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)

We had previously reported that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces Parkinson's disease in humans and animals, inhibited tyrosine hydroxylation, the rate-limiting step of dopamine synthesis, in striatal tissue slices after its conversion to 1-methyl-4-phenylpyridinium ion by monoamine oxidase. In this report, structurally related compounds of 1-methyl-4-phenylpyridinium ion (MPP+) were synthesized and tested for their ability to inhibit tyrosine hydroxylation in rat striatal tissue slices. The following pyridinium salts showed inhibitory effect on tyrosine hydroxylation: pyridinium salts that substituted the alkyl group for the methyl group of MPP+ (1-ethyl-, 1-propyl-, 1-isopropyl-4-phenylpyridinium ions); pyridinium salts that changed the position of the phenyl group (1-methyl-2-phenyl-, 1-methyl-3-phenylpyridinium ions); pyridinium salts that modified the phenyl ring at 4 position (1-methyl-4-tolylpyridinium ion, 1-methyl-4-(4'-methoxyphenyl)pyridinium ion); and N-methylisoquinolinium ion. In contrast, pyridinium salts in which the phenyl group was replaced with hydrogen, methyl or methoxycarbonyl group, paraquat (1,1'-dimethyl-4,4'-dipyridinium chloride, one of bipyridinium compounds and a widely used herbicide), and N-methylquinolinium ion, showed no inhibitory effect. Nomifensine, an inhibitor of dopamine uptake, prevented the inhibition caused by 1-methyl-2-phenylpyridinium ion. The result suggests that the effective pyridinium salts are taken up into dopaminergic neurons likewise MPP+ by the dopamine transport system and inhibit tyrosine hydroxylation in striatal tissue slices. N-methylisoquinolinium ion could be one of the candidates of endogenous or environmental factors that produce Parkinson's disease.
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PMID:The effects of pyridinium salts, structurally related compounds of 1-methyl-4-phenylpyridinium ion (MPP+), on tyrosine hydroxylation in rat striatal tissue slices. 309 74

1. Selective inhibitors of the monoamine oxidase (MAO) isoenzymes, types A and B, are of potential therapeutic utility. Brain selectivity would overcome the risk of tyramine interactions which have been shown to occur with selective MAO-A but not MAO-B inhibitors. 2. (E)-3-Fluoroallylamines of general structure, FHC = C(R)CH2NH2 have been designed as enzyme-activated, irreversible inhibitors of these enzymes. Two compounds, MDL 72145 (R = 3,4 dimethoxyphenyl) and MDL 72974 (R = 4-fluorophenethyl), are selective and irreversible inhibitors of MAO type B which in vivo show high inhibitory potency against the rat brain enzyme (ED50 0.35 and 0.18 mg/kg p.o., respectively). In animals, these inhibitors do not potentiate the cardiovascular effects of tyramine and have no amphetamine-like effects. However, they do potentiate the central effects of L-Dopa and prevent the neurotoxic effects of MPTP in both mice and monkeys. 3. In early clinical studies, MDL 72145 has been shown to be a potent, long-acting inhibitor of MAO type B. Doses of 16 mg per patient totally inhibit platelet enzyme without potentiating the cardiovascular effects of oral tyramine. Compounds of this type should prove useful in Parkinson's disease. 4. Selective inhibition of brain MAO-A can be achieved by using the bioprecursor amino acid MDL 72394 (E-beta-fluoromethylene-m-tyrosine). This amino acid is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to liberate MDL 72392 (R = 3-hydroxyphenyl), a potent irreversible inhibitor of MAO-A. Combination of MDL 72394 with a peripherally selective inhibitor of AADC (e.g., carbidopa) restricts MAO inhibition to the brain. Consequently, under these conditions, there is a greatly reduced propensity to potentiate the cardiovascular effects of tyramine. 5. This has been confirmed in human volunteers; MDL 72394 (8 mg), combined with carbidopa, substantially decreased urinary MHPG and plasma DHPG concentrations with minimal potentiation of the cardiovascular effects of i.v. tyramine. These results predict that such therapy has potential in the treatment of affective disorders.
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PMID:Design and early clinical evaluation of selective inhibitors of monoamine oxidase. 326 32

