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PubMed1995

Changes in levels of monoamines and their metabolites in incompletely ischemic brains of spontaneously hypertensive rats.

In order to investigate changes in levels of monoamines and their related substances together with those of other neurotransmitters (acetylcholine and GABA), choline and substances related to energy metabolism (ATP, lactate and glucose) accompanying incomplete cerebral ischemia, a bilateral common carotid artery occlusion model of spontaneously hypertensive rats (SHR) was utilized. Animals were subjected to 1 or 2 h ischemia. Then the concentrations of substances were measured in the cerebral cortex, hippocampus and striatum and compared with control values. Due to the incomplete ischemia, ATP showed a moderate decrease, while lactate and choline increased remarkably, and GABA underwent a moderate increase. With regard to monoamines, both noradrenaline and serotonin levels were reduced in the cerebral cortex and hippocampus, whereas dopamine levels increased in the hippocampus. All monoamine metabolites, i.e. metabolites by monoamine oxidase (MAO), metabolites by catechol-O-methyltransferase (COMT), and metabolites by both MAO and COMT, underwent increases. The 3-methoxytyramine level in particular showed marked increases. Furthermore levels of precursor amino acids as well as 5-hydroxytryptophan rose. Acetylcholine decreased moderately only in the cerebral cortex. Among these changes, sustained increases in all the monoamine metabolites were characteristic of changes in the incompletely ischemic brain, suggesting that both COMT and MAO retain their activities in the incompletely ischemic brain.

Acetylcholine↗
PubMed1987

Potentiation of central effects of L-dopa by an inhibitor of catechol-O-methyltransferase.

The effects of a COMT-inhibitor, U-0521, and a MAO-B-inhibitor, 1-deprenyl, on L-dopa-induced circling behaviour were compared in 6-OHDA-lesioned rats. The actions of U-0521 and 1-deprenyl on the anti-cataleptic effect of L-dopa were also studied. Both U-0521 and 1-deprenyl were found to potentiate L-dopa-induced circling behaviour and anti-cataleptic effect of L-dopa. In both test systems the L-dopa potentiation of 1-deprenyl was longer-lasting than that caused by U-0521. Thus inhibition of COMT, like inhibition of MAO, is able to enhance the central effects of L-dopa. This principle might be beneficial in the treatment of Parkinson's disease especially if COMT-inhibitors with greater performance can be developed.

Animals↗
PubMed1997

Effect of monoamine oxidase A and B and of catechol-O-methyltransferase inhibition on L-DOPA-induced circling behavior.

The effect of enzyme-inhibiting adjuvants on L-DOPA + benserazide-induced contralateral turning in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats was studied. Both the number of turns and the duration of turning were examined. Inhibition of MAO-A with 10 mg/kg Ro 41-1049 increased both parameters; inhibition of COMT with 30 mg/kg Ro 40-7592 had a similar effect. In contrast, inhibition of MAO-B with 10 mg/kg Ro 19-6327 did not change turning behavior. A further potentiation of turning behavior was observed after the combined administration of both the MAO-A and COMT inhibitor. MAO-A inhibition in conjunction with MAO-B inhibition prolonged the duration of L-DOPA-induced turning but had no effect on the number of turns. However, in conjunction with COMT inhibition, 10 mg/kg of the MAO-B inhibitor, Ro 19-6327, significantly affected both the number and duration of turning behavior. An even further potentiation of turning behavior was observed after the combined administration of all three enzyme-inhibitors.

Animals↗
PubMed1976

Catechol-O-methyltransferase activity in psychotic children.

Catechol-O-Methyltransferase (COMT) activity was studied in three groups of institutionalized children: (1) a group of schizophrenic children; (2) a heterogeneous group of chronic psychotic children characterized by severe symptomatology and onset before 5 years of age; (3) a group of acting-out but nonpsychotic children. Erythrocyte COMT activity was found to be significantly lower among the schizophrenic subjects in contrast to the greater activity in both the other groups--the nonpsychotic and chronic psychotic children. The difference in COMT activity between psychotic groups appeared to be related to diagnosis and age of onset of disorder. Generality of findings is limited by the small sample size (N = 42) and by the difficulties inherent in the diagnosis of severe mental disorder in children. However, this preliminary study suggests that enzymatic activity may be associated with the development of schizophrenia in children.

Adolescent↗
PubMed1991

(-)-Deprenyl treatment of patients with Parkinson's disease does not affect erythrocyte catechol-O-methyl transferase activity.

