Identification and optimization of nitrophenolic analogues as dopamine metabolic enzyme inhibitors for the treatment of Parkinson's disease.

Progressive loss of dopaminergic neurons leads to the depletion of the striatal neurotransmitter dopamine, which is the main cause of Parkinson's disease (PD) motor symptoms. Simultaneous inhibition of the two key dopamine metabolic enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B), could potentially be a breakthrough in achieving clinical efficacy. Representative compound C12 exhibits good COMT inhibitory activity (IC50 = 0.37 µM), metal chelation ability, and BBB permeability. Furthermore, results from in vivo biological activity evaluations indicate that C12 can improve dopamine levels and ameliorate MPTP-induced PD symptoms in mice. Preliminary in vivo and in vitro study results highlight the potential of compound C12 in PD treatment.

The Catechol O-Methyltransferase Inhibitor Entacapone in the Treatment of Parkinson's Disease: Personal Reflections on a First-in-Class Drug Development Programme 40 Years On.

In the 1980s, Orion Pharma, then a mid-ranking Nordic area pharmaceutical company, established a drug development programme on the inhibition of catechol O-methyltransferase (COMT). This enzyme, which plays an important role in the inactivation of catecholamine neurotransmitters and drugs with a catechol structure, thus came under consideration as a target in the innovative translational and clinical programme we describe in this historical review. The starting point was the conjecture that a peripherally acting COMT inhibitor might improve entry of levodopa into the brain. This had potentially significant implications for the medical treatment of Parkinson's disease (PD). The rationale was that more efficient delivery of levodopa to the brain might allow the high therapeutic doses of levodopa to be reduced and the dose interval to be extended. Elucidation of structure-activity relations paved the way for the discovery and development of entacapone, a 5-nitrocatechol that was a potent and highly specific inhibitor of COMT. Experience in phase III clinical trials established that entacapone, used as an adjunct to regular or controlled-release levodopa preparations (also including a peripherally acting dopa-decarboxylase inhibitor), increased ON-time and reduced OFF-time and improved clinical condition in patients with PD experiencing wearing-off, often with a reduced daily levodopa dose. Several of these studies also identified that entacapone improved patients' quality of life and was cost-effective. Subsequently, entacapone has been amalgamated into a triple-combination preparation (Stalevo®) with levodopa and carbidopa to create a flexible and convenient drug therapy for patients with PD who have end-of-dose motor fluctuations not stabilised on levodopa/dopa-decarboxylase inhibitor treatment. This review offers a historical perspective on a successful programme of drug development by researchers who played central roles in the progress from exploratory hypothesis to registered pharmaceutical product.

Interaction between catechol-O-methyltransferase Val/Met polymorphism and cognitive reserve for negative symptoms in schizophrenia.

BACKGROUND: Cognitive reserve (CR) and the catechol-O-methyltransferase (COMT) Val/Met polymorphism are reportedly linked to negative symptoms in schizophrenia. However, the regulatory effect of the COMT genotype on the relationship between CR and negative symptoms is still unexamined. AIM: To investigate whether the relationship between CR and negative symptoms could be regulated by the COMT Val/Met polymorphism. METHODS: In a cross-sectional study, 54 clinically stable patients with schizophrenia underwent assessments for the COMT genotype, CR, and negative symptoms. CR was estimated using scores in the information and similarities subtests of a short form of the Chinese version of the Wechsler Adult Intelligence Scale. RESULTS: COMT Met-carriers exhibited fewer negative symptoms than Val homozygotes. In the total sample, significant negative correlations were found between negative symptoms and information, similarities. Associations between information, similarities and negative symptoms were observed in Val homozygotes only, with information and similarities showing interaction effects with the COMT genotype in relation to negative symptoms (information, ß = -0.282, 95%CI: -0.552 to -0.011, P = 0.042; similarities, ß = -0.250, 95%CI: -0.495 to -0.004, P = 0.046). CONCLUSION: This study provides initial evidence that the association between negative symptoms and CR is under the regulation of the COMT genotype in schizophrenia.

Catechol-O-methyltransferase and monoamine oxidase B inhibitory activities of Australian bee pollen.

Bee pollen is an apicultural product collected by honeybees from flower stamens and used as a functional food worldwide. In the present study, we aim to elucidate the functions of Australian bee pollen. Australian bee pollen extracts and their main components were tested for catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAOB) inhibitory activities. These enzymes are key neurotransmitters involved in Parkinson's disease and depression. Myricetin (5), tricetin (6), and luteolin (7) exhibited high COMT inhibitory activities (half maximal inhibitory concentration [IC50] = 23.3, 13.8, and 47.4 µM, respectively). In contrast, 5, 7, and annulatin (8) exhibited MAOB inhibitory activities (IC50 = 89.7, 32.8, and 153 µM, respectively). Quantitative analysis via high-performance liquid chromatography revealed that 5 was abundant in Australian bee pollen extracts. Our findings suggest that 5 contributes to the COMT and MAOB inhibitory activities of Australian bee pollen.