The effects of the putative dopamine agonist, ciladopa hydrochloride (AY 27,110) a non-ergot compound, were investigated in animal models of dopaminergic activity to evaluate its possible role in the treatment of Parkinson's disease. Ciladopa induced stereotyped behavior in both rats and guinea pigs. Unlike apomorphine, however, ciladopa did not produce a maximum behavioral response, i.e. stereotyped gnawing. Pretreatment with haloperidol and sulpiride blocked the effects induced by ciladopa. Pretreatment with reserpine and alpha-methyl-p-tyrosine did not alter the behavioral effects of ciladopa. Ciladopa caused contralateral rotation in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine. Ciladopa induced vomiting in dogs. Small doses of ciladopa decreased locomotor activity in rats, an effect presumably mediated by presynaptic autoreceptors. The chronic injection of both subthreshold and suprathreshold doses of ciladopa failed to induce behavioral supersensitivity. Ciladopa binds to D-2 dopamine receptors in the mammalian caudate nucleus. These data indicate that ciladopa can cause stimulation of central dopaminergic receptors and that the drug is a partial dopamine agonist with direct-acting properties. Ciladopa differs from other available dopaminergic drugs and may possess therapeutic advantages for the treatment of Parkinson's disease.
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PMID:Evaluation of ciladopa hydrochloride as a potential anti-Parkinson drug. 377 30

A procedure is described for the rapid determination of the major indoles and catechols. Analysis with picogram detection limits was done by high-pressure liquid chromatography on a C18 reverse-phase column using electrochemical detection (LCEC). This method provides a comprehensive list of compounds which can be simultaneously determined in brain samples and for which there is no necessity of derivatization or pre-column purification. The regional distribution of 9 neurochemicals from rat brain and the levels of 10 neurochemicals from human brain are presented. DOPA, TYR, NE, MHPG, DOPAC, 5-HIAA, TRP, DA, HVA, 3-MT and 5-HT were detected in the caudate nucleus and putamen. The levels of neurochemicals from the caudate and putamen of a demented patient with Parkinson's disease were variably decreased; catechol and indole losses were greatest in the putamen. The levels of neurochemicals in the caudate and putamen of patients with Alzheimer's disease (SDAT) were also variably decreased; loss of NE was seen only in putamen and losses of DA, HVA and 5-HT were uniform across both caudate and putamen. The CSF of SDAT patients showed changes in NE only.
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PMID:Determination of tyrosine, tryptophan and their metabolic derivatives by liquid chromatography-electrochemical detection: application to post mortem samples from patients with Parkinson's and Alzheimer's disease. 396 72

Reduction of dopamine concentrations in the brains of patients with Parkinsonism, together with reported clinical improvement after the administration of dihydroxyphenylalanine, has led to the hypothesis that impaired hydroxylation of tyrosine may be associated with the disease. To test this hypothesis oral loading tests with L-phenylalanine and tyrosine were carried out in patients and controls. After phenylalanine lower blood levels of this were found in Parkinsonian patients than in controls, but tyrosine levels were the same. After tyrosine lower levels of this were also found in patients compared with controls. It is suggested that these findings indicate a decreased rate of tyrosine utilization in Parkinson's disease together with intestinal malabsorption; the latter is supported by the finding of abnormal D-xylose tolerance in these patients.
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PMID:Oral phenylalanine and tyrosine tolerance tests in Parkinsonian patients. 576 91

Tyrosine hydroxylase was used to identify catecholaminergic neurons in the substantia nigra and ventral tegmental area of the human mesencephalon. High enzyme activity in the normal ventral tegmental area indicated the presence of numerous cathecholaminergic neurons, most likely dopamine cells. Tyrosine-hydroxylase activity was decreased in the ventral tegmental area of parkinsonian patients, implying a lesion of the mesocortical dopamine system in Parkinson disease.
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PMID:Is the mesocortical dopaminergic system involved in Parkinson disease? 610 65

