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 toxic effects of methamphetamine on dopamine and serotonergic neurons have recently been linked to the endogenous formation of 6-hydroxydopamine and 5,7-dihydroxytryptamine, respectively. It has been speculated that the ability of methamphetamine to both release dopamine and serotonin as well as to inhibit monoamine oxidase activity leads to the non-enzymatic oxidation of dopamine and serotonin to the neurotoxins. This hypothesis was evaluated by pretreating rats with high doses of an antioxidant (ascorbic acid) prior to the administration of methamphetamine. It was observed that the administration of 25.0 mg/kg of methamphetamine at 12 hour intervals for a four day period caused a long-lasting depletion of dopamine and serotonin. Pretreatment with 100.0 mg/kg of ascorbic acid 30 minutes before each methamphetamine injection significantly (but not completely) attenuated this neurotoxic action of methamphetamine. These observations are discussed in reference to animal models of Parkinson's disease.
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PMID:Pretreatment with ascorbic acid attenuates the neurotoxic effects of methamphetamine in rats. 399 9

The concentrations of 5-hydroxytryptamine (5HT), noradrenaline, and dopamine were estimated post mortem in brain stem, hypothalamus, and caudate nucleus in 33 patients who had been treated with isocarboxazid, clorgyline, or tranylcypromine and 11 controls. Similar and highly significant increases in 5HT and noradrenaline concentration occurred with all three drugs. The distribution was unimodal, but about a quarter of the patients showed only a small increase in brain amines. Tranylcypromine seemed to have a significantly greater effect on dopamine in caudate nucleus and hypothalamus compared with isocarboxazid and clorgyline. In the doses used chlorpromazine did not reduce the amine concentrations. Four patients with Parkinson's syndrome had low concentrations of dopamine in caudate nucleus in spite of monoamine oxidase inhibitor administration.
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PMID:Brain amine concentrations after monoamine oxidase inhibitor administration. 500 39

The integrity of the endothelial cell lining of the cerebrovascular bed constitutes a morphological blood-brain barrier mechanism to neurotransmitter monoamines. Circulating monoamines are prevented from entering the brain primarily at the luminal membrane of the endothelial ling. The small percentage of amines that may pass this membrane is deaminated within the endothelial cells and pericytes of brain microvessels (capillaries, venules, and small veins) and, in the case of large parenchymal and pial vessels, in the smooth muscle layers, where O-methylation also takes place. In the choroid plexus a corresponding deamination and O-methylation takes place in the epithelial cells. The presence of these enzymes constitutes a further, enzymatic, blood-brain barrier in the brain vessels for these monoamines. The monoamine precursors L-3,4-dihydroxyphenylalanine (L-dopa) and L-5-hydroxytryptophan readily pass from the luminal endothelial cell membrane but are trapped by another enzymatic barrier mechanism. Within the endothelial cells and pericytes of the microvasculature, these compounds are decarboxylated to their corresponding amines and then immediately deaminated. One clinical implication of these enzymatic barrier mechanisms is the use of decarboxylase and monoamine oxidase inhibitors as adjuncts to L-dopa treatment of Parkinson disease; these substances facilitate the entry of L-dopa into brain and thus increase the amount of dopamine available at receptor sites. A brief hypertensive or hypertonic stimulus can transiently open the blood-brain barrier through an effect on endothelial cell linings. High circulating concentrations of monoamines can also open the morphological barrier, but probably only indirectly by inducing an acute rise in systemic blood pressure. Once the barrier is open, systemically administered monoamines enter the brain parenchyma, where they can induce pronounced changes in cerebral blood flow and metabolism.
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PMID:Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface. 610 37

Monoamine oxidase inhibitors have been used in psychiatric disorders for many years. However, due to the toxic side effects of the drugs they are often replaced by the tri- and tetracyclic antidepressants. Selective monoamine oxidase inhibitors like deprenyl, however, have been tried with success as adjuvant therapy in Parkinson's disease and depression because of their ability to inhibit dopamine oxidation. Perhaps their greatest advantage is their lack of pressor response.
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PMID:Monoamine oxidase inhibitors as anti-depressant drugs and as adjunct to L-dopa therapy of Parkinson's disease. 610 29

The intracellular generation of reactive forms of reduced oxygen, namely, hydrogen peroxide, superoxide and hydroxyl radical, can damage dopamine neurons. Oxy-radicals, and hydrogen peroxide generated by monoamine oxidase, can contribute to increased rates of senescence of dopamine neurons in Parkinson's disease. The evidence that oxy-radicals and monoamine oxidase are potentially cytotoxic is reviewed, and a pathobiology of dopamine neuron senescence in Parkinson's disease is proposed.
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PMID:The pathobiology of Parkinson's disease: biochemical aspects of dopamine neuron senescence. 632 51