Inhibition of catechol-O-methyltransferase (COMT) by heparin oligosaccharides with specific structures.

COMT inhibitors are commonly used to improve the effectiveness of levodopa in treating Parkinson's disease by inhibiting its conversion to 3-O-methyldopa. Because of the serious side effect of nitrocatechol COMT inhibitors, it is necessary to develop non-nitrocatechol COMT inhibitors with a higher safety profile. Heparin has been observed to bind to COMT. However, the exact functional significance of this interaction is not fully understood. In this study, the contribution of different substitution of heparin to its binding with COMT was investigated. In vitro and in vivo, heparin oligosaccharides can bind to COMT and inhibit its activity. Furthermore, we enriched the functional heparin oligosaccharides that bind to COMT and identified the sequence UA2S-GlcN(S/Ac)6(S/H)-UA2S-GlcNS6(S/H)-UA2(S/H)-GlcNS6S as the characteristic structural domain of these functional oligosaccharides. This study has elucidated the relationship between the structure of heparin oligosaccharides and their activity against COMT, providing valuable insights for the development of non-nitrocatechol COMT inhibitors with improved safety and efficacy.

Spasmolytic Effect of Flopropione Does Not Involve Catechol-O- methyltransferase (COMT) Inhibition.

Flopropione (Flo) has been used for gallstone and urolithiasis as a spasmolytic agent almost exclusively in Japan. According to the package insert, its main mechanism is catechol-O-methyltransferase (COMT) inhibition and anti-serotonergic effect. This is obviously contrary to pharmacological common sense, but it is described that way in pharmacology textbooks and occurs in questions in the National Examination for Pharmacists in Japan. As this is a serious problem in education, we re-examined the action of Flo. The guinea pig ureter was hardly contracted by serotonin, but noradrenaline (NA) elicited repetitive twitch contraction, which was inhibited by Flo. The sphincter of Oddi (SO) exhibited a spontaneous repetitive twitch contraction, which was inhibited by NA and Flo. The inhibitory effect of NA was reversed by α- and ß-blockers, whereas that of Flo was not. Entacapone, a representative COMT inhibitor, did not affect the movement of the ureter and the SO. Nifedipine suppressed carbachol-induced contraction of the taenia coli, spontaneous movement of the SO, and NA-induced contraction of the ureter to almost the same extent, whereas Flo did not inhibit the taenia coli, but inhibited the contraction of the SO and the ureter. The inhibitory pattern of Flo resembled that of the ryanodine receptor agonist 4-chloro-m-cresol and the inositol 1,4,5-trisphosphate (IP3) receptor antagonist 2-aminoethoxydiphenyl borate. It is concluded that COMT inhibition or serotonin inhibition is not involved in the spasmolytic action of Flo. Flo might act on ryanodine receptors and/or IP3 receptors, which are responsible for periodic Ca release from Ca stores, to disrupt coordinated Ca dynamics.

A systematic review of the cognitive effects of the COMT inhibitor, tolcapone, in adult humans.

OBJECTIVE: The catechol-o-methyltransferase (COMT) inhibitor tolcapone constitutes a potentially useful probe of frontal cortical dopaminergic function. The aim of this systematic review was to examine what is known of effects of tolcapone on human cognition in randomized controlled studies. METHODS: The study protocol was preregistered on the Open Science Framework. A systematic review was conducted using PubMed to identify relevant randomized controlled trials examining the effects of tolcapone on human cognition. Identified articles were then screened against inclusion and exclusion criteria. RESULTS: Of the 22 full-text papers identified, 13 randomized control trials were found to fit the pre-specified criteria. The most consistent finding was that tolcapone modulated working memory; however, the direction of effect appeared to be contingent on the COMT polymorphism (more consistent evidence of improvement in Val-Val participants). There were insufficient nature and number of studies for meta-analysis. CONCLUSION: The cognitive improvements identified upon tolcapone administration, in some studies, are likely to be due to the level of dopamine in the prefrontal cortex being shifted closer to its optimum, per an inverted U model of prefrontal function. However, the results should be interpreted cautiously due to the small numbers of studies. Given the centrality of cortical dopamine to understanding human cognition, studies using tolcapone in larger samples and across a broader set of cognitive domains would be valuable. It would also be useful to explore the effects of different dosing regimens (different doses; and single versus repeated administration).

A newly synthesized flavone avoids COMT-catalyzed methylation and mitigates myocardial ischemia/reperfusion injury in H9C2 cells via JNK and P38 pathways.