(-)-Deprenyl has been increasingly used in recent years as an adjuvant with levodopa and a decarboxylase inhibitor in the treatment of Parkinson's disease. The inhibition of dopa decarboxylase and monoamine oxidase B resulting from this combination suggests that there may be a counter-regulatory increase in the activity of the third main enzyme in the catabolism of levodopa, i.e. catecholamine-O-methyl transferase (COMT). The current study on 36 patients with Parkinson's disease under long-term treatment with levodopa/dopadecarboxylase inhibitor showed, however, that the erythrocyte-COMT was unaffected by additional (-)-deprenyl medication. The patients in this study received levodopa and benserazide either with (-)-deprenyl (n = 21) or without (-)-deprenyl (n = 15). When allowance was made for the different genotypes, COMTLL, COMTLH, and COMTHH, there were no differences in the enzyme activities between the two treatment groups and the untreated controls (n = 26). On the basis of these results, consideration is given to the conditions in which COMT inhibitors are likely to be of value in the treatment of Parkinson's disease.

Aged↗
PubMed2000

[Inhibition of catechol-O-methyltransferase. Optimizing dopaminergic therapy in idiopathic Parkinson syndrome with entacapone].

Registration of the inhibitor of the catechol-O-methyltransfersase (COMT) tolcapone has been stopped due to the possible relationship of tolcapone treatment to three cases of fatal hepatitis. As a result, strong uncertainty has emerged among neurologists about the principle of COMT inhibition itself. We review data, especially on the remaining COMT inhibitor, entacapone, with regard to pre-clinical and clinical efficacy and safety.

Antiparkinson Agents↗
PubMed1999

Detection of tolcapone in the cerebrospinal fluid of parkinsonian subjects.

The cerebral availability of the peripherally and centrally acting catechol-O-methyltransferase (COMT) inhibitor tolcapone is not known in humans. Therefore, we determined the concentration of tolcapone in cerebrospinal fluid (CSF) of 12 parkinsonian subjects 1-4 h after oral application of 200 mg of the drug. The mean concentration was 56.4+/-35.5 nmol/l (mean +/- SD). This concentration was calculated to cause 75.2+/-15% (mean +/- SD) inhibition of COMT in CSF. Thus, tolcapone efficiently inhibits COMT after crossing the blood-brain barrier in humans.

Administration, Oral↗
PubMed1996

Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects.

OBJECTIVE: The purpose of this study was to assess the multiple-dose clinical pharmacology of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, in elderly subjects. METHODS: The drug was administered orally t.i.d. for 7 days to four sequential groups of eight elderly subjects (gender ratio 1:1) at doses of 100, 200, 400 and 800 mg in a double-blind, randomised, placebo-controlled, ascending-multiple-dose design. On days 2 and 7, a single dose of levodopa/benserazide 100/25 mg was given 1 h after the first intake of tolcapone. Plasma concentrations of tolcapone; its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa were determined during the course of the study in conjunction with COMT activity in erythrocytes. RESULTS: Tolcapone was well tolerated at all dose levels, with a slight increase in gastrointestinal adverse events in females at higher doses. The drug was rapidly absorbed and eliminated and showed no changes in pharmacokinetics with time during multiple doses of 100 and 200 mg t.i.d. At doses of 400 and 800 mg t.i.d., tolcapone accumulated moderately as reflected in increased Cmax and AUC values. Despite the long halflife of 3-O-methyltolcapone (39 h), only minor accumulation occurred due to suppression of its formation by tolcapone. The pharmacodynamics of tolcapone did not change during the week of treatment as reflected in inhibition of COMT activity in erythrocytes, the derived parameters of the plasma concentration-effect relationship (inhibitory Emax model with constant EC50 values) and the effect on levodopa pharmacokinetics (1.6 to 2.5-fold increase in bioavailability). This suggests the absence of tolerance development and the insignificance of the altered pharmacokinetics at 400 and 800 mg t.i.d. with regard to the pharmacodynamics. CONCLUSION: The results of this study offer promising perspectives for the application of tolcapone as adjunct therapy to levodopa in the treatment of Parkinson's disease.

Aged↗
PubMed2003

A candidate-gene approach to clone the sorghum Brown midrib gene encoding caffeic acid O-methyltransferase.

