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)

Recent evidence of functional interactions between D1 and D2 dopamine receptor subtypes has led to the concept that many of the behavioural effects of dopamine agonists occur only with activation of both receptor subtypes. Thus, combined treatment with dopamine agonists selective for each of the D1 and D2 receptors may be an effective therapy for Parkinson's disease, chiefly characterized by loss of central dopamine-containing neurons. In addition, recent hypotheses of the possible pathogenesis of this disorder have suggested that metabolism of dopamine by monoamine oxidase in the presynaptic terminal may contribute to the loss of dopaminergic cells, through the production of reactive by-products. Therefore, the effects of chronic (15 day) treatment of rats with different doses of (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, a D2 receptor agonist), SKF 38393 (a D1 receptor partial agonist) or combinations of both drugs on levels of brain monoamines and some of their acidic metabolites were investigated. Little or no effects of the drugs were observed on measures of dopamine or noradrenaline when given separately, while each selective agonist dose-dependently reduced serotonin levels. Combined treatment with the two agonists produced profound effects on the catecholamines, but with no effect on 3,4-dihydroxyphenylacetic acid, the metabolite of dopamine produced by monoamine oxidase. In addition, the effects of combined treatment on serotonin levels were opposite of those of the drugs given independently. Concomitant treatment of animals with both D1 and D2 receptor agonists can therefore increase tissue levels of dopamine without increasing the potentially harmful metabolism of dopamine by monoamine oxidase.
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PMID:Chronic treatment with D1 and D2 dopamine receptor agonists: combined treatments interact to differentially affect brain levels of monoamines. 168 87

Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone. Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity to MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons. Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline. Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article.
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PMID:A review of the pharmacology of selegiline. 168 54

The neurotransmitter deficits of dementias, including Alzheimer's dementia, Lewy body dementia and Parkinson's disease are discussed in relation to cognitive and behavioural impairments together with neuropathological changes and available data on the status of receptor transmembrane signalling. Potential therapeutic strategies for dementia are outlined based on the following systems: excitatory amino acids, gamma-amino butyric acid, acetylcholine (muscarinic and nicotinic), noradrenaline, serotonin and peptides. These include the attenuation of transmitter deficits by agonists and agents inhibiting transmitter breakdown and support for surviving neurons by suppression of inhibitory inputs, trophic factors and neural implantation.
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PMID:Dementia: the neurochemical basis of putative transmitter orientated therapy. 168 28

The relationship between oxidative polymorphisms and the cause of Parkinson's disease is controversial. The drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces parkinsonism in humans and in some animal models, is metabolized by cytochrome P450 db1 isozyme (the same enzymatic system implicated in 4-hydroxylation of debrisoquine). In this study, we treated females of three rat species, which differ in their ability to hydroxylate debrisoquine, with MPTP (three doses of 30 mg/kg s.c. at 12-h intervals), and we measured their motor activity and brain monoamine levels. Female dark-adapted rats (poor metabolizers of debrisoquine) showed a more pronounced and more maintained reduction of their motor activity after treatment with MPTP. MPTP-treated, dark-adapted rats also had a depletion of noradrenaline in the diencephalon and a depletion of dopamine and serotonine and their respective metabolites in the limbic system when compared with the other two species. These results suggest that oxidative polymorphism of debrisoquine plays a role in the acute effects of MPTP.
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PMID:Acute effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in a model of rat designated a poor metabolizer of debrisoquine. 171 Nov 1

Protracted long-term treatment of common marmosets with 15 doses (0.5-4.5 mg/kg, i.p.) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; total dose 25 mg/kg, given over 29 days) caused transitory changes in motor behaviour reminiscent of human Parkinson's disease. 16 days from the start of MPTP administration, all animals showed motor impairment, consisting of profound akinesia and a rigid posture, but in no case resting tremor. Biogenic amines were measured in nigrostriatal regions one month after finishing MPTP treatment. There was a profound loss of dopamine and serotonin in the substantia nigra and in the striatum; noradrenaline was only reduced in the putamen. Continuous analyses of the concentrations of biogenic amine metabolites in the CSF during this study revealed persistent dopaminergic disturbances and temporary alterations in serotoninergic and noradrenergic function.
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PMID:Neurochemical and behavioural features induced by chronic low dose treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset: implications for Parkinson's disease? 171 88

