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PubMed1979

Developmental changes in the activity of catechol-O-methyl transferase in rat and rabbit fetuses.

Variations in the activity of catechol-O-methyltransferase (COMT) in peripheral organs in the brain of rat and rabbit fetus during development have been studied. The pattern of changes in COMT activity in rat fetus differed to a great extent according to the respective organs studied. In kidney and liver sharp declines occurred between days 18 and 20 and days 16 and 18 of fetal life respectively, followed by progressive increases up to onset of birth. Brain COMT of rat fetus declined progressively from day 16 of fetal life up to 0 hours after birth, while COMPT activity in adrenal and heart showed its maximum value at the 20th day of fetal life and at 0 hours after birth respectively. In the contrary, the developmental changes in activity of rabbit fetus were very similar in all the organs except in the adrenals, since it decreased between day 24 to 8 hours after birth in heart, liver, brain and kidney. In the adrenals an important increase could be seen between the 24th and 28th days of fetal life. Rat COMT activity during 4 and 8 hours of postnatal life in heart, liver and kidney declined from 0-hour value but it increased in the brain and adrenals. COMT in rabbit increased after birth in all the organs studied. The results suggest that metabolic degradation of catecholamines by 3-O-methylation in rat and rabbit fetus may have different developmental patterns to some extent according to the physiological status of the organ concerned. These species related differences for monoamine inactivation during fetal development may suggest a physiological role for COMT as a marker of the maturation of the autonomic nervous system.

Adrenal Glands↗
PubMed2003

High-performance liquid chromatography-fluorescent assay of catechol-O-methyltransferase activity in rat brain.

A method to measure catechol- O-methyltransferase (COMT) activity using high performance liquid chromatography-fluorescence detection with norepinephrine (NE) as a natural substrate was optimized for both soluble (S-) and membrane-bound (MB-) COMT activities in rat brain areas, cerebral cortex, cerebellum, hippocampus, brain stem, hypophysis, and hypothalamus. The highest S-COMT activity in Sprague-Dawley rat brain was found in hippocampus. MB-COMT activities in all brain areas were about 3-8 times lower than S-COMT activities. However, considering Vmax/ Km values, specificity constants for NE to S- and MB-COMT contributes mainly to the metabolism of NE in cerebral cortex and cerebellum.

Animals↗
PubMed1998

Pharmacokinetics and pharmacodynamics after oral and intravenous administration of tolcapone, a novel adjunct to Parkinson's disease therapy.

OBJECTIVE: To evaluate fully the pharmacokinetics and pharmacodynamics of tolcapone, a novel inhibitor of catechol-O-methyltransferase (COMT), after oral and intravenous administration. METHODS: Sixteen healthy male volunteers were given tolcapone in single doses of 200 mg orally and 50 mg intravenously, separated by a washout period of 7 days or more, in a single-center, open-label, randomized, cross-over study. Pharmacokinetic parameters were calculated using both compartmental and non-compartmental methods; pharmacodynamics were evaluated from erythrocyte COMT activity. RESULTS: After an initial lag time of 0.5 h, tolcapone was rapidly absorbed (peak plasma concentrations were reached within approximately 2 h) following either zero- or first-order absorption kinetics. The absolute bioavailability of an oral dose was approximately 60%. The volume of distribution was approximately 9 1, and the total clearance was approximately 71.h-l, resulting in a mean plasma half-life of 1.8 h. The degree of erythrocyte COMT inhibition was closely related to tolcapone plasma concentration; a rebound in COMT activity was observed after tolcapone withdrawal. Both oral and intravenous tolcapone were well tolerated. DISCUSSION: Because of its relatively low systemic clearance, tolcapone exhibits only a small degree of first-pass metabolism and a relatively good oral bioavailability, which explains the higher plasma concentrations and stronger COMT inhibition observed with tolcapone compared with entacapone, another COMT inhibitor. The pharmacokinetic and pharmacodynamic profile of tolcapone obtained in this study underlines the potential of the agent to be used as an adjunct to levodopa in the treatment of Parkinson's disease.

Administration, Oral↗
PubMed1999

Pharmacokinetics of oral entacapone after frequent multiple dosing and effects on levodopa disposition.

