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)

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

Idiopathic Parkinson's disease (PD) involves a documentable decline in the activity of mitochondrial complex I in substantia nigra (1-3). We have EPR spectroscopy to investigate complex I in human substantia nigra and globus pallidus. EPR signals characteristic of the iron-sulfur centers of complexes I and II were observed with globus pallidus, with no significant difference between control and PD. These complex 1 signals could not be clearly observed in substantia nigra. Instead, nitric oxide (NO.) radicals in PD nigra were detected at g approximately 2.08, 1.98 due to [haem-NO] formation. Although an EPR signal indicative of haem-NO was observed with control nigra, it lacked the distinctive g approximately 1.98 trough observed with PD nigra. As PD is associated with a reactive gliosis, the difference in the haem-NO EPR signal, between control and PD nigra, may result from cytotoxic NO. generated by microglia in PD substantia nigra.
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PMID:Detection of nitrosyl complexes in human substantia nigra, in relation to Parkinson's disease. 892 Sep 9

Current concepts of the pathogenesis of Parkinson's disease (PD) center on the formation of reactive oxygen species and the onset of oxidative stress leading to oxidative damage to substantia nigra pars compacta. Extensive postmortem studies have provided evidence to support the involvement of oxidative stress in the pathogenesis of PD; in particular, these include alterations in brain iron content, impaired mitochondrial function, alterations in the antioxidant protective systems (most notably superoxide dismutase [SOD] and reduced glutathione [GSH]), and evidence of oxidative damage to lipids, proteins, and DNA. Iron can induce oxidative stress, and intranigral injections have been shown to induce a model of progressive parkinsonism. A loss of GSH is associated with incidental Lewy body disease and may represent the earliest biochemical marker of nigral cell loss. GSH depletion alone may not result in damage to nigral neurons but may increase susceptibility to subsequent toxic or free radical exposure. The nature of the free radical species responsible for cell death in PD remains unknown, but there is evidence of involvement of hydroxyl radical (OH.), peroxynitrite, and nitric oxide. Indeed, OH. and peroxynitrite formation may be critically dependent on nitric oxide formation. Central to many of the processes involved in oxidative stress and oxidative damage in PD are the actions of monoamine oxidase-B (MAO-B). MAO-B is essential for the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion, for a component of the enzymatic conversion of dopamine to hydrogen peroxide (H2O2), and for the activation of other potential toxins such as isoquinolines and beta-carbolines. Thus, the inhibition of MAO-B by drugs such as selegiline may protect against activation of some toxins and free radicals formed from the MAO-B oxidation of dopamine. In addition, selegiline may act through a mechanism unrelated to MAO-B to increase neurotrophic factor activity and upregulate molecules such as glutathione, SOD, catalase, and BCL-2 protein, which protect against oxidant stress and apoptosis. Consequently, selegiline may be advantageous in the long-term treatment of PD.
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PMID:Oxidative stress and the pathogenesis of Parkinson's disease. 895 85

There have been many claims that the selective monoamine oxidase type B (MAO-B) inhibitor selegiline may have distinct properties in slowing the progression of Parkinson's disease (PD). Degeneration of nigro-striatal dopaminergic neurons is the primary histopathological feature of PD. Although many different hypotheses have been advanced, the cause of chronic nigral cell death and the underlying mechanisms remain elusive as yet. Therefore, there is no clear knowledge regarding an understanding of the reported effects of selegiline on the progression of PD. However, there is a considerable body of indirect evidence that oxidative stress may play a role in the pathogenesis of this illness. Oxidative stress refers to cytotoxic consequences of hydrogen peroxide and oxygen-derived free radicals such as the hydroxyl radical (.OH), the superoxide anion (.O2), and nitric oxide (NO), which are generated as byproducts of normal and aberrant metabolic processes that utilize molecular oxygen. On the other hand, an increasing body of experimental data has implicated excitotoxicity as a mechanism of cell death in both acute and chronic neurological disease. One of the receptor which is particularly involved in the toxic effects of excitatory amino acids is the NMDA (N-methyl-D-aspartate) receptor. Excessive stimulation of this type of receptor by glutamic acid or NMDA agonists leads to a massive influx of calcium ions into the neuron followed by activation of a variety of calcium-dependent enzymes, impaired mitochondrial function, and the generation of free radicals. This article will consider the concept that excitotoxicity is linked with the generation of free radicals. In view of this idea it will be further discussed how selegiline might exert its neuroprotective effects via indirect actions on the polyamine binding site of the NMDA receptor. Under treatment with the MAO-B inhibitor selegiline, the degradation of putrescine via MAO, a key factor in regulating the polyamine metabolism, might be diminished in the Parkinsonian brain, which in turn would suppress the polyamine synthesis. Hence, the reported neuroprotective effect of selegiline might also receive a contribution from the diminished potentiation of the NMDA receptor by the polyamine binding site. On the other hand, since N1-acetylated spermine and spermidine are also good substrates of MAO-B, it is likely that these compounds will be present in the brain in increased concentrations. It therefore seems possible that they will exert a neuroprotective effect via an antagonistic modulation of the polyamine binding site of the NMDA receptor.
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PMID:New horizons in molecular mechanisms underlying Parkinson's disease and in our understanding of the neuroprotective effects of selegiline. 898 58

