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)

Several studies suggest that nitric oxide (NO.) contributes to cell death following activation of NMDA receptors in cultured cortical, hippocampal, and striatal neurons. In the present study we investigated whether 7-nitroindazole (7-NI), a specific neuronal nitric oxide synthase inhibitor, can block dopaminergic neurotoxicity seen in mice after systemic administration of MPTP. 7-NI dose-dependently protected against MPTP-induced dopamine depletions using two different dosing regimens of MPTP that produced varying degrees of dopamine depletion. At 50 mg/kg of 7-NI there was almost complete protection in both paradigms. Similar effects were seen with MPTP-induced depletions of both homovanillic acid and 3,4-dihydroxyphenylacetic acid. 7-NI had no significant effect on dopamine transport in vitro and on monoamine oxidase B activity both in vitro and in vivo. One mechanism by which NO. is thought to mediate its toxicity is by interacting with superoxide radical to form peroxynitrite (ONOO-), which then may nitrate tyrosine residues. Consistent with this hypothesis, MPTP neurotoxicity in mice resulted in a significant increase in the concentration of 3-nitrotyrosine, which was attenuated by treatment with 7 NI. Our results suggest that NO. plays a role in MPTP neurotoxicity as well as novel therapeutic strategies for Parkinson's disease.
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PMID:Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice. 753 Feb 97

Deprenyl is a selective monoamine oxidase B (MAO-B) inhibitor and has been used in the treatment of Parkinson's disease. However, it is not known whether deprenyl effects are symptomatic or pharmacological. Aging mice were partially lesioned with MPTP. Control and MPTP-treated mice were given deprenyl in drinking water for 14 days. Brain tissue (including the striatum, olfactory tubercle and cerebral cortex) was assayed for MAO-B and neurotransmitter levels. The results show that deprenyl treatment, given alone or after MPTP, reduced MAO-B activity in all the three regions. No change was seen in dopamine (DA), 3,4-dihydroxyphenyl acetic acid (DOPAC), and homovanillic acid (HVA) content in any of the three areas. Cortical norepinephrine (NE) levels were also unaltered. However, striatal serotonin (5-HT) levels were decreased while its metabolite, 5-HIAA levels were significantly increased in the olfactory tubercle in animals receiving deprenyl alone. These data suggest that deprenyl treatment reduces MAO-B activity in regions in addition to the striatum without affecting norepinephrine, dopamine (DA) and its metabolites.
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PMID:Effects of deprenyl on monoamine oxidase and neurotransmitters in the brains of MPTP-treated aging mice. 754 44

Dopamine is equally well deaminated oxidatively by monoamine oxidase (MAO) A and B types. Selegiline (L-deprenyl), a selective inhibitor of MAO-B, ameliorates the "wearing off" akinesia and delays the need for levodopa in mild, previously untreated Parkinson's disease. The therapeutic potential of selective inhibition of MAO-A in Parkinson's disease has not been examined in detail. MAO-A accounts for only about 20% of total MAO activity in the human basal ganglia, and it differs from MAO-B in distribution. In contrast to MAO-B, which is confined to the extraneuronal compartment, MAO-A is found both extraneuronally and within the presynaptic dopaminergic terminals. The inhibition of MAO-A might alter the intraneuronal handling of dopamine reuptaken from synaptic clefts and thereby prolong oral levodopa benefit. We have given moclobemide, a selective, reversible inhibitor of MAO-A, to nondepressed patients with Parkinson's disease receiving standard levodopa/peripheral decarboxylase inhibitor or levodopa with dopaminergic agonist (bromocriptine, pergolide). Selegiline was discontinued at least 8 weeks earlier. A standard oral levodopa challenge was performed at the patient's entry to the study and repeated on the 22nd day of moclobemide treatment (150 mg thrice daily). The overall time spent "on" and "off" before the onset of treatment and during the last week on the drug was estimated from the patients' diaries. Neuropsychological assessments were also made before and after 3 weeks of moclobemide to measure possible effects on cognitive performance and mood. In acute levodopa challenge, the latency of motor response was significantly shortened and its duration was prolonged during moclobemide treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The therapeutic potential of moclobemide, a reversible selective monoamine oxidase A inhibitor in Parkinson's disease. 759 32