OBJECTIVE: Entacapone is a peripherally acting catechol O-methyltransferase (COMT) inhibitor used as an adjunct to each daily levodopa/dopa decarboxylase (DDC) inhibitor dose in the treatment of Parkinson's disease. Parkinsonian patients with advanced disease and motor fluctuations take several doses of levodopa daily, due to the short action of levodopa in this patient population. The present study was conducted in order to evaluate the pharmacokinetics of entacapone after multiple dosing and the pattern of COMT inhibition in erythrocytes during the first day of dosing as well as during steady state. Furthermore, the disposition of plasma levodopa and carbidopa was studied after a single dose of levodopa/carbidopa during the same conditions. METHODS: Twelve healthy male volunteers received 200 mg entacapone eight times daily during study day 1 and day 6 at 2-h intervals from 0800 hours to 2200 hours. During days 3, 4 and 5, 200 mg of entacapone was taken ten times daily, from 0800 hours to 0200 hours on the following day. One levodopa/carbidopa tablet (100/25 mg) was taken on study day 1 and day 6 at 1000 hours. Plasma entacapone concentrations and erythrocyte COMT activities were measured frequently on study days 1-2 and 6-7, and twice daily on study days 3-5. Pharmacokinetic parameters calculated from plasma drug concentrations on days 1-2 and 6-7 were compared with each other. RESULTS: There were no differences in maximal plasma concentration (Cmax), time to maximal drug concentration in plasma (tmax), elimination half-life (t1/2) and area under the plasma concentration-time curve (AUC) of entacapone between day 1 and day 6. The mean t1/2 values of entacapone were 1.3 h and 1.8 h during the first and sixth days, respectively; the difference was not significant. No signs of accumulation of entacapone were noted after the first day. Entacapone reduced erythrocyte COMT activity after the first dose, and this effect was quite stable during frequent dosing. There were no indications of accumulation of COMT inhibition during frequent dosing of entacapone. There were no between-day differences in Cmax, t1/2 (2.4 h on days 1-2 and 2.3 h on days 6-7) or AUC of levodopa, whereas tmax occurred at 0.8 h on day 1 and at 1.2 h on day 6 (P = 0.03). There were no between-day differences in the pharmacokinetic parameters (Cmax, tmax and AUC) of carbidopa. CONCLUSION: Even when dosed frequently, there are neither indications of accumulation of entacapone nor of its COMT inhibiting activity.

Adult↗
PubMed2006

Down-regulation of the maize and Arabidopsis thaliana caffeic acid O-methyl-transferase genes by two new maize R2R3-MYB transcription factors.

The maize (Zea mays L.) caffeic acid O-methyl-transferase (COMT) is a key enzyme in the biosynthesis of lignin. In this work we have characterized the involvement of COMT in the lignification process through the study of the molecular mechanisms involved in its regulation. The examination of the maize COMT gene promoter revealed a putative ACIII box, typically recognized by R2R3-MYB transcription factors. We used the sequence of known R2R3-MYB factors to isolate five maize R2R3-MYB factors (ZmMYB2, ZmMYB8, ZmMYB31, ZmMYB39, and ZmMYB42) and study their possible roles as regulators of the maize COMT gene. The factors ZmMYB8, ZmMY31, and ZmMYB42 belong to the subgroup 4 of the R2R3-MYB family along with other factors associated with lignin biosynthesis repression. In addition, the induction pattern of ZmMYB31 and ZmMYB42 gene expression on wounding is that expected for repressors of the maize COMT gene. Arabidopsis thaliana plants over-expressing ZmMYB31 and ZmMYB42 down-regulate both the A. thaliana and the maize COMT genes. Furthermore, the over-expression of ZmMYB31 and ZmMYB42 also affect the expression of other genes of the lignin pathway and produces a decrease in lignin content of the transgenic plants.

Amino Acid Sequence↗
PubMed1991

Purification and characterization of S-adenosyl-L-methionine: caffeic acid 3-O-methyltransferase from suspension cultures of alfalfa (Medicago sativa L.).