The brown midrib (bmr) mutants of sorghum have brown vascular tissue in the leaves and stem as a result of changes in lignin composition. The bmr mutants were generated via chemical mutagenesis with diethyl sulfate (DES) and resemble the brown midrib (bm) mutants of maize. The maize and sorghum brown midrib mutants are of particular value for the comparison of lignin biosynthesis across different, yet evolutionarily related, species. Although the sorghum brown midrib mutants were first described in 1978, none of the Brown midrib genes have been cloned. We have used a candidate-gene approach to clone the first Brown midrib gene from sorghum. Based on chemical analyses of the allelic mutants bmr12, bmr18 and bmr26, we hypothesized that these mutants had reduced activity of the lignin biosynthetic enzyme caffeic acid O-methyltransferase (COMT). After a northern analysis revealed strongly reduced expression of the COMT gene, the gene was cloned from the mutants and the corresponding wild types using PCR. In all three mutants, point mutations resulting in premature stop codons were identified: bmr12, bmr18 and bmr26 are therefore mutant alleles of the gene encoding COMT. RT-PCR indicated that all three mutants express the mutant allele, but at much lower levels relative to the wild-type controls. Molecular markers were developed for each of the three mutant alleles to facilitate the use of these mutant alleles in genetic studies and breeding programs.

Alleles↗
PubMed2002

3-OMD and homocysteine plasma levels in parkinsonian patients.

One main metabolizing pathway of levodopa is O-methylation to 3-O-methyldopa (3-OMD) by catechol-O-methyltransferase (COMT). Since COMT requires Mg2+ and S-adenosylmethionine as methyl donor for this transmethylating process, COMT converts S-adenosylmethionine to S-adenosylhomocysteine and subsequent homocysteine. Objective of this study was to demonstrate relations between plasma levodopa, 3-OMD and total homocysteine in treated parkinsonian subjects. We measured homocysteine, levodopa and 3-OMD by HPLC. We compared plasma homocysteine in two groups of treated parkinsonian subjects subdivided according to their 3-OMD level. Homocysteine was significantly (p = 0.002) elevated in the group with higher 3-OMD concentrations and positively (r = 0.52, p = 0.0006) correlated to 3-OMD. Homocysteine induces vascular disease. Previous studies showed an increase of ischaemic heart- and cerebrovascular disease in treated parkinsonian patients.

Dihydroxyphenylalanine↗
PubMed1999

Parkinson's Disease: Motor Fluctuations.

Motor fluctuations represent important late complications of Parkinson's disease treated with levodopa. Although treatment of these problems has improved with the emergence of numerous pharmacologic and surgical therapies, the various options can make it confusing. Pharmacologic treatment is the first step. Polytherapy is often the rule in this case with a variety of agents available as adjunctive therapy with levodopa. These adjuncts include dopamine agonists (bromocriptine, pergolide, pramipexole, ropinirole), catechol-O-methyltransferase (COMT) inhibitors (tolcapone), controlled-release formulations of levodopa, monoamine oxidase (MAO) B inhibitors (selegiline), and amantadine. The treatment can consist of any of a number of combinations of these agents. No single algorithm can be used in all patients; therapy should be individualized. Physicians treating these patients need to be well versed in late complication patterns as well as the medications chosen. In addition, optimal doses vary, and often patients are considered treatment failures and taken off medications before reaching that level. In the more complicated cases, patients should be evaluated by specialists in movement disorders. With this in mind, some guidelines are offered for the pharmacologic approach to patients with fluctuating responses to medications. For simple wearing off, controlled-release levodopa (Sinemet CR, Dupont Pharmaceuticals, Wilmington, DE), COMT inhibitors, MAO inhibitors, and dopamine agonists are reasonable options. For more complicated fluctuations, dopamine agonists with limits on levodopa are the first choice, especially when dyskinesia is present; when dyskinesia is not a factor, COMT inhibitors may be used. For dyskinesia specifically, dopamine agonists or addition of amantadine can be helpful. Surgery should be a treatment of last resort for patients in whom medical therapy fails. Patients who are candidates for medial pallidotomy should be fluctuators with severe dyskinesia and "off" periods that have not improved with pharmacologic therapy. Thalamic deep brain stimulation (DBS) should be used only in patients with tremor-predominant disease and severe intractable tremor that is unresponsive to medication and occurs not only at rest but with posture and action as well. Surgical therapy should be performed only in centers with surgeons experienced in stereotactic techniques and movement disorder specialists to ensure that the appropriate patients come to surgery and that complications are kept to a minimum. Dietary adjustment has a limited role in treating advanced Parkinson's disease.