The rates of synthesis of serotonin, acetylcholine, and, under certain circumstances, dopamine and norepinephrine by brain neurons depend considerably on the availability to brain of the respective dietary precursors. This precursor dependence seems to be related to the fact that the enzyme catalyzing the rate-limiting step in the synthetic pathway for each transmitter is unsaturated with substrate at normal brain concentrations. Moreover, brain levels of the individual precursors rise following oral or parenteral administration of the pure compound or the ingestion of certain foods. Precursor-induced increases in brain transmitter formation seem to influence a variety of brain functions and behaviors, which suggests that transmitter release has been enhanced. It now appears that these precursors may become useful as therapeutic agents for the treatment of selected disease states, wherein the disease is related to reduced release of transmitter. Examples of Parkinson's disease (tyrosine), myasthenia gravis (choline or phosphatidylcholine), depression (tyrosine), and possibly abnormal appetite (tryptophan). Perhaps the future will bring the identification of still other neurotransmitters, whose rates of synthesis depend on precursor availability. Two potential candidates for which some information is already available are glycine (a spinal cord transmitter) and the prostaglandins (some of which may function as neuromodulators or transmitters) (48, 49). Each time a new precursor-product relationship is described, an opportunity becomes available for determining whether the precursor might be useful in treating disease states related to reduced transmitter release by neurons. The opportunities are worth exploring, since the use of a natural dietary constituent, even in purified form, is likely to produce fewer unwanted side-effects than are seen following administration of synthetic drugs.
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PMID:Dietary precursors and brain neurotransmitter formation. 611 81

Brain function can be affected by the availability of dietary precursors of neurotransmitters. This occurs because the rate-limiting synthetic enzymes are not "saturated" with substrate under normal circumstances. Tyrosine affects catecholaminergic neurons that fire rapidly, whether in the brain stem to decrease blood pressure in hypertension or in the adrenal gland to increase blood pressure in hypotension, and has been used in the treatment of Parkinson's disease and depression. Choline forms acetylcholine and has been used successfully in the treatment of tardive dyskinesia and memory disorders. Tryptophan, which forms serotonin, has been used for chronic pain therapy, sleep disorders, depression, and appetite control. Although these substances may lack the potency of traditionally used agonists, they offer an increase in specificity because the enzymes necessary to convert them to neurotransmitters are found only in neurons. Precursors are also "physiological"; they are consumed as foods and, therefore, should be relatively safe therapeutic agents.
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PMID:Neurotransmitter precursors and brain function. 612 95

In parkinsonian brain, TH and the BP cofactor, as well as DBH and PNMT with phenylethanolamine as substrate, are decreased. However, decrease in AADC with L-DOPA as substrate was not statistically significant. TH activity has also been shown to be decreased in striatonigral degeneration and Shy-Drager syndrome. TH reduction only in striatum but not in substantia nigra was found in a case of juvenile Parkinson's disease. Changes in AADC with L-DOPA or L-5-HTP as substrates varied in parkinsonian brains. PNMT with norepinephrine as substrate was also significantly decreased in parkinsonian brains. After administration of tyrosine to mice, the BP concentration was increased in striatum, adrenals, and serum. Mean BP concentration in serum of parkinsonian patients was slightly but significantly lower than that in controls. The serum BP increased three- to sevenfold in response to an oral tyrosine load in controls, whereas there was no increase or only a minor one (less than threefold) in parkinsonian patients. Our present results indicate that all catecholamine-synthesizing enzymes and BP synthesis may be impaired in Parkinson's disease.
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PMID:Catecholamine-related enzymes and the biopterin cofactor in Parkinson's disease and related extrapyramidal diseases. 614 12

To determine whether 1-tyrosine administration can enhance dopamine synthesis in humans as it does in rats, we measured levels of tyrosine and the major dopamine metabolite, homovanillic acid, in lumbar spinal fluids of 23 patients with Parkinson's disease before and during ingestion of 100 mg/kg/day of tyrosine. Nine patients took 100 mg/kg/day of probenecid in six divided doses for 24 hours prior to each spinal tap; 14 patients did not receive probenecid. L-tyrosine administration significantly increased CSF tyrosine levels in both groups of patients (p less than .01) and significantly increased homovanillic acid levels in the group of patients pretreated with probenecid (p less than .02). These data indicate that l-tyrosine administration can increase dopamine turnover in patients with disorders in which physicians wish to enhance dopaminergic neurotransmission.
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PMID:Effects of oral L-tyrosine administration on CSF tyrosine and homovanillic acid levels in patients with Parkinson's disease. 617 72


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