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 present review paper describes results indicating the influence of nitric oxide (NO) on motor control. Our last studies showed that systemic injections of low doses of inhibitors of NO synthase (NOS), the enzyme responsible for NO formation, induce anxiolytic effects in the elevated plus maze whereas higher doses decrease maze exploration. Also, NOS inhibitors decrease locomotion and rearing in an open field arena. These results may involve motor effects of this compounds, since inhibitors of NOS, NG-nitro-L-arginine (L-NOARG), N(G)-nitro-L-arginine methylester (L-NAME), N(G)-monomethyl-L-arginine (L-NMMA), and 7-Nitroindazole (7-NIO), induced catalepsy in mice. This effect was also found in rats after systemic, intracebroventricular or intrastriatal administration. Acute administration of L-NOARG has an additive cataleptic effect with haloperidol, a dopamine D2 antagonist. The catalepsy is also potentiated by WAY 100135 (5-HT1a receptor antagonist), ketanserin (5HT2a and alfal adrenergic receptor antagonist), and ritanserin (5-HT2a and 5HT2c receptor antagonist). Atropine sulfate and biperiden, antimuscarinic drugs, block L-NOARG-induced catalepsy in mice. L-NOARG subchronic administration in mice induces rapid tolerance (3 days) to its cataleptic effects. It also produces cross-tolerance to haloperidol-induced catalepsy. After subchronic L-NOARG treatment there is an increase in the density NADPH-d positive neurons in the dorsal part of nucleus caudate-putamen, nucleus accumbens, and tegmental pedunculupontinus nucleus. In contrast, this treatment decreases NADPH-d neuronal number in the substantia nigra compacta. Considering these results we suggest that (i) NO may modulate motor behavior, probably by interfering with dopaminergic, serotonergic, and cholinergic neurotransmission in the striatum; (ii) Subchronic NO synthesis inhibition induces plastic changes in NO-producing neurons in brain areas related to motor control and causes cross-tolerance to the cataleptic effect of haloperidol, raising the possibility that such treatments could decrease motor side effects associated with antipsychotic medications. Finally, recent studies using experimental Parkinson's disease models suggest an interaction between NO system and neurodegenerative processes in the nigrostriatal pathway. It provides evidence of a protective role of NO. Together, our results indicate that NO may be a key participant on physiological and pathophysiological processes in the nigrostriatal system.
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PMID:Role of nitric oxide on motor behavior. 1604 47

Oxidative damage to dopaminergic nigrostriatal (DNS) neurons plays a central role in the pathogenesis of Parkinson's disease (PD). Glucose-6-phosphate dehydrogenase (G6PD) is a key cytoprotective enzyme that provides NADPH, the major source of the reducing equivalents of a cell. Mutations of this enzyme are the most common enzymopathies worldwide. We have studied in vivo the role of G6PD overexpressed specifically in the DNS pathway and show that the increase of G6PD activity in the soma and axon terminals of DNS neurons, separately from other neurons or glial cells, protects them from parkinsonism. Analysis of DNS neurons by histological, neurochemical, and functional methods showed that even a moderate increase of G6PD activity rendered transgenic mice more resistant than control littermates to the toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The neuroprotective action of G6PD was also observed in aged animals despite that they had a greater susceptibility to MPTP. Therefore, overexpression of G6PD in dopaminergic neurons or pharmacological activation of the native enzyme should be considered as potential therapeutic strategies to PD.
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PMID:Neuroprotection by transgenic expression of glucose-6-phosphate dehydrogenase in dopaminergic nigrostriatal neurons of mice. 1664 Dec 29