In four human controls, four cases of Parkinson's disease and three cases of amyotrophic lateral sclerosis analysis of dopamine, noradrenaline, serotonin and the metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid was performed in various segments of postmortem spinal cord. In controls the concentrations of dopamine are about 1/3 to 1/4 that of noradrenaline; the significantly highest content of noradrenaline was found in the lumbar, and dopamine in thoracic, lumbar and sacral segments of the spinal cord. Intersegmental distribution of monoamines was only present in spinal cord of controls, while in the spinal cord of parkinsonian patients such a difference was not found. Otherwise, biogenic amine and metabolite concentrations in spinal cord segments of parkinsonian patients did not differ significantly from those in the control subjects. However, it cannot be excluded that these segments are sensitive to drugs including neuroleptics and combined L-DOPA treatment. In subjects with amyotrophic lateral sclerosis significantly lower concentrations of noradrenaline in the cervical and thoracic, and of dopamine and homovanillic acid in the thoracic and lumbar segments were found in comparison with controls. The concentrations of serotonin and 5-hydroxyindoleacetic acid in the thoracic segments of amyotrophic lateral sclerosis were significantly lower than that of controls. Differences in the inter-segmental distribution of noradrenaline in lumbar, lumbar-sacral, and serotonin in lumbar segments of spinal cord were found in this group.
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PMID:Biogenic amines and metabolites in spinal cord of patients with Parkinson's disease and amyotrophic lateral sclerosis. 171 5

In an attempt to define neurochemically the part played by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a potential Parkinson's disease-inducing neurotoxin, we measured the tissue concentrations of the monoamines dopamine, noradrenaline and serotonin in 45 brain regions in nine rhesus monkeys (Macaca mulatta) receiving repeated intramuscular injections of a total amount of 2.1-7.5 mg/kg MPTP-HCl. Four monkeys treated with MPTP during a period of one to five weeks developed permanent Parkinsonism, and five animals receiving the neurotoxin during a period of two to seven months remained asymptomatic. We found that, compared with the distribution pattern established in the brain of seven normal (drug-free) rhesus monkeys, in the MPTP-treated monkeys none of the three major brain monoamine neuron systems was completely resistant to the neurotoxin. In addition, each brain monoamine had a characteristic regional pattern of MPTP-induced changes. As expected, the most significant alterations were found within the nigrostriatal dopamine system, i.e. profound dopamine loss in caudate nucleus, putamen and substantia nigra. However, many extrastriatal regions of the subcortex and brainstem also suffered significant loss of dopamine, with the noradrenaline loss in the regionally subdivided brainstem being less widespread, and the serotonin levels least affected. Thus, in subcortex/brainstem the ranking order of sensitivity to MPTP was: dopamine greater than noradrenaline much greater than serotonin. In the cerebral (neo- and limbic) cortex, all three monoamine neuron systems suffered widespread statistically significant losses. The ranking order of MPTP sensitivity of the cortical monoamines was: noradrenaline greater than serotonin greater than dopamine. In the cerebellar cortex, dopamine and noradrenaline concentrations were significantly reduced, whereas the serotonin level remained unchanged. A remarkable observation was that many of the subcortical and cortical changes found in the symptomatic monkeys were also found in the asymptomatic animals. Our data are compatible with several possible mechanisms by which MPTP may have produced the observed patterns of monoamine loss in the brain of the rhesus monkey. Our study demonstrates that in the rhesus monkey MPTP mimicked, in addition to the profound striatal dopamine loss, some of the extrastriatal dopamine, noradrenaline and serotonin changes often seen in the brain of patients with idiopathic Parkinson's disease. However, using our treatment regimen, we have not been able to reproduce in the rhesus monkey the inter-regional pattern of striatal dopamine loss typical of idiopathic Parkinson's disease, i.e. a significantly greater loss of dopamine in the putamen compared with the caudate nucleus.
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PMID:Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on the regional distribution of brain monoamines in the rhesus monkey. 175 53

