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)

Fourteen di- and tripeptide analogues of MIF, Pro-Leu-Gly-NH2, have been synthesized and assayed for inhibition of oxotremorine-induced tremor. Replacement of Pro by HCO-Pro or cyclopentanecarboxylic acid gave inactive analogues, while some peptides of the general structure less than Glu-Leu-Gly-NR1R2 were highly active. Thus, R1 = C3H8 and R2 = H gave 4 times the activity of MIF, R1 = I-C3H8 and R2 = H gave 13 times the activity of MIF, and R1 = R2 = CH3 gave 29 times the activity of MIF. cyclo(-Pro-Leu-), Pro-Lys-Gly-NH2, and Pro-Arg-Gly-NH2 had no activity. Apparently, small modifications in the structure of MIF can yield highly active analogues with potential clinical value, e.g., in the treatment of Parkinson's disease or mental depression.
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PMID:Tripeptide analogues of melanocyte-stimulating hormone release-inhibiting hormone (Pro-Leu-Gly-NH2) as inhibitors of oxotremorine-induced tremor. 4 28

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

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

The concentration of nitrite, a metabolite of nitric oxide (NO), was increased in the cerebrospinal fluid (CSF) of untreated patients with Parkinson's disease and in patients treated with L-DOPA in comparison with a group of patients without dopaminergic dysfunction. There was no difference in the concentration of L-arginine (ARG), a precursor of NO, between the groups. There was a highly significant, linear relationship between the concentration of nitrite and ARG in the CSF suggesting that the production of NO is dependent on the availability of ARG. The results support the possibility that production of NO is increased in the brain in Parkinson's disease.
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PMID:Increased cerebrospinal fluid concentration of nitrite in Parkinson's disease. 852 32

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

The present behavioral study was undertaken to investigate whether neuronal nitric oxide (NO) synthase mediates the abnormal consequences of increased NMDA receptor-mediated synaptic transmission in models of postural tremor, Parkinson's disease and epilepsy. We used 7-nitroindazole, a selective inhibitor of neuronal NO synthase, and NG-nitro-L-arginine (L-NAME), an unspecific NO synthase inhibitor, and compared their action with that of the competitive NMDA receptor antagonist 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid (D-CPPene). In both mice and rats, 7-nitroindazole, L-NAME and D-CPPene dose dependently reversed the harmaline-induced increase of cerebellar cyclic guanosine-5'-monophosphate (cGMP) levels. For subsequent behavioral experiments we used doses of 7-nitroindazole, L-NAME and D-CPPene which were equipotent in preventing harmaline-induced cGMP increase. Harmaline-induced tremor in mice and rats was suppressed by D-CPPene, but not by 7-nitroindazole or by L-NAME. This effect of D-CPPene was not due to unspecific suppression of motor activity, since D-CPPene did not affect locomotor activity at doses which reduced tremor. D-CPPene, but not 7-nitroindazole and L-NAME potentiated the antiparkinsonian action of the dopamine agonist lisuride in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. D-CPPene antagonized seizures induced by intracerebroventricular injection of NMDA in mice. In contrast, 7-nitroindazole and L-NAME had only a tendency to prevent seizures and to delay the latency to onset of seizures. We conclude from these results that neuronal NO synthase does not serve as a major mediator of increased NMDA receptor-mediated synaptic transmission in animal models of Parkinson's disease, postural tremor and epilepsy. The novel observation that D-CPPene suppresses harmaline-induced tremor leads us to suggest that NMDA receptor antagonists should be considered as novel therapeutics for postural tremor.
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PMID:Effects of 7-nitroindazole, NG-nitro-L-arginine, and D-CPPene on harmaline-induced postural tremor, N-methyl-D-aspartate-induced seizures, and lisuride-induced rotations in rats with nigral 6-hydroxydopamine lesions. 890 Oct 1

We studied regional cerebral blood flow (rCBF) in 8 patients with non-demented Parkinson's disease (PD). 1 patient with progressive supranuclear palsy (PSP), 1 patient with multiple system atrophy (MSA), and 7 normal control subjects using single photon emission computed tomography (SPECT) with the IMP-ARG method. Regions of interest were studied in the cerebral cortex (upper frontal, lower frontal, temporal, occipital, parietal), thalamus, basal ganglia, and cerebellum. In patients with PD, rCBF was normal in 4/8, and decreased in occipital lobe in 4/8. In patient with PSP, rCBF was decreased in the upper and lower frontal lobes, and in the cerebellum. In patient with MSA, rCBF was diminished in the cerebellum. The results of our study were almost compatible with the conventional rCBF study by positron emission tomography (PET), however, the decrease of rCBF in occipital lobe had rarely been reported, suggesting that might be related to visuospatial dysfunction in Parkinson's disease.
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PMID:[Analysis of Parkinson's disease and related syndromes using 123I-IMP-SPECT with the ARG method]. 901 57