R(-)-Deprenyl, an archetypical MAO-B inhibitor, has been shown to delay the onset of the disabling syndrome of Parkinson's disease and to be useful in the treatment of Alzheimer's disease. Recently, R(-)-deprenyl has been claimed to be capable of preventing apoptosis of PC12 cells, which had been primed with nerve growth factor (NGF) and followed by withdrawal of serum. We investigated the effect of R(-)-deprenyl in a non-neuronal cell model, namely, apoptosis of mouse thymocytes induced by dexamethasone. Trypan blue exclusion and lactate dehydrogenase activity were applied to assess the cell survival. R(-)-Deprenyl did not exhibit any detectable protective effect to the thymocytes from apoptosis. The result is further confirmed by examining the apoptotic DNA fragmentation using gel electrophoresis and assessing the soluble DNA released by a spectrophotometric method.
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PMID:Lack of protective effect of R(-)-deprenyl on programmed cell death of mouse thymocytes induced by dexamethasone. 759 17

The author has tried to extrapolate on several neurological diseases of the ageing, Knoll's proposition to treat Parkinson's disease chronically for relapse prevention, by MAO-B. At this occasion, the author makes a critical review of the clinical trial results concerning the new different series of depression treatments, as most authors propose today to use some new ones not only in depression, but in Parkinson's and Alzheimer's diseases and in ageing.
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PMID:Can an adjuvant treatment or a pharmacologic prevention be common to several diseases? The case of those associated to neuromediator defects. 766 35

A single-stranded conformational polymorphism in the monoamine oxidase B gene was shown to be A or G, 36 bases upstream from the intron 13-exon 14 boundary. An allelic association study revealed no statistically significant associations between this single-base polymorphism and Parkinson's disease, unlike the results of a previous study.
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PMID:An allelic association study of monoamine oxidase B in Parkinson's disease. 769 41

Some treatments used for Parkinson's disease attenuate locomotor depression in rats treated with reserpine and alpha-methyl-p-tyrosine. In the present study memantine (2.5, 5.0 mg/kg), amantadine (10, 20 mg/kg) (both uncompetitive NMDA antagonists), and L-deprenyl (1.0, 5.0 mg/kg; MAO-B inhibitor) were tested for possible synergistic interactions with the dopamine agonists: bromocriptine (2.5, 5.0 mg/kg) and L-dopa (50, 100 mg/kg, +benserazide, 100 mg/kg). At higher doses, memantine (10 mg/kg), amantadine (40 mg/kg), bromocriptine (5 and 10 mg/kg) and L-dopa (100, 200 mg/kg) but not L-deprenyl (up to 10 mg/kg) produced a pronounced increase in locomotor activity when given alone. The combination of memantine, amantadine and L-deprenyl with bromocriptine did not result in synergism of action and, at best, an additive effect was seen. On the other hand the combination of these agents with L-dopa produced a pronounced synergistic effect. Hence, the clinical observation that coadministration of L-dopa with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl.
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PMID:Memantine, amantadine, and L-deprenyl potentiate the action of L-dopa in monoamine-depleted rats. 771 Jul 39

Although the involvement of monoamine oxidase B (MAO-B) in physiological function is not yet well understood, its inhibitors have been shown to be quite useful in the treatment of various neuropsychiatric disorders. Platelet MAO-B activity has been found to be reduced in several psychiatric disorders, related to substance abuse and associated with different personalities. 1-Deprenyl (selegiline), an archetypical MAO-B inhibitor, alone does not seem to exert an antidepressive effect, however, it may become useful when administered in combination with amine neurotransmitter precursors. MAO-B inhibitors are useful adjunct drugs to 1-DOPA in the symptomatic treatment of Parkinson's disease. Interestingly, 1-deprenyl alone can slow down the progress of otherwise disabled syndromes of Parkinson's disease. It has been proposed that 1-deprenyl may play a role in neuroprotection and neurorescue. MAO-B inhibitors can selectively and dramatically increase the level of beta-phenylethylamine, which has been shown to potentiate dopamine and noradrenaline function in the central nervous system. Several new types of highly selective, reversible and irreversible MAO-B inhibitors have recently been developed. The mechanism(s) of neuroprotective and rescue actions of 1-deprenyl and other MAO-B inhibitors will help to shed some light on our understanding of the neurodegenerative process.
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PMID:Pharmacological and clinical implications of MAO-B inhibitors. 772 Oct 26