Surrounding bovine chromaffin cells by a semipermeable membrane may protect the transplanted cells from a host immune response and shield them from the inflammatory process resulting from the surgical trauma. Encapsulation of the chromaffin cells was achieved by interfacial adsorption of a polycation on a polyanionic colloid matrix in which the chromaffin cells were entrapped. Basal and potassium-evoked release of catecholamines from encapsulated bovine chromaffin cells was analyzed over a 4-week period in vitro. Norepinephrine and dopamine release remained constant over time whereas epinephrine release significantly decreased. The chromaffin cells also retained the capacity for depolarization-elicited catecholamine release 4 weeks following the encapsulation procedure. Morphological analysis revealed the presence of intact chromaffin cells with well-preserved secretory granules. Striatal implantation of chromaffin cell-loaded capsules significantly reduced apomorphine-induced rotation compared to empty polymer capsules in animals lesioned with 6-hydroxydopamine for at least 4 weeks. Intact chromaffin cells expressing tyrosine hydroxylase and dopamine-beta-hydroxylase were observed in all capsules implanted in the striatum for 4 weeks. The assessment of the clinical potential of transplanting encapsulated adrenal chromaffin cells of either allo- or xenogeneic origin for Parkinson's disease will require long-term behavioral studies. The present study suggests, however, that the polymer encapsulation procedure may offer an alternative to adrenal autografts as a source of dopaminergic tissue.
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PMID:Transplantation of microencapsulated bovine chromaffin cells reduces lesion-induced rotational asymmetry in rats. 176 Jul 45

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) gives rise to motor deficits in humans and other primates which closely resemble those seen in patients with Parkinson's disease. These deficits are associated with a relatively selective loss of cells in the pars compacta of the substantia nigra and severe reductions in the concentrations of dopamine, noradrenaline and serotonin in the striatum. Similarly, in mice of various different strains the administration of MPTP also induces a marked loss of dopaminergic cells with severe depletion of biogenic amines, but higher doses of MPTP are required to produce these effects in mice than in primates. This review summarises advances made in understanding the biochemical events which underlie the remarkable neurotoxic action of MPTP. Major steps in the expression of neurotoxicity involve the conversion of MPTP to the toxic agent 1-methyl-4-phenylpyridinium ion (MPP+) by type B monoamine oxidase (MAO-B) in the glia, specific uptake of MPP+ into the nigro-striatal dopaminergic neurones, the intraneuronal accumulation of MPP+, and the neurotoxic action of MPP+. This is exerted mainly through the inhibition of the enzymes of the respiratory chain (Complex I), the disturbance of Ca2+ homeostasis, and possibly by the formation of free radicals. The relevance of the MPTP model to idiopathic Parkinson's disease is discussed.
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PMID:MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease. 181 82

The aim of the present study was to examine the effects of neurotensin in an animal model of Parkinson's disease (PD). Bilateral administration of 6-OHDA in the medial forebrain bundle at the level of the posterolateral hypothalamus of rats resulted in the appearance of the 3 principal neurological signs of PD: hypokinesia, rigidity and tremor. These symptoms were accompanied by severe losses of dopamine and its main metabolites in terminal regions of well-known dopamine pathways. Norepinephrine concentrations were also decreased in several regions but to a lesser extent than dopamine. Intracerebroventricular administration of neurotensin, in doses ranging from 7.5 to 120.0 micrograms, resulted in dose related attenuations of both muscular rigidity and tremors of animals. However, hypokinesia, defined as decreased motor activity was not significantly affected by the peptide. Administration of 120.0 micrograms of [Ala]NT, an inactive analogue of neurotensin, failed to alter any of the 3 neurological signs. Together, these results reveal selective antiparkinson-like effects of neurotensin in an animal model. The theoretical significance of these findings is discussed.
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PMID:Antiparkinson-like effects of neurotensin in 6-hydroxydopamine lesioned rats. 190 4


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