Recent studies have demonstrated that activated microglia play an important role in dopamine (DA) neuronal degeneration in Parkinson disease (PD) by generating NADPH-oxidase (NADPHO)-derived superoxide. However, the molecular mechanisms that underlie microglial activation in DA cell death are still disputed. We report here that matrix metalloproteinase-3 (MMP-3) was newly induced and activated in stressed DA cells, and the active form of MMP-3 (actMMP-3) was released into the medium. The released actMMP-3, as well as catalytically active recombinant MMP-3 (cMMP-3) led to microglial activation and superoxide generation in microglia and enhanced DA cell death. cMMP-3 caused DA cell death in mesencephalic neuron-glia mixed culture of wild-type (WT) mice, but this was attenuated in the culture of NADPHO subunit null mice (gp91(phox-/-)), suggesting that NADPHO mediated the cMMP-3-induced microglial production of superoxide and DA cell death. Furthermore, in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected animal model of PD, nigrostriatal DA neuronal degeneration, microglial activation, and superoxide generation were largely attenuated in MMP-3-/- mice. These results indicate that actMMP-3 released from stressed DA neurons is responsible for microglial activation and generation of NADPHO-derived superoxide and eventually enhances nigrostriatal DA neuronal degeneration. Our results could lead to a novel therapeutic approach to PD.
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PMID:A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation. 1711 47

Angiotensin II (AII) plays a major role in the progression of inflammation and NADPH-derived oxidative stress (OS) in several tissues. The brain possesses a local angiotensin system, and OS and inflammation are key factors in the progression of Parkinson's disease. In rat mesencephalic cultures, AII increased 6-OHDA-induced dopaminergic (DA) cell death, generation of superoxide in DA neurons and microglial cells, the expression of NADPH-oxidase mRNA, and the number of reactive microglial cells. These effects were blocked by AII type-1 (AT1) antagonists, NADPH inhibitors, or elimination of glial cells. DA degeneration increased angiotensin converting enzyme activity and AII levels. In rats, 6-OHDA-induced dopaminergic cell loss and microglial activation were reduced by treatment with AT1 antagonists. The present data suggest that AII, via AT1 receptors, increases the dopaminergic degeneration process by amplifying the inflammatory response and intraneuronal levels of OS, and that glial cells play a major role in this process.
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PMID:Brain angiotensin enhances dopaminergic cell death via microglial activation and NADPH-derived ROS. 1849 66

The members of the NOX/DUOX family of NADPH oxidases mediate such physiologic functions as host defense, cell signaling, and thyroid hormone biosynthesis through the generation of reactive oxygen species (ROS), including superoxide anion and hydrogen peroxide. Moreover, ROS are involved in a broad range of fundamental biochemical and cellular processes, and data accumulated in recent years indicate that the NOX enzymes comprise one of the most important biological sources of ROS. Given the high biochemical reactivity of ROS, it is not surprising that they have been implicated in a wide variety of pathologies and diseases. Prominent among the settings that feature ROS-mediated tissue injury are disorders associated with inflammation, aging, and progressive degenerative changes in cells and organ systems, and it appears that essentially no organ system is exempt. Among the disorders currently believed to be mediated at least in part by NOX-derived ROS are hypertension, aortic aneurysm, myocardial infarction (and other ischemia-reperfusion disorders), pulmonary fibrosis and hypertension, amyotropic lateral sclerosis, Alzheimer's disease, Parkinson's disease, ischemic stroke, diabetic nephropathy, and renal cell carcinoma. Several small-molecule and peptide inhibitors of the NOX enzymes have been useful in experimental studies, but issues of specificity, potency, and toxicity militate against any of the existing published compounds as candidates for drug development. Given the broad array of disease targets documented in recent work, the time is here for vigorous efforts to develop clinically useful inhibitors of the NOX enzymes. As most (though not all) NOX-related diseases appear to be mediated by a single member of the NOX family, agents with isoform specificity will be preferred, although broadly active NOX inhibitors may prove to be useful in some settings.
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PMID:NOX enzymes as novel targets for drug development. 1850 46