Caffeic acid O-methyltransferase (COMT) is one of a group of proteins present in alfalfa cell cultures which can be photoaffinity labeled with S-adenosyl-L-[methyl-3H]methionine. The enzyme was purified to homogeneity from elicitor-treated suspension cultures and shown to exist as an active monomer of subunit Mr 41,000. COMT could be separated into two forms on the basis of their isoelectric points and relative affinities for S-adenosyl-methionine and S-adenosylhomocysteine. Both forms had equal affinities for caffeic acid, were highly specific for the 3-hydroxyl group of substituted cinnamic acids, and exhibited negligible activity toward flavonoid substrates. An antiserum raised against COMT from aspen immunoprecipitated alfalfa COMT activity. Peptide mapping studies indicated that the two forms of COMT and an isoflavone O-methyltransferase from alfalfa are closely related proteins. The extractable activity of COMT doubled over a 48-h period following exposure of alfalfa cell suspensions to a yeast elicitor preparation, and this was associated with a small change in the relative proportions of the two forms of the enzyme.

Affinity Labels↗
PubMed1995

Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans.

OBJECTIVES: To assess the tolerability, pharmacokinetics and pharmacodynamics of single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor tolcapone in healthy volunteers. METHODS: In this double-blind, placebo-controlled, ascending-single-dose study, doses of 5 to 800 mg tolcapone were administered orally to eight sequential groups of six young healthy male volunteers. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of tolcapone and its 3-O-methylmetabolite were determined. Pharmacodynamics were assessed by determination of COMT activity in erythrocytes. RESULTS: Tolcapone was well tolerated at all dose levels and did not exert a detectable influence on vital sign measurements. The drug was rapidly absorbed and showed dose-proportional pharmacokinetics. Its mean elimination half-life was 2.0 +/- 0.8 hours (n = 42). Plasma levels of the 3-O-methylmetabolite of tolcapone were not proportional to dose, and its formation was delayed at higher doses. Its elimination half-life was 32 +/- 7 hours (n = 29). Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes. At doses of 200 mg and higher, COMT activity was inhibited by more than 80%. The pharmacokinetic-pharmacodynamic relationship could be described by an inhibitory Emax model and suggested that metabolites of tolcapone did not substantially contribute to its inhibitory activity. CONCLUSIONS: The novel COMT inhibitor tolcapone was well tolerated at oral doses of 5 to 800 mg. Tolcapone concentration-dependently inhibited COMT activity in erythrocytes and exhibited dose-proportional kinetics. Further investigations into its applicability in the treatment of Parkinson's disease are warranted.

Administration, Oral↗
PubMed1988

Effects of estrogens and progesterone on the catecholaminergic activity of the adrenal medulla in female rats.

Some reports in the literature allow to suspect the existence of an effect of sexual steroids on the adrenal catecholamines. To test this possibility, we have examined the catecholaminergic activity in the adrenal medulla of normal cycling rats in three phases of estrous cycle and of ovariectomized (OVX) rats injected with pharmacological doses of estradiol (ES), 2-hydroxyestradiol (HE) and/or progesterone (P). Adrenomedullary content of norepinephrine (NE) was similar during the estrous cycle, while epinephrine (E) content was increased during diestrous. This increase was concomitant with an increased phenylethanolamine-N-methyltransferase (PNMT) activity. Moreover, the monoamine oxidase (MAO) activity was significantly increased during proestrous, while the catechol-O-methyltransferase (COMT) activity was significantly decreased during estrous. In addition to these observations, ovariectomy caused a significant reduction of the E/NE ratio and of COMT and MAO activities. Administration of ES to OVX rats increased the E content, the E/NE ratio and the COMT activity as compared to vehicle-treated OVX rats. Administration of P to OVX animals led also to a significant increase of the E/NE ratio and of the COMT activity but not of the E content, while the administration of this steroid to OVX rats previously treated with ES only increased the COMT activity. Finally, administration of HE caused non-significant changes in NE and E contents and in MAO, COMT and PNMT activities. We can conclude that sexual steroids seem to be able to modify the catecholamine metabolism in the adrenal medulla and, hence, they could alter the ability of this gland to store and release these amines.

Adrenal Medulla↗
PubMed1996

Validation of assay of catechol-O-methyltransferase activity in human erythrocytes.

