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)

The substantia nigra (SN) receives afferents from cholinergic neurons of the pedunculopontine tegmental nucleus (PPTg), a neuronal population that shows high levels of nitric oxide synthase (NOS), the enzyme responsible for the synthesis of nitric oxide. We have investigated the effects of the injection in PPTg of two neurotoxins, kainic acid (an excitotoxic neurotoxin), and ethylcholine mustard azirinium ion (AF64A, a non-excitotoxic neurotoxin), upon the SN cells of the rat, by using choline acetyltransferase (ChAT) immunohistochemistry as a marker of cholinergic neurons, and nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry and NOS immunohistochemistry as markers of nitric oxide-producing neurons. Our results show that in normal rats, the SN contains two populations of NOS-positive neurons: large cholinergic neurons of PPTg that invade the caudal region of the SN, and small elongated neurons lying in the SN pars compacta. After ipsilateral PPTg lesion, another population of nigral cells, constituted by medium sized neurons, became NADPHd/NOS-positive. This was much more evident in AF64A-injected rats, in which many medium sized neurons showed enzymatic activity and normal morphological features, at least during the 90 days after injection. Kainic acid-injected rats, in contrast, showed nigral cell degeneration, an effect not found in AF64A material, and only a few NOS-positive neurons. NADPHd/NOS activity was never present in degenerating neurons. These findings suggest that induction of NOS activity is not involved in nigral cell degeneration, and that nitric oxide could have a protective rather than a neurotoxic role. The possible role of nitric oxide in the pathogenesis of Parkinson's disease is discussed.
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PMID:NOS expression in nigral cells after excitotoxic and non-excitotoxic lesion of the pedunculopontine tegmental nucleus. 951 71

The objective of the present study was to investigate the potential role of the free radical nitric oxide (NO) in the development of fetal rat mesencephalic neurons grafted in a 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease. First, using nitric oxide synthase (NOS)-immunocytochemistry and reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry, we investigated the presence of the neuronal isoform of NOS (nNOS) in intrastriatal mesencephalic grafts. During the course of the experiment (16 weeks) an increase in the staining intensity and the number of nNOS/NADPH-d positive cells within the grafts was observed, as well as a gradual maturation of dopaminergic neurons. In addition, within both the host striatal and grafted mesencephalic tissue, a NO-dependent accumulation of cyclic guanosine monophosphate (cGMP) was detected, indicating the presence of guanylate cyclase, i.e., the target-enzyme for NO. Secondly, to determine the impact of NO on the survival of grafted dopaminergic neurons, 6-OHDA lesioned rats received mesencephalic grafts and were subsequently treated with the competitive NOS-inhibitor Nomega-nitro-l-arginine methylester (l-NAME). After chronic treatment for 4 weeks, tyrosine hydroxylase immunocytochemistry revealed no apparent differences between the survival of grafted dopaminergic neurons in control- or l-NAME treated animals, respectively. As the maturation of grafted dopaminergic neurons coincides with a gradual increase in the expression of nNOS within the graft and since dopaminergic cell numbers are not changed upon administration of l-NAME, it is concluded that endogenously produced and potentially toxic NO does not affect the survival of grafted fetal dopaminergic neurons.
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PMID:Sustained pharmacological inhibition of nitric oxide synthase does not affect the survival of intrastriatal rat fetal mesencephalic transplants. 959 18

Most Parkinson's disease (PD) treatments palliate symptoms by increasing nigrostriatal dopaminergic tone. A unique strategy for accomplishing this pharmacological end-point proposes using reduced nicotinamide adenine dinucleotide (NADH) to boost endogenous dopamine production, since NADH indirectly supplies reducing equivalents to the rate-limiting, tyrosine hydroxylase-catalysed step of dopamine synthesis. Support for using NADH in PD treatment includes claims that NADH stimulates tyrosine hydroxylase and dopamine biosynthesis in tissue culture and humans, as well as case series associating intravenous and oral NADH administration with PD rating scale improvements. Theoretical and practical arguments against NADH include underlying NADH disposal impairment in PD and failure of a placebo-controlled trial to show any clear benefit. While NADH may yet prove to ameliorate parkinsonism, recommendations for its use in PD are premature.
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PMID:Is NADH effective in the treatment of Parkinson's disease? 980 7