Journal Article↗
PubMed1978

Catechol-O-methyltransferase activity in erythrocytes of pregnant women.

Catechol-O-methyltransferase (COMT) is the enzyme that converts catechols, e.g., catecholamines and catechol estrogens, to their methyl ethers. COMT activity measured in erythrocytes (RBC's) of healthy men (No. = 47) and healthy nonpregnant women (No. = 53) was 8.2 +4- 0.17 nmoles X ml.-1 (mean and standard error). The COMT activity in RBC's of healthy pregnant women (No. = 100) was 10.7 +/- 0.29 nmoles X ml.-1 RBC X hr.-1, a value which is significantly higher than that found in RBC's of men and nonpregnant women (p less than 0.001).

Adolescent↗
PubMed1983

Characterization of catechol-O-methyltransferase activity in human uterine decidua vera tissue.

In the present investigation, we characterized the activity of catechol-O-methyltransferase (COMT) in homogenates prepared from human decidua vera tissue. The specific activity of COMT in decidua vera is greater than that in liver and myometrium and much greater than that in adipose tissue and erythrocytes. The specific activity of COMT in decidua vera obtained at term was significantly greater (p less than 0.001) than that obtained early in gestation. However, we do not as yet ascribe physiologic significance to this finding since the period of time between delivery of the tissue and assay of the enzyme activity may have varied between the two groups.

Adipose Tissue↗
PubMed1982

Effect of 3',4'-dihydroxy-2-methyl-propriophenone (U-0521) on catechol-O-methyltransferase activity and on DOPA accumulation in rat red blood cells and corpus striatum.

The effects of the catechol-O-methyltransferase (COMT) inhibitor 3',4'-dihydroxy-2-methyl-propriophenone (U-0521) were studied in red blood cells (RBC) and corpus striatum in the rat. In vitro U-0521 inhibited RBC COMT activity in a dose-dependent manner with an IC50 of 6 x 10(-6)M. In vivo maximum inhibition (90%) of enzyme activity in RBC was obtained with 250 mg/kg with a peak effect at 5 min and enzyme recovery within 90 min. In U-0521-pretreated rats L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation in RBC and corpus striatum, after injection of L-DOPA, was significantly higher than in nonpretreated rats. The use of COMT inhibitor along with L-DOPA may be of benefit in the treatment of Parkinson's disease.

Animals↗
PubMed1988

Effects of butylated hydroxyanisole on glutathione S-transferase and catechol O-methyltransferase activities in Syrian golden hamsters.

The effects of dietary butylated hydroxyanisole (BHA) on the enzyme activities of glutathione (GSH) S-transferase and catechol O-methyltransferase (COMT) in the forestomach, small intestinal mucosa, and liver of Syrian golden hamsters and ICR/Ha mice were examined. GSH S-transferase activity in the hamster tissues was not enhanced appreciably after 1 or 4 weeks of feeding diets containing various concentrations of BHA. In general, short term (1 week) feeding of diets containing BHA did not differ from longer term (4 weeks) feeding of the same diets. In the forestomach of hamsters, a positive dose response on the activity of GSH S-transferase was obtained with increasing concentration of BHA in the diet for 1 or 4 weeks. The maximum effect of dietary BHA in hamsters was observed in the forestomach after 1 week of feeding, which induced an increase in GSH S-transferase activity to twice that of the control level. The same induction effect, however, was not apparent in the liver or in the small intestinal mucosa. Dietary BHA, at all concentrations studied, did not elicit any significant change in the activity of the GSH S-transferase enzyme in these two tissues. While the increase of enzyme activity in the forestomach of ICR/Ha mice was similar to that observed in the forestomach of hamsters, the induction of GSH S-transferase activity in the liver and in the small intestinal mucosa of the two animal species was drastically different. In contrast to the lack of response to dietary BHA in the hamster tissues, the induction of increased enzyme activity in the liver and intestinal mucosa of ICR/Ha mice, after 1 week of 2% BHA feeding, was greater than 7 and 11 times that of control respectively. The ineffectiveness of BHA as an enzyme inducer in the hamster tissues was similar for the activity of COMT. The enzyme activity in all three hamster tissues examined did not change significantly as a result of BHA incorporation into the diet for 1 week. In contrast, the COMT activity in the forestomach and small intestinal mucosa of the mouse was increased with increasing concentration of dietary BHA. At 2% BHA, the enzyme activity in the two tissues was 3 and 2 times that of the control level, respectively, whereas the enzyme activity in the liver remained at control level. These findings suggest that the overall unresponsiveness of detoxifying enzyme systems in the Syrian golden hamsters may be critical in the formation of forestomach tumors caused by BHA.