The neurotoxin MPTP reproduces most of the biochemical and pathological hallmarks of Parkinson's disease. In addition to reactive oxygen species (ROS) generated as a consequence of mitochondrial complex I inhibition, microglial NADPH-derived ROS play major roles in the toxicity of MPTP. However, the exact mechanism regulating this microglial response remains to be clarified. The peptide angiotensin II (AII), via type 1 receptors (AT1), is one of the most important inflammation and oxidative stress inducers, and produces ROS by activation of the NADPH-oxidase complex. Brain possesses a local angiotensin system, which modulates striatal dopamine (DA) release. However, it is not known if AII plays a major role in microglia-derived oxidative stress and DA degeneration. The present study indicates that in primary mesencephalic cultures, DA degeneration induced by the neurotoxin MPTP/MPP(+) is amplified by AII and inhibited by AT1 receptor antagonists, and that protein kinase C, NADPH-complex activation and microglial activation are involved in this effect. In mice, AT1 receptor antagonists inhibited both DA degeneration and early microglial and NADPH activation. The brain angiotensin system may play a key role in the self-propelling mechanism of Parkinson's disease and constitutes an unexplored target for neuroprotection, as previously reported for vascular diseases.
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PMID:The inflammatory response in the MPTP model of Parkinson's disease is mediated by brain angiotensin: relevance to progression of the disease. 1924 63

Oxidative stress during development may predispose humans to neurodegenerative disorders in old age. Moreover, numerous ailments of brain disproportionately affect one of the genders. We therefore hypothesized that, activities of enzymes regenerating and utilizing glutathione (GSH) show sexual dimorphism and developmental differences in rat brain. To test this hypothesis, we collected cortex tissue from male and female Sprague-Dawley rats at post-natal day (PN) 5, PN 10, PN 20, PN 30, and PN 60. We measured tissue levels of NADP-linked isocitrate dehydrogenase (NADP-ICDH), glucose-6-phosphate dehydrogenase (G6PDH), and, glutathione reductase (GR) by UV spectrophotometry and determined glutathione peroxidase (GPx) expression therein by western blotting. Our results showed that sexual maturation had an impact on activities of enzymes that regenerate and utilize GSH and rat female cortex had more anti-oxidant capacity. Moreover, age-related decline in the activities of these key enzymes were observed. Reduced glutathione and NADPH protects the brain from oxidative stress. Thus, our results may have implications for neurodegenerative disorders like Parkinson's disease and developmental disorders of brain like autism in which oxidative stress plays a key role.
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PMID:Reduced glutathione regenerating enzymes undergo developmental decline and sexual dimorphism in the rat cerebral cortex. 1945 May 67

Since the discovery of a renin-angiotensin system (RAS) in the brain, several studies have linked this central RAS to neurological disorders such as ischaemia, Alzheimer's disease and depression. In the last decade, evidence has accumulated that the central RAS might also play a role in Parkinson's disease. Although the exact cause of this progressive neurodegenerative disorder of the basal ganglia remains unidentified, inflammation and oxidative stress have been suggested to be key factors in the pathogenesis and the progression of the disease. Since angiotensin II is a pro-inflammatory compound that can induce the production of reactive oxygen species due to activation of the NADPH-dependent oxidase complex, this peptide might contribute to dopaminergic cell death. In this review, three different strategies to interfere with the pathogenesis or the progression of Parkinson's disease are discussed. They include inhibition of the angiotensin-converting enzyme, blockade of the angiotensin II type 1 receptor and stimulation of the angiotensin II type 2 receptor.
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PMID:The role of the central renin-angiotensin system in Parkinson's disease. 1986 46