This article summarizes the evidence that oxy-radicals are involved in the destruction of catecholamine neurons by polyphenolic neurotoxins. Superoxide-mediated damage by 6-hydroxydopamine can be suppressed by intracellular catecholamines, which act as scavengers of the superoxide radical. Administration of exogenous hydroxyl radical-scavenging agents protects peripheral sympathetic neurons from destruction by 6-hydroxydopamine, 6- aminodopamine or 5,7-dihydroxytryptamine. Intraneuronal monoamine oxidase may drive cellular senescence of the nigrostriatal tract in patients with Parkinson's disease by generating hydrogen peroxide and derived oxy-radicals during the metabolism of endogenous dopamine.
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PMID:Oxy-radical toxicity in catecholamine neurons. 632 7

The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces an irreversible neurological syndrome in man and monkey which is similar to idiopathic Parkinson's disease in its clinical, pathological, neurochemical and pharmacological response properties. MPTP is selectively neurotoxic to the dopaminergic regions of the brain, destroying neurones in the substantia nigra (A8 and A9 cells, nigrostriatal system) but not the ventral tegmental area (A10 cells, mesolimbic system). Selective dopamine depletion and nigral cell loss after MPTP treatment has also been reported recently in the mouse. The mechanism by which a peripherally administered, low-molecular weight compound exerts permanent but selective toxic effects on dopamine systems in the brain may be relevant to parkinsonian syndromes induced by other toxins and to the disease process in idiopathic Parkinson's disease. We report here that MPTP is oxidized in the brain to a pyridinium species (a compound with potent herbicidal activity) and, in the monkey, is trapped intraneuronally. Furthermore, we demonstrate that this enzymatic oxidation is blocked in vivo in the mouse by a monoamine oxidase inhibitor, a condition which also blocks the neurotoxicity, indicating that the oxidative metabolism of MPTP is required for its neurotoxic effect.
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PMID:Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism. 633 88

The role of deprenyl, a selective monoamine oxidase B inhibitor, in the treatment of Parkinson's disease has been evaluated with special reference to the multiple pharmacological actions of the monoamine oxidase-inhibitory group of drugs.
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PMID:Monoamine oxidase inhibitors and their pharmacological significance. 642 47

Bupropion is an antidepressant, thought to be an indirect dopaminergic agonist. No significant sympathomimetic, anti-cholinergic, or MAO inhibitor effects have been reported. We evaluated this drug in 20 patients with idiopathic Parkinson's disease. Parkinsonism lessened by at least 30% (Northwestern University Disability Scale or Modified New York University Parkinson's Disease Scale) in half the patients. Depression, present in 12 of 20, was alleviated in only 5. Bupropion is mildly efficacious in Parkinson's disease, although side effects were frequent and were dose-limiting in five patients.
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PMID:Bupropion in Parkinson's disease. 643 14

Basic aspects and recent advances in the understanding of the pharmacological mechanism of action of the clinically most used antiparkinson drugs are reviewed. Recent human and animal biochemical investigations clearly confirm and extend previous findings indicating that benserazide is much more potent than carbidopa as peripheral decarboxylase inhibitor. L-DOPA in combination with benserazide or carbidopa constitutes the best available therapy for Parkinson's disease (PD). To reduce peaks and rapid fluctuations of L-DOPA plasma levels (possibly responsible for peak-dose dyskinesias and end-of-dose deterioration) a slow-release formulation of L-DOPA in combination with benserazide or with benserazide plus catechol-O-methyltransferase inhibitors should be developed. In parkinsonian patients under long-term L-DOPA therapy monoamine oxidase inhibitors type B (MAO-B) e.g. (-)deprenyl and direct dopamine receptor agonists (bromocriptine, lisuride, pergolide etc.), due to their L-DOPA-sparing effects, alleviate in some cases L-DOPA-induced side-effects e.g. dyskinesias and on-off phenomena. However, since (-)deprenyl, due to its metabolism to (-)methamphetamine and (-)amphetamine, seem to have indirect sympathomimetic activity, new selective MAO-B inhibitors devoid of indirect sympathomimetic effects should be tested clinically to assess the functional role of pure MAO-B inhibition in the therapy of PD. The auxiliary therapy with direct dopamine receptor agonists of the D-2 subtype represents another valid approach which should be further investigated in order to find novel dopamine agonists, less expensive than bromocriptine, and strictly selective for D-2 receptor sites.
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PMID:The pharmacology of Parkinson's disease: basic aspects and recent advances. 643 57


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