The aetiology and pathogenesis of Alzheimer's disease are currently poorly understood, but symptomatic disease is associated with amyloid plaques, neurofibrillary tangles, neuronal loss and numerous alterations of neurotransmitter systems in the CNS. Monoamine oxidase type B is known to be increased in Alzheimer diseased brains. The distribution and abundance of catalytic sites for monoamine oxidases A and B in post mortem human brains of 11 Alzheimer disease cases and five age-matched controls were investigated by quantitative enzyme radioautography. Using tritiated monoamine oxidase inhibitors (Ro41-1049 and lazabemide)--as high affinity substrates selective for monoamine oxidases A and B, respectively--it was found that monoamine oxidase B activity increased up to three-fold exclusively in temporal, parietal and frontal cortices of Alzheimer disease cases compared with controls. This increase was restricted to discrete patches (approximately 185 microns in diameter) which occupied approximately 12% of the cortical areas examined. In other brain regions (hippocampal formation >> caudate-putamen > cerebellum), patches of [3H]lazabemide-enriched binding were less abundant. [3H]Ro41-1049 binding (i.e. monoamine oxidase A) was unchanged in all tissues of diseased versus control brains. The monoamine oxidase B-enriched patches in all cortical regions correlated, in their distribution and frequency, with glial fibrillary acidic protein-immunoreactive clusters of astrocytes. Diffuse and mature beta-amyloid-immunoreactive senile plaques as well as patches of high density binding of [3H]PK-11195--a high-affinity ligand for peripheral-type (mitochondrial) benzodiazepine binding sites in microglia/macrophages--were found throughout Alzheimer diseased cortices. The up-regulation of monoamine oxidase B in plaque-associated astrocytes in Alzheimer's disease--in analogy to its proposed role in neurodegenerative disorders such as Parkinson's disease--might, indirectly, be a potential source of cytotoxic free radicals. Lazabemide, a selective reversible monoamine oxidase B inhibitor, is currently under clinical evaluation for the treatment of Parkinson's and Alzheimer's diseases. We conclude that enzyme radioautography with [3H]lazabemide is a reliable high resolution assay for plaque-associated astroglioses in Alzheimer's disease. Its clinical diagnostic utility for positron emission tomography or single photon emission computer tomography studies is being investigated.
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PMID:Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. 781 97

The current research has demonstrated that MPP+ can induce lipid peroxidation in the nigrostriatal system of rat in vivo. Antioxidant agent U-78517F and .OH scavenger DMSO may protect against MPP+ toxicity through the inhibition of .OH radical-mediated oxidative injury in the substantia nigra. These findings indicate that the cytotoxic hydroxyl radical generated from dopamine oxidation in the iron-rich basal ganglia may contribute to the mechanism underlying the selective A9 melanized nigral degeneration in MPTP-Parkinsonism and possibly in idiopathic Parkinson's disease. In addition, the present studies also clearly demonstrate that deprenyl can substantially protect dopaminergic neurons against MPP+ toxicity in the substantia nigra zona compacta in vivo. The neuroprotective effect provided by deprenyl may not be the consequence of its inhibition of MAO-B activity or prevention of the uptake of MPP+ by dopaminergic neurons. A unique antioxidant property of deprenyl by suppressing .OH formation and associated oxidative injury induced by MPP+ may contribute to the apparent neuroprotective action. In perspective, this putative antioxidant effect of deprenyl may provide another mechanism to its overt neuroprotective effects against oxygen radical-mediated oxidative injury in some neurotoxic chemicals, such as 6-OHDA and DSP-4, and probably in Alzheimer's disease and senescent changes. Finally, based on the present data, a possible neuroprotective therapeutic window of deprenyl in the treatment of early Parkinson's disease has been proposed. It is suggested that deprenyl should be introduced as early as possible in de novo Parkinsonian patients to achieve its full neuroprotective effect on nigral degeneration. Moreover, a combination of early detection of individuals at risk of developing Parkinson's disease and early intervention of deprenyl and/or other centrally active antioxidants to these patients may provide a new preventive therapeutic strategy in the future, in addition to the current conventional levodopa treatment of Parkinson's disease.
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PMID:Antioxidant mechanism and protection of nigral neurons against MPP+ toxicity by deprenyl (selegiline). 783 30


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