The multistep assay of specific catechol-O-methyltransferase (COMT) activity in human erythrocytes was validated. Enzyme preparations from lysed erythrocytes were incubated with a substrate (3,4-dihydroxybenzoic acid) in the presence of Mg2+ and S-adenosylmethionine. The reaction products (vanillic acid and isovanillic acid) were analyzable by HPLC with electrochemical detection directly in the incubation medium after protein precipitation. The precision was calculated in order to define the random variability associated with the method by intra-assay and inter-assay relative standard deviations (RSDs) for the assays of both reaction products and protein. The intra-assay RDSs for the specific activities were between 4.8 and 11.9% (n = 5-6) at two levels of COMT activity. The inter-assay RSDs were between 6.4 and 14.2% (n = 5-6), respectively. The total variation was mostly caused by the protein assay and the HPLC assay, and contributions from the sample preparation and incubation steps were minor. Some results from the clinical application of the erythrocyte COMT assay are also reported. For both normal volunteers and patients having Parkinson's disease, a single 400 mg dose of entacapone, a peripherally acting COMT inhibitor, decreased the erythrocyte COMT activity. The application demonstrates that the assay was able to detect differences between the subjects and the effect of COMT inhibition in the clinical study.

Blood Proteins↗
PubMed1995

Neuronal and non-neuronal catechol-O-methyltransferase in primary cultures of rat brain cells.

Previous biochemical and histochemical studies have suggested that catechol-O-methyltransferase (COMT) is a predominantly glial enzyme in the brain. The aim of this work was to study its localization and molecular forms in primary cultures, where cell types can be easily distinguished with specific markers, COMT immunoreactivity was studied in primary astrocytic cultures from newborn rat cerebral cortex, and in neuronal cultures from rat brain from 18-day-old rat embryos using antisera against rat recombinant COMT made in guinea pig. Double-staining studies with specific cell markers to distinguish astrocytes, neurons and oligodendrocytes were performed. COMT immunoreactivity colocalized with a specific oligodendrocyte marker galactocerebroside in cells displaying oligodendrocyte morphology, flat cells displaying type-1 astrocyte morphology and glial fibrillary acidic protein, in branched cells displaying type-2 astrocyte morphology and in cell bodies of neurons, the processes of which displayed neurofilament immunoreactivity. Western blots detected both soluble 24 kDa and membrane-bound 28-kDa COMT proteins in neuronal and astrocyte cultures. The results suggest that COMT is synthesized by cultured astrocytes, oligodendrocytes and neurons.

Animals↗
PubMed2005

Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure-activity relationship and molecular-modeling studies.

(-)-Epigallocatechin-3-gallate (EGCG) is the major polyphenol present in green tea. We previously demonstrated that EGCG was both a substrate and potent inhibitor of human liver cytosolic catechol-O-methyltransferease (COMT). We now report the structure-activity relationship for the inhibition of COMT-catalyzed O-methylation of catecholestrogens in human liver cytosol by tea catechins and some of their metabolites. The most potent inhibitors were catechins with a galloyl-type D-ring, including EGCG (IC(50)=0.07 microM), 4''-O-methyl-EGCG (IC(50)=0.10 microM), 4',4''-di-O-methyl-EGCG (4',4''-DiMeEGCG) (IC(50)=0.15 microM), and (-)-epicatechin-3-gallate (ECG) (IC(50)=0.20 microM). Catechins without the D-ring showed two to three orders of magnitude less inhibitory potency. Enzyme kinetic analyses revealed that EGCG behaved as a mixed inhibitor, whereas 4',4''-di-O-methyl-EGCG exhibited competitive kinetics for the S-adenosylmethionine (SAM), and noncompetitive kinetics for the catechol binding site. These compounds may represent a new type of COMT inhibitor. In silico molecular-modeling studies using a homology model of human COMT were conducted to aid in the understanding the catalytic and inhibitory mechanisms. Either D-ring or B-ring of EGCG could be accommodated to the substrate binding pocket of human COMT. However, the close proximity (2.6A) of 4''-OH to the critical residue Lys144, the higher acidity of the hydroxyl groups of the D-ring, and the hydrophobic interactions between the D-ring and residues in the binding pocket greatly facilitated the interaction of the D-ring with the enzyme, and resulted in increased inhibitory potency. These results provide mechanistic insight into the inhibition of COMT by commonly consumed tea catechins.

Catechin↗
PubMed2006

Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond.