Poly(ADP-ribose) polymerase (PARP) is a DNA binding protein that uses nicotinamide adenine dinucleotide (NAD+) as a substrate. Evidence from in vitro studies on nonneuronal cells in culture have shown that when fully activated by free radical-induced DNA damage, PARP depletes cellular NAD+ and consequently adenosine triphosphate (ATP) levels within a matter of minutes, and that this depletion is associated with a cell death that can be prevented by PARP inhibitors. The present in vivo study utilized the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse, a model of central nigrostriatal dopamine neurotoxicity that recapitulates certain features of Parkinson's disease (PD), and one in which we have previously shown PARP inhibitors to be protective, to examine whether MPTP acutely caused region- and time-dependent changes in levels of NAD+ and ATP in the brain in vivo and whether such effects were modified by treatments with neuroprotective doses of the PARP inhibitor benzamide. The results confirm that MPTP reduces striatal ATP levels, as previously reported by Chan et al., show that MPTP causes a regionally-selective (striatal and midbrain) loss of NAD+, and indicate that the PARP inhibitor benzamide can prevent these losses without interfering with MPTP-induced striatal dopamine release. These findings suggest an involvement of PARP in the control of brain energy metabolism during neurotoxic insult, provide further evidence in support of the participation of PARP in MPTP-induced neurotoxicity in vivo and suggest that PARP inhibitors might be beneficial in the treatment of PD.
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PMID:Implication of poly (ADP-ribose) polymerase (PARP) in neurodegeneration and brain energy metabolism. Decreases in mouse brain NAD+ and ATP caused by MPTP are prevented by the PARP inhibitor benzamide. 1066 29

The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) leads to the hypothesis that Parkinson's disease (PD) is may be initiated or precipitated by endogenous toxins by the mechanism similar to that of MPTP in genetically-predisposed individuals. The higher cerebrospinal fluid levels of N-methylated azaheterocyclic amines, such as beta-carboline and tetrahydroisoquinoline, have been found in parkinsonian patients compared with age-matched controls. To estimate the N-methylation ability for azaheterocyclic amines in parkinsonian patient, nicotinamide was dosed with 100 mg to 26 parkinsonians and 20 controls consisted of 16 other neurogenic disease patients and 4 healthy volunteers. The urine was collected for 4 h, and then analyzed urinary its metabolites by an improved HPLC method. Nicotinamide has a pyridine ring in its structure and may be metabolized through the pathways similar to those for the endogenous neurotoxins. The urinary excretions of nicotinamide metabolites were significantly affected by aging. The excretion of N1-methylnicotinamide decreased along with aging both in PD patients and controls. In younger (65 years old or younger) PD patients, the excretion amount of N1-methylnicotinamide was significantly higher than that in younger controls. The decline rate of N1-methylnicotinamide excretion in parkinsonians was significantly greater than that in controls; the rate is more than 2-fold higher in parkinsonian patients. The age-associated decrease in 1-methyl-2-pyridone-5-carboxyamide excretion was observed only in parkinsonian patients, but not in controls. The total excreted amount of N-methylated metabolites (N1-methylnicotinamide plus 1-methyl-2-pyridone-5-carboxyamide) was also observed the age-related decline in both groups. The urinary excretions of nicotinamide and nicotinamide-N-oxide were not influenced by aging. These results would indicate that the excess N-methylation ability for azaheterocyclic amines before the onset had been implicated in PD. On the other hand, the present results suggested that the contribution of aberrant cytochrome P450 or aldehyde oxidase activity acting on the pyridine ring, that could act as detoxification routes of endogenous neurotoxins, would be small in the etiology of PD.
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PMID:N-methylation ability for azaheterocyclic amines is higher in Parkinson's disease: nicotinamide loading test. 1104 Dec 77

Altropane, 2beta-carbomethoxy-3beta-(4-fluorophenyl)-N-(3-iodo-E-allyl)nor tropane, is an imaging agent that was developed recently for early detection of Parkinson's disease. Its promise as a useful radiopharmaceutical for single-photon emission computed tomography or positron emission tomography imaging of the brain has been well demonstrated, and it is currently undergoing clinical trials. This paper presents methods development and validation of capillary electrophoresis (CE) techniques to analyze Altropane in aqueous environments as well as in rat plasma, using an internal standard, nicotinamide. N-Allylaltropane, 2beta-carbomethoxy-3beta-(4-fluorophenyl)-N-allylnortropane, which is a known degradation product of the Altropane precursor (tributyltinaltropane), was used to verify the method's specificity. A solid-phase extraction method for extraction of Altropane from rat plasma is also described. The results presented in this paper demonstrate the applicability of CE methods to study the pharmacokinetic properties of Altropane in animal models. The results of the pharmacokinetic study will be published later, as Part II.
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PMID:Analysis of 2beta-carbomethoxy-3beta-(4-fluorophenyl)-N-(3-iodo-E-allyl)nortropane in rat plasma. I. Method development and validation by capillary electrophoresis. 1110 51