Microglial activation selectively kills certain neuron populations in mixed neuronal/glial cultures, which may prove useful for modeling neurodegenerative diseases such as Parkinson's disease. In mesencephalic mixed neuronal/glial cultures, microglial activation by zymosan A killed more dopaminergic neurons, assessed by [3H]dopamine uptake and by counting tyrosine hydroxylase-immunoreactive neuron number, than did microglial activation by lipopolysaccharide (LPS). The additional toxicity of zymosan resulted from microglial protein kinase C (PKC) activation. Both zymosan and PMA, but not LPS, activated PKC in enriched microglial preparations. In the mixed neuronal/glial cultures, activation of PKC by phorbol myristate acetate (PMA) increased LPS-induced nitric oxide (NO; by nitrite measurements), but not zymosan-induced NO production, and increased LPS-induced dopaminergic neurotoxicity, but not zymosan-induced dopaminergic neurotoxicity. Additive effects of PMA and LPS, similar to zymosan effects alone, reflected activation of distinct neurotoxic pathways in the microglia. The NO synthase inhibitor N-nitro-L-arginine methyl ester (NAME) totally blocked the neurotoxicity of LPS, and partially blocked zymosan-induced neurotoxicity; NAME did not block the PKC component of neurotoxicity. In addition to stimulating NO production as effectively as LPS, zymosan also activates microglial PKC and associated non-NO-mediated neurotoxic pathways that may be important in human neurodegenerative diseases. Since the role of NO in human microglia-induced neurotoxicity is controversial, zymosan may prove more useful than LPS as a microglial activator in the rodent mixed neuronal/glial culture model.
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PMID:Role of protein kinase C in microglia-induced neurotoxicity in mesencephalic cultures. 905 44

In order to gain a better insight in the serotonergic disorder affecting the parkinsonian brain, the growth hormone (GH) response to the 5-HT 1 serotonergic receptor agonist sumatriptan was tested. Sumatriptan was injected subcutaneously in 10 de novo parkinsonian patients (aged 58-69 years) and in 9 age-matched normal controls. On different occasions, subjects were also tested with GH-releasing hormone (GH-RH; 1 micrograms/kg body weight in an intravenous bolus) and L-arginine (30 g in 50 ml normal saline over 30 min), which releases GH from somatostatin inhibition, to determine whether GH secretion in response to alternate secretagogues is preserved in Parkinson's disease. In addition, a control test with the administration of normal saline instead of drug treatments was performed. Plasma GH levels were recorded over 2 h in all tests. Placebo administration did not change plasma GH levels in any subject. Similar GH responses were observed in normal controls and parkinsonian patients when GH-RH or arginine were administered. A significant GH increase was observed in normal controls after sumatriptan injection; in contrast, GH secretion was not modified by sumatriptan administration in parkinsonian patients. These data show that Parkinson's disease is associated with an impairment in the 5-HT1-receptor-mediated serotonergic transmission in the control of GH secretion, suggesting that this specific defect might alter other serotonergic-mediated mechanisms in the parkinsonian brain.
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PMID:Defective 5-HT 1-receptor-mediated neurotransmission in the control of growth hormone secretion in Parkinson's disease. 909 98

We measured the CSF levels of 21, and the plasma levels of 26, amino acids in 31 patients with Parkinson's disease (PD) and in 45 matched controls. We used an ion-exchange chromatography method. When compared to controls, PD patients had lower CSF levels of taurine, alanine, valine, leucine, isoleucine, ethanolamine, citrulline, ornithine, lysine, histidine, arginine, and alpha-aminobutyric acid. PD patients not treated with levodopa or with dopamine agonists had higher CSF tyrosine and phenylalanine levels than those not treated with these drugs and also than controls. PD patients had higher plasma levels of phosphoserine, threonine, methionine, tyrosine, sarcosine and alpha-aminoadipic acid, and lower plasma levels of valine, leucine, and tryptophan, than controls. The CSF/plasma ratio of many of these amino acids was significantly lower in PD patients than those of controls, suggesting that PD patients might have a dysfunction in the transport of neutral and basic amino acids across the blood-brain barrier.
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PMID:Decreased cerebrospinal fluid levels of neutral and basic amino acids in patients with Parkinson's disease. 926 38


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