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

PDZ domains are multifunctional protein-interaction motifs that often bind to the C-terminus of protein targets. Nitric oxide (NO), an endogenous signaling molecule, plays critical roles in nervous, immune, and cardiovascular function. Although there are numerous physiological functions for neuron-derived NO, produced primarily by the neuronal NO synthase (nNOS), excess nNOS activity mediates brain injury in cerebral ischemia and in animal models of Parkinson's disease. Subcellular localization of nNOS activity must therefore be tightly regulated. To determine ligands for the PDZ domain of nNOS, we screened 13 billion distinct peptides and found that the nNOS-PDZ domain binds tightly to peptides ending Asp-X-Val. This differs from the only known (Thr/Ser)-X-Val consensus that interacts with PDZ domains from PSD-95. Preference for Asp at the -2 peptide position is mediated by Tyr-77 of nNOS. A Y77D78 to H77E78 substitution changes the binding specificity from Asp-X-Val to Thr-X-Val. Guided by the Asp-X-Val consensus, candidate nNOS interacting proteins have been identified including glutamate and melatonin receptors. Our results demonstrate that PDZ domains have distinct peptide binding specificity.
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PMID:PDZ domain of neuronal nitric oxide synthase recognizes novel C-terminal peptide sequences. 909 34

It has been suggested a possible role of oxidative stress, neuromelanin, mitochondrial dysfunction, calcium-binding protein deficiency, nitric oxide, trophic factors deficiency, and cytokines, in the pathogenesis of Parkinson's disease. Based on these mechanisms it might be established neuroprotective therapies but, up to date, the results reported are inconsistent. Many experimental data suggest the usefulness of some restorative therapy, such as neural grafts, genic therapies, etc. This article reviews the current knowledge on the possible neuroprotective and restorative treatments in Parkinson's disease.
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PMID:[Neuroprotective and neurorestorative therapy in Parkinson's disease]. 928 Jun 87

Current views on the pathogenesis of Parkinson's disease are presented. Studies, particularly those carried out during the last decade, highlight the significance of endogenic processes responsible for a cumulative production of neurotoxic substances, especially free oxygen radicals which exert chronic effect on neurons. In Parkinson's disease, overproduction of free radicals and concomitant failure of protective mechanisms are most likely. An excess of free radicals is cytotoxic because of their very high chemical activity and uncontrolled chain reactions with numerous organic compounds, especially those which are mostly responsible for vital functions of cells. Oxidative stress disturbs metabolism of the cell what finally leads to its death most probably due to damage of cell membrane. That results in increased plasma membrane permeability for calcium ions which activate several subcellular mechanisms and initiate the final phase of cell death. Nonprotein-bound "free" iron ions are the strongest and most dangerous generators of free oxygen radicals. It is thought that ferric (Fe-3+" iron bound to neuromelanin may play a profound role in the overproduction of especially cytotoxic hydroxyl radicals, derivatives of molecular oxygen. Both, oxygen stress inducing factor and the sequence of related biochemical disorders remain still unknown. However, the synergy of the excess of reactive oxygen metabolites (mainly free radicals), nitric oxide, "free" iron ions and neuromelanin may contribute considerably to the generation of oxygen stress.
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PMID:[Current views on the mechanisms of dopaminergic neuron death of the nigrostriatal system in Parkinson's disease]. 938 Feb 59

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

Nitric oxide (NO) is involved in important physiological functions of the CNS, including neurotransmission, memory and synaptic plasticity. Depending on the redox state of NO, it can act as a neurotoxin or it can have a neuroprotective action. Data suggest that NO may have a role in the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease. Additionally, these data indicate that inhibitors of the NO-synthesising enzyme, NO synthase, may be useful as neuroprotective agents in these diseases. In animal models, NOS inhibitors have been shown to prevent the neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and other dopaminergic toxins. However, the clinical effects of NOS inhibitors remain unknown.
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PMID:The role of nitric oxide in neurodegeneration. Potential for pharmacological intervention. 957 90


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