This review summarizes our current understanding of catechol-o-methyltransferase (COMT) and how it relates to brain function and schizophrenia. We begin by considering the COMT gene, its transcripts and proteins, and its relevance for central catecholamine function. We then describe how variation in COMT activity affects the function of the prefrontal cortex (PFC) and associated areas, reviewing evidence that COMT modulates executive function and working memory and highlighting recent data that also implicate it in emotional processing. Finally, we discuss briefly the genetic association between COMT and schizophrenia, focusing in particular on the complex interaction of functional loci within the gene that may underlie the mixed results of studies to date. We conclude by outlining preliminary data indicating that COMT is a promising therapeutic target for ameliorating the cognitive deficits associated with schizophrenia.

Amino Acid Substitution↗
PubMed2007

Catechol-O-methyl transferase and expression of schizophrenia in 73 adults with 22q11 deletion syndrome.

BACKGROUND: Catechol-O-methyl transferase (COMT) is a candidate gene for schizophrenia with a role in dopamine metabolism, particularly in frontal cortex. COMT is within the region commonly deleted in 22q11 deletion syndrome (22q11DS), a syndrome with high prevalence of schizophrenia. We examined the role of COMT in schizophrenia-related expression in 22q11DS. METHODS: We genotyped the COMT functional Val(158/108)Met allele in 73 Caucasian adults with 22q11DS (36 men, 37 women; aged 33.8, SD 10.1 years; 37 Met, 36 Val hemizygosity) blind to clinical data and assessed effects on symptoms and frontal functioning. RESULTS: The lower activity Met allele was not significantly more prevalent than the Val allele in 33 subjects with schizophrenia. Excitement symptoms were more severe, however, and three frontal cognitive tests (theory of mind, Trails B, and olfactory identification), communication, and social functioning measures showed significantly worse performance with Met allele hemizygosity, even after accounting for effects of schizophrenia. CONCLUSIONS: The results suggest that hemizygosity of the COMT functional allele exerts an effect on some measures of frontal functioning in 22q11DS. Elevated levels of tonic dopamine activation associated with the COMT Met allele may underlie these aspects of expression. We must look elsewhere for causes of the high prevalence of schizophrenia in 22q11DS, however.

Adult↗
PubMed2005

Polymorphic catechol-O-methyltransferase gene, duration of estrogen exposure, and breast cancer risk: a nested case-control study in Taiwan.

BACKGROUND: Polymorphic catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol estrogens, which are hypothesized to participate in estrogen-induced carcinogenesis. METHODS: We examined 87 cases and 341 population controls in Taiwan to determine the association between the functional genetic Val158Met polymorphism in membrane-bound form of COMT gene and female breast cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by conditional logistic regression. RESULTS: There was no overall association between COMT genotype and individual susceptibility to breast cancer. However, COMT-L variant genotypes appear to pose increased risk of breast cancer in women with greater duration from menarche to first full-term pregnancy (>8 years) (OR, 2.67; 95% CI, 1.00-7.36). CONCLUSIONS: This study based on limited sample sizes suggests that there may be no overall association of COMT genotype with breast cancer, but the COMT-L allele could pose enhanced risk of breast cancer in the presence of relevant environmental exposures, as most low penetrance gene are expected to act through gene-environment interactions.

Adult↗
PubMed2004

Association between the low activity genotype of catechol-O-methyltransferase and myocardial infarction in a hypertensive population.

AIM: Estrogens regulate several biological processes involved in the pathogenesis of myocardial infarction. Catechol-O-methyltransferase (COMT) is a key enzyme in the degradation of estrogens. There is a functional polymorphism in the COMT gene (Val158Met), affecting the activity of the enzyme. We investigated if the low activity genotype of COMT is associated with an altered risk of myocardial infarction. METHODS AND RESULTS: In a prospectively followed hypertensive cohort we identified 174 patients who suffered a myocardial infarction during the study and compared them to 348 controls from the same cohort. The COMT polymorphism and serum levels of sex hormones were analysed. Patients homozygous for the low activity COMT genotype had a decreased risk of myocardial infarction compared to those with the high activity genotype, odds ratio 0.65 (95% CI 0.44-0.97, p=0.033 ). The protective effect of the low activity genotype was most evident among older patients (> 58 years of age), odds ratio 0.43 (95% CI 0.23-0.79, p=0.006 ). Serum levels of estradiol were increased ( p=0.006 ) in males with the low activity genotype. CONCLUSIONS: Our findings suggest that the low activity COMT genotype is protective against myocardial infarction. One may speculate that the altered estrogen status could be involved in this effect.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

The role of physicochemical properties of entacapone and tolcapone on their efficacy during local intrastriatal administration.