Disorders of the function of the tyrosine hydroxylase play an important role in the occurrence of the Parkinson syndrome. The enzyme that catalyses the first, rate-limiting step in the biosynthesis to dopamine requires the cofactor tetrahydrobiopterin. This compound supplies the reduction equivalent for activation of molecular oxygen. Binding of the cofactor to the enzyme is affected by phosphorylation or dephosphorylation of the enzyme protein and, thereby, influences the activity. Nerve and chromaffin cells that synthesize dopamine, noradrenaline and serotonin are able to synthesize the cofactor tetrahydrobiopterin de novo from guanosine-triphosphate as a precursor. In patients suffering from Parkinson's disease a remarkable decrease in biopterin content was found in the brain. The function of the dopaminergic system was studied with an experimental Parkinson model. The antimetabolite 6-aminonicotinamide induces a dopamine deficit in the striatum with a significant slowdown in the utilization of this transmitter. The abolition of the 6-aminonicotinamide-induced muscular rigidity by l-DOPA and dopamine agonists implies that the antimetabolite produces a Parkinson-like syndrome in rats. There are reports on the molecular basis of this effect which are also important for understanding possible disturbances of the synthesis of biopterins. The effector 6-aminonicotinamide-adenine-dinucleotide-phosphate (6-ANADP), which blocks the pentose phosphate pathway, is formed by an enzymatic neurotoxic synthesis. The clonal cell line PC-12 was used to study the molecular basis of the disturbances occurring in the dopaminergic system. These cells contain all the enzymes for catecholamine synthesis, including those for the synthesis of the cofactor tetrahydrobiopterin. Addition of 6-aminonicotinamide to the culture medium resulted in the synthesis of the neurotoxic agent, 6-ANADP, by a glycohydrolase localized in the endoplasmic reticulum. The synthesis of biopterin was depressed after application of 6-aminonicotinamide. The decrease of intracellular tetrahydrobiopterin and total biopterin resulted in reduced DOPA production. The decreased content of biopterin cofactor synthesis was compensated for by the addition of the precursor sepiapterin, indicating that the NADPH-dependent reductases in biopterin synthesis were not inhibited by the antimetabolic nucleotide 6-ANADP. DOPA production was not fully normalized by sepiapterin. Addition of NADH to the medium resulted in a further increase of DOPA production, probably by activation of the recycling pathway. The first step in the synthesis of biopterin from GTP to 7,8-neopterin-triphosphate seems to be particularly sensitive to the action of exogenous neurotoxins. A further sensitive site of action in synthesis to the cofactor BH(4) concerns the function of the dihydropteridin-reductase, which recycles qBH(2) to BH(4). Neurotoxin-induced impairment of biopterin synthesis is probably a pathogenetically important disorder at the initial stage of Parkinson's disease.
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PMID:Neurotoxin-induced impairment of biopterin synthesis and function: Initial stage of a Parkinson-like dopamine deficiency syndrome. 2050 23

Epidemiological studies have reported that the incidence of Parkinson's disease (PD) is higher in postmenopausal than in premenopausal women of similar age. Several laboratory observations have revealed that estrogen has protective effects against dopaminergic toxins. The mechanism by which estrogen protects dopaminergic neurons has not been clarified, although estrogen-induced attenuation of the neuroinflammatory response plays a major role. We have recently shown that activation of the nigral renin-angiotensin system (RAS), via type 1 (AT1) receptors, leads to NADPH complex and microglial activation and induces dopaminergic neuron death. In the present study we investigated the effect of ovariectomy and estrogen replacement on the nigral RAS and on dopaminergic degeneration induced by intrastriatal injection of 6-OHDA. We observed a marked loss of dopaminergic neurons in ovariectomized rats treated with 6-OHDA, which was significantly reduced by estrogen replacement or treatment with the AT1 receptor antagonist candesartan. We also observed that estrogen replacement induces significant downregulation of the activity of the angiotensin converting enzyme as well as downregulation of AT1 receptors, upregulation of AT2 receptors and downregulation of the NADPH complex activity in the substantia nigra in comparison with ovariectomized rats. The present results suggest that estrogen-induced down-regulation of RAS and NADPH activity may be associated with the reduced risk of PD in premenopausal women, and increased risk in conditions causing early reduction in endogenous estrogen, and that manipulation of brain RAS system may be an efficient approach for the prevention or coadjutant treatment of PD in estrogen-deficient women.
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PMID:Estrogen and angiotensin interaction in the substantia nigra. Relevance to postmenopausal Parkinson's disease. 2058 Jul 12


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