Parkinson's disease (PD) may be initiated or precipitated by endogenous toxins with a structure similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in genetically-predisposed individuals. Nicotinamide N-methyltransferase (NNMT) catalyzes N-methylation of nicotinamide and other pyridines to form pyridinium ions. The protein amount of NNMT was measured in the lumbar cerebrospinal fluid of PD patients by immunoblot analysis using anti-human NNMT antibody. In younger (65 years old or younger) PD patients, the relative level of NNMT protein was significantly higher than that in younger controls. The NNMT protein was significantly affected by aging: the amount decreased along with aging in PD patients. These findings suggested that excess NNMT in the central nervous system might be implicated in the PD pathogenesis.
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PMID:Nicotinamide-N-methyltransferase is higher in the lumbar cerebrospinal fluid of patients with Parkinson's disease. 1115 40

The purpose of this study is to present a hypothesis to explain the aetiology of bovine spongiform encephalopathy (BSE) which is more credible than any at present available, and to increase its credibility by varying the hypothesis to supply explanations for Alzheimer's disease, Parkinson's disease and certain other conditions. The method used has been to utilize material from biochemical textbooks and similar sources. It has been concluded that BSE is caused by the failure to synthesize sufficient cyclic guanosine monophosphate (cGMP), with the result that neurons die because they are no longer able to prevent the entry of toxic quantities of calcium ions into their cytoplasm. Several causes for the failure to synthesize sufficient cGMP have been identified; these involve selenium and folate deficiencies, and problems with the availability of nicotinamide adenosine dinucleotide (NAD). It is proposed that BSE is initiated by a combination of selenium deficiency and the destruction of NAD by a bacterial toxin of the same type as causes cholera, that folate deficiency is the predominant cause of Alzheimer's disease, and that the failure to synthesize sufficient tetrahydrobiopterin and cGMP from guanosine triphosphate results in Parkinson's disease.
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PMID:A biochemical theory to explain the cause of bovine spongiform encephalopathy and other encephalopathies. 1139 7

Poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) is known as a nuclear enzyme that is activated by DNA strand breaks to participate in DNA repair. It is also called poly(ADP-ribose) synthase (PARS) or poly(ADP-ribose) transferase (PADRT). In physiological conditions, PARP plays an important role in maintaining genomic stability. However, for several pathological situations, which include massive DNA injury (brain ischemia for example), excessive activation of PARP can deplete stores of nicotinamide adenine dinucleotide (NAD+), the PARP substrate, which, with the subsequent ATP depletion, leads to cell death. PARP activation appears to play a major role in neuronal death induced by cerebral ischemia, traumatic brain injury, Parkinson disease and other pathologies. PARP inhibitors (3-aminobenzamide and other compounds) and PARP gene deletion induced dramatic neuroprotection in experimental animals (rats, mice). Accordingly, these data suggest that PARP inhibitors could provide a novel therapeutic approach in a wide range of neurodegenerative disorders including cerebral ischemia and traumatic brain injury.
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PMID:[Neuronal death: potential role of the nuclear enzyme, poly (ADP-ribose) polymerase]. 1150 Dec 63

This study tested the hypothesis, that nicotinamide N-methyltransferase (NAMT) activity in the brain could convert nicotinamide to 1-methylnicotinamide (MNA) and by that means damage the nigro-neostriatal dopaminergic neurons. The NAMT activities of rat brain and liver were assayed with gas chromatographic-mass spectrometric analysis in a selected ion monitoring system. They amounted to 0.30 nmol/mg x h and 0.51 nmol/mg x h, respectively. The MNA injection in rat substantia nigra pars compacta significantly decreased dopamine content in the striatum. NADH oxidation and lipid peroxidation by MNA via rat brain submitochondrial particles (SMP) under the condition of pH ranging from pH 6.0 to 10.0 were verified. The pH optimum for the NADH oxidation was 9.0. The pH optimum for the peroxidation of the lipid composing SMP by MNA was also 9.0. The lipid peroxidation in this assay was suppressed by superoxide dismutase. The superoxide anion formed by MNA via mitochondria might be involved in the etiology of Parkinson's disease.
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PMID:Possible role of 1-methylnicotinamide in the pathogenesis of Parkinson's disease. 1192 89


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