkinson's disease (PD) are thought to be associated with increased microglial activity, suggesting that NO production may be increased. Alternatively, in circumstances of reduced levels of intracellular L-arginine or BH4, NO production is diminished and neurotoxic oxygen radicals may be produced. Since BH4 is decreased in AD and PD brains, these diseases may be associated with decreased NO production. We investigated these two alternatives by measuring the NO degradation products nitrite and nitrate in cerebrospinal fluid (CSF) of PD (n = 103), AD (n = 13), and multiple system atrophy (MSA; n = 14) patients and controls (n = 20). We found for all patient groups, compared with controls, significantly decreased levels of nitrate, but not nitrite. This finding seems to indicate a decreased NO production of the central nervous system (CNS) in these neurodegenerative disorders.
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PMID:Decreased cerebrospinal fluid nitrate levels in Parkinson's disease, Alzheimer's disease and multiple system atrophy patients. 813 11

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway damage similar to that observed in Parkinson disease (PD). To study the role of NO radical in MPTP-induced neurotoxicity, we injected MPTP into mice in which nitric oxide synthase (NOS) was inhibited by 7-nitroindazole (7-NI) in a time- and dose-dependent fashion. 7-NI dramatically protected MPTP-injected mice against indices of severe injury to the nigrostriatal dopaminergic pathway, including reduction in striatal dopamine contents, decreases in numbers of nigral tyrosine hydroxylase-positive neurons, and numerous silver-stained degenerating nigral neurons. The resistance of 7-NI-injected mice to MPTP is not due to alterations in striatal pharmacokinetics or content of 1-methyl-4-phenylpyridinium ion (MPP+), the active metabolite of MPTP. To study specifically the role of neuronal NOS (nNOS), MPTP was administered to mutant mice lacking the nNOS gene. Mutant mice are significantly more resistant to MPTP-induced neurotoxicity compared with wild-type littermates. These results indicate that neuronally derived NO mediates, in part, MPTP-induced neurotoxicity. The similarity between the MPTP model and PD raises the possibility that NO may play a significant role in the etiology of PD.
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PMID:Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. 864 44

Parkinson's disease is characterized by dopaminergic neuronal degeneration, but its pathogenic mechanism is still unknown. In the dopaminergic neurons, oxygen radicals such as hydrogen peroxide are released through dopamine oxidation. Many factors are involved in radical formation, but glutamate and nitric oxide (NO) are the major effectors of the radical-induced neurotoxicity mediated primarily through calcium influx. In the cultured embryonic rat mesencephalon, we investigated the dopaminergic and non-dopaminergic neuronal death induced by glutamate and by NO-generating agents. Although glutamate had a neurotoxic effect on both dopaminergic and non-dopaminergic neurons, it showed slightly greater effect in the dopaminergic neurons. In contrast to glutamate, NO-generating agents (S-nitrosocysteine and sodium nitroprusside) showed neurotoxic effects restricted exclusively to non-dopaminergic neurons. Although N omega-nitro-L-arginine, and NO synthase inhibitor, had no significant effect on the glutamate-induced cytotoxicity in dopaminergic neurons, it had a significant antagonistic effect on that in non-dopaminergic neurons. These findings indicate the presence of two different mechanisms of glutamate-induced neuronal death, one being neurotoxicity not mediated by NO, found in dopaminergic neurons, and the other being that mediated via NO, found in non-dopaminergic neurons.
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PMID:Different mechanisms of glutamate-induced neuronal death between dopaminergic and non-dopaminergic neurons in rat mesencephalic culture. 869 37

Parkinson's disease is characterized by a loss of dopaminergic neurons in the mesencephalon. Although the mechanism of this neuronal loss is still unknown, oxidative stress is very likely involved in the cascade of events leading to nerve cell death. Since nitric oxide could be involved in the production of free radicals, we analysed, using immunohistochemistry and histochemistry, the production systems of nitric oxide in the mesencephalon of four patients with idiopathic Parkinson's disease and three matched control subjects. Using specific antibodies directed against the inducible isoform of nitric oxide synthase (the enzyme involved in the synthesis of nitric oxide), we found evidence to suggest that this isoform was present solely in glial cells displaying the morphological characteristics of activated macrophages. Immunohistochemical analysis performed with antibodies against the neuronal isoform of nitric oxide synthase, however, revealed perikarya and processes of neurons but no glial cell staining. The number of nitric oxide synthase-containing cells was investigated by histoenzymology, using the NADPH-diaphorase activity of nitric oxide synthase. Histochemistry revealed (i) a significant increase in NADPH-diaphorase-positive glial cell density in the dopaminergic cell groups characterized by neuronal loss in Parkinson's disease and (ii) a neuronal loss in Parkinson's disease that was two-fold greater for pigmented NADPH-diaphorase-negative neurons than for pigmented NADPH-diaphorase-positive neurons. These data suggest a potentially deleterious role of glial cells producing excessive levels of nitric oxide in Parkinson's disease, which may be neurotoxic for a subpopulation of dopaminergic neurons, especially those not expressing NADPH-diaphorase activity. However, it cannot be excluded that the presence of glial cells expressing nitric oxide synthase in the substantia nigra of patients with Parkinson's disease represents a consequence of dopaminergic neuronal loss.
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PMID:Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. 873 6

Several diseases related to brain aging seem to be due to neuronal loss and decreased synaptic functions. Therefore it is important to clarify the cellular and molecular mechanism of age-related-neuronal death and -reduction in synaptic activities in the brain. I here review recent advances in cellular and molecular studies on neuronal death and the decrease in synaptic functions. Neuronal death is caused not only with physiological aging but also by several pathological states such as 1) results from abnormal metabolism of beta APP (Alzheimer's disease), 2) increased level of extraneuronal glutamate and intracellular Ca2+/NO (cerebral ischemia), and 3) appearance of neurotoxic MPP+ (1-methyl-4-phenyl-pyridinium ion) (Parkinson's disease) etc. From neurotoxicological aspect of neuro-glial interaction, I introduce recent findings on signaling pathways of NO synthase induction in glial cells and cytotoxic action of NO in neurons. Furthermore I also describe and discuss our findings obtained in the brain of old rats as well as in senescence accelerated mice (accelerated aging substrain of AKR/J-mouse) regarding age-related changes in synaptic activity and neurotransmittor receptor-mediated signaling system.
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PMID:[Neurochemical aspect of brain aging--neuronal death and decreased synaptic functions]. 875 25

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7-Nitroindazole (7-NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS) that blocks MPTP neurotoxicity in mice. We now show that 7-NI protects against profound striatal dopamine depletions and loss of tyrosine hydroxylase-positive neurons in the substantia nigra in MPTP-treated baboons. Furthermore, 7-NI protected against MPTP-induced motor and frontal-type cognitive deficits. These results strongly implicate a role of nitric oxide in MPTP neurotoxicity and suggest that inhibitors of neuronal NOS might be useful in treating Parkinson's disease.
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PMID:Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. 878 45


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