Animals↗
PubMed1994

Catechol-O-methyltransferase as a target for melanoma destruction?

Catechols may interfere in melanogenesis by causing increased levels of toxic quinones. Several catechols and known inhibitors of the enzyme catechol-O-methyltransferase (COMT) were therefore tested for their toxicity towards a pigmented melanoma cell line, UCLA-SO-(M14). The inhibition of thymidine incorporation as a result of exposure to the compounds was measured. All agents were compared to 4-hydroxyanisole (4HA), a depigmenting agent extensively studied as an antimelanoma drug. The compounds were also tested on the epithelial cell line, CNCM-I-(221) in the presence and absence of tyrosinase. All the compounds were more effective than 4HA towards the M14-cells at either 10(-4) M or 10(-5) M. The toxicity of 4HA towards the 221-cells was shown to be completely dependent on the presence of tyrosinase. Effects of the test agents on the 221-cells were also observed in the absence of tyrosinase. Although some of them were shown to be good substrates for tyrosinase only small changes in toxicity were observed as a result of the presence of the enzyme in comparison with 4HA. No direct correlation of the toxicity of the agents and COMT inhibition was observed. The possible mode of action of the compounds through inhibition of COMT and interference in melanogenesis is discussed together with other possibilities and factors involved.

Anisoles↗
PubMed1979

Immunohistochemical demonstration of catechol-o-methyltransferase in mammalian brain.

Catechol-O-methyltransferase (COMT)(EC 2.1.1.6) was localized using fluorescence immunohistochemistry in rat liver and kidney and in rat, chinchilla, and bovine brains. In the brain, specific fluorescence was visable only in non-neuronal cellular elements in all three species. Ventricular ependymal cells and cells of the choroid plexuses exhibited the greatest intensity of immunofluorescence. Glial immunofluorescence appeared prominently in large myelinated fiber tracts. Interfascicular and perineuronal satellite oligodendrocytes as well as fibrous astrocytes were immunoreactive, though myelin itself did not exhibit a positive reaction. Bergmann glial cells in the cerebellum also stained brightly for COMT. Although this study indicates that the predominant localization of COMT is non-neuronal, it is important to note that the presence of small quantities of this enzyme in neurons cannot be excluded. The patterns of localization observed in the non-neuronal elements suggest that this enzyme may function as a barrier to free diffusion of catechol compounds within the central nervous system.

Animals↗
PubMed1981

Modulation of slow postsynaptic potentials by dopamine, in rabbit sympathetic ganglion.

(1) Temporary exposure of rabbit's superior cervical ganglion (SCG) to dopamine (DA), in the presence of an inhibitor of catechol-o-methyltransferase (COMT) is consistently followed by a potentiation of the slow (s)-EPSP and s-IPSP, lasting for some hours. The fast (f)-EPSP is not significantly increased, but it is better maintained than in control ganglia. (2) Exposure to the COMT-inhibitor U-0521 alone induces less but substantial potentiations of both s-PSPs. This effect is explained as due to protection of DA released intraganglionically at rest. (3) This evidence suggests that COMT may significantly limit the access of catecholamines to postsynaptic receptors, for at least certain types of neuron-to-neuron synaptic actions. (4) The potentiation of both s-PSPs, whether induced by DA in the presence of U-0521 or by U-0521 alone, is depressed by DA-1 antagonists that have been found to depress DA-stimulation of adenyl cyclase in rabbit SCG; these are spiroperidol, butaclamol and, to a lesser extent, bromocriptine. The specific 'DA-2' antagonists metoclopramide and sulpiride, and the alpha-adrenergic antagonist dihydroergotamine, did not depress potentiation. (5) Potentiation of s-EPSP is viewed as identical in nature to the previously discovered DA-modulatory enhancement of direct muscarinic depolarizing actions (by acetylcholine or its agonists). Potentiation of s-IPSP may be due to a similar DA-modulation of other muscarinic response(s) involved in mediating the s-IPSP. The consistency and comparative ease with which these DA-modulatory effects can be induced, under presently described experimental conditions, should facilitate future study of this mode of synaptic action.

Animals↗