Aqueous solubility, apparent partition coefficient (logPapp) and catechol-O-methyltransferase (COMT, EC 2.1.1.6) inhibiting potency of entacapone and tolcapone were compared in vitro. Both drugs (at 10 and 100 microM) were also delivered directly into rat striatum via a microdialysis probe. Extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations were measured to evaluate the inhibition of striatal COMT in vivo. Although entacapone had 15-fold better aqueous solubility than tolcapone at pH 7.4, also tolcapone had sufficient aqueous solubility to remain in solution at 100 microM. The logPapp of tolcapone was higher than that reported for entacapone in the pH range from 5.0 to 7.4. Entacapone and tolcapone inhibited equally rat striatal COMT in vitro with Ki values of 1.86 and 2.50 nM, respectively. Both drugs had similar outflow from the microdialysis probe in vitro. Perfusion of 100 microM entacapone increased significantly extracellular DOPAC levels compared to the control group. Both entacapone and tolcapone (at 10 and 100 microM) decreased significantly HVA levels, but entacapone was significantly more effective than tolcapone at 100 microM. In conclusion, entacapone and tolcapone are equally potent COMT inhibitors against rat striatal COMT in vitro. After local intrastriatal administration, entacapone appeared to inhibit COMT faster and more effectively than the more lipophilic tolcapone. Thus, intrastriatal administration led to opposite results compared to those reported in the brain after systemic administration. The present results also suggest that the local distribution of entacapone and tolcapone differ when the drugs are delivered directly into the brain.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Polymorphism of estrogen metabolism genes and cataract.

Cataract is the leading cause of visual impairment in older adults in the world. Age-related lens opacities are common and are frequent causes of loss of vision. The incidence of cataract increases significantly with increasing age in women only. The onset coincides with estrogen deficiency that occurs after menopause. Hormone replacement therapy has proven beneficial to selected postmenopausal women. Estrogen effects on biological system are modulated via the estrogen receptors (ER) and/or estrogen metabolites. Although ER have been detected in ocular tissue, whether ER polymorphism is related to cataract is not known at present. The polymorphisms of estrogen metabolizing enzymes are also related to the serum concentration and activity of estrogen. Polymorphism such as cytochrome P450c17 (A2/A2), cytochrome P450c1A (vt/vt) will result in increased formation of catechol estrogen, while people with catechol-O-methyltransferase (COMT) polymorphism COMT (L/L) will have decreased metabolism of catechol estrogen and decreased level of methoxyestradiol. COMT was also involved in tamoxifen metabolism which may further decrease the activity of COMT in breast cancer patients treated with tamoxifen. It is known that a 4-7% increase in cataract was found in tamoxifen-treated breast cancer patients than non-user. The 7.0% COMT (L/L) genotype in general population corresponded well with the 4-7% of cataract formation in tamoxifen-treated breast cancer patients. Our hypothesis is that breast cancer patients with COMT (L/L) genotype may be at increased risk of cataract formation after tamoxifen treatment.

Biomarkers, Tumor↗
PubMed2006

Prostaglandin J2 reduces catechol-O-methyltransferase activity and enhances dopamine toxicity in neuronal cells.

There is clear evidence that an inflammatory reaction is mounted within the CNS following trauma, stroke, infection and seizures, thus augmenting brain damage. Furthermore, chronic inflammation of the CNS is implicated in many neurodegenerative disorders. However, the effects of products of inflammation on neuronal cells are poorly understood. Herein, we characterize the effects of a neurotoxic product of inflammation, prostaglandin J2 (PGJ2), on catechol-O-methyltransferase (COMT) in human dopaminergic-like neuroblastoma SK-N-SH cells and rat (P2) cortical neurons. COMT metabolizes catechols and catecholamines, a pathway relevant to neurodegeneration. PGJ2 treatment reduced the expression and activity of COMT, induced its sequestration into perinuclear aggregates and potentiated dopamine toxicity. The large COMT aggregates were co-localized with the centrosome, suggesting an aggresome-like structure. Our results indicate that COMT impairment induced by PGJ2 treatment may increase the concentration of dopamine (or its metabolites) to neurotoxic levels. Thus, COMT impairment following pro-inflammatory events may be a potential risk factor in neurodegeneration.

Animals↗