Objectives: Luteolin is a flavone that provides defense against myocardial ischemia/reperfusion (I/R) injury. However, this compound is subjected to methylation mediated by catechol-O-methyltransferase (COMT), thus influencing its pharmacological effect. To synthesize a new flavone from luteolin that avoids COMT-catalyzed methylation and find out the protective mechanism of LUA in myocardial I/R injury. Materials and Methods: Luteolin and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) were used to synthesize the new flavone known as LUAAPH-1 (LUA). Then, the myocardial ischemia/reperfusion injury cell model was established using H9c2 cells to detect the effect in myocardial ischemia/reperfusion regulation and to identify the underlying mechanism. Results: Pretreatment with LUA (20 µmol/l) substantially increased cell viability while reducing cell apoptosis rate and caspase-3 expression induced by I/R, and the protective effect of LUA on cell viability was stronger than diosmetin, which is the major methylated metabolite of luteolin. In addition, intracellular reactive oxygen species (ROS) production and calcium accumulation were both inhibited by LUA. Furthermore, we identified that LUA markedly relieved the promotive effects of I/R stimulation upon JNK and p38 phosphorylation. Conclusion: LUT pretreatment conveys significant cardioprotective effects after myocardial I/R injury, and JNK and p38 MAPK signaling pathway may be involved.

Effects of functional polymorphisms of opioid receptor mu 1 and catechol-O-methyltransferase on the neural processing of pain.

AIM: Pain is reconstructed by brain activities and its subjectivity comes from an interplay of multiple factors. The current study aims to understand the contribution of genetic factors to the neural processing of pain. Focusing on the single-nucleotide polymorphism (SNP) of opioid receptor mu 1 (OPRM1) A118G (rs1799971) and catechol-O-methyltransferase (COMT) val158met (rs4680), we investigated how the two pain genes affect pain processing. METHOD: We integrated a genetic approach with functional neuroimaging. We extracted genomic DNA information from saliva samples to genotype the SNP of OPRM1 and COMT. We used a percept-related model, in which two different levels of perceived pain intensities ("low pain: mildly painful" vs "high pain: severely painful") were employed as experimental stimuli. RESULTS: Low pain involves a broader network relative to high pain. The distinct effects of pain genes were observed depending on the perceived pain intensity. The effects of low pain were found in supramarginal gyrus, angular gyrus, and anterior cingulate cortex (ACC) for OPRM1 and in middle temporal gyrus for COMT. For high pain, OPRM1 affected the insula and cerebellum, while COMT affected the middle occipital gyrus and ACC. CONCLUSION: OPRM1 primarily affects sensory and cognitive components of pain processing, while COMT mainly influences emotional aspects of pain processing. The interaction of the two pain genes was associated with neural patterns coding for high pain and neural activation in the ACC in response to pain. The proteins encoded by the OPRM1 and COMT may contribute to the firing of pain-related neurons in the human ACC, a critical center for subjective pain experience.

Moderating effects of preoperative knee pain and pain catastrophizing on the relation between COMT rs4680 genotypes and chronic postsurgical pain in total knee arthroplasty patients.

BACKGROUND: The Catechol-O-methyltransferase (COMT) gene, responsible for encoding an enzyme crucial in the metabolism of catecholamines, is known to play a significant role in pain perception. Polymorphisms within this gene, particularly the COMT rs4680 genotypes, have been linked to various acute pain phenotypes. This prospective cohort study examines interactions among the genetic polymorphism COMT rs4680 genotypes, preoperative knee pain, and pain catastrophizing in chronic postsurgical pain (CPSP) at 3, 6, and 12 months post-total knee arthroplasty (TKA). STUDY DESIGN: A total of 280 patients undergoing primary unilateral TKA participated, sharing demographic details, preoperative knee pain levels, psychological variables (pain catastrophizing), and COMT rs4680 genotyping via venous blood samples. Telephone interviews at specified intervals enabled the application of binary logistic regressions and interaction models. RESULTS: Significant influences of preoperative knee pain and pain catastrophizing on postsurgical outcomes were observed. Specifically, at the first time point (T1, 3 months post-TKA), a notable moderation effect was identified in preoperative knee pain (R2 change = 0.026, p = 0.026). The Johnson-Neyman regions of significance (RoS) indicated these moderation effects were significant above a threshold of 17.18 (p = 0.05), accounting for 26.4%. At the third time point (T3, 12 months post-TKA), a complex three-way interaction among genotypes (GG, GA, and AA carriers) was evident, resulting in an R2 change of 0.051 (p = 0.009). Here, the RoS for pain catastrophizing was above 32.74 for 30.5% of GG genotype carriers, above 22.38 for 50.8% of GA carriers, and below 11.94 for 63.2% of AA carriers. CONCLUSION: This study illuminates the significant role of the COMT Val158Met rs4680 polymorphism in susceptibility to prolonged pain following TKA. It also elucidates how these genetic genotypes interplay with preoperative knee pain and pain catastrophizing. Such intricate genetic-psychological-pain relationships necessitate additional investigation to confirm these findings and potentially guide post-TKA pain management strategies.

Catechol-O-methyltransferase gene (COMT) is associated with neurocognitive functioning in patients with sickle cell disease.

PURPOSE: Neurocognitive impairment is a common and debilitating complication of sickle cell disease (SCD) resulting from a combination of biological and environmental factors. The catechol-O-methyltransferase (COMT) gene modulates levels of dopamine availability in the prefrontal cortex. COMT has repeatedly been implicated in the perception of pain stimuli and frequency of pain crises in patients with SCD and is known to be associated with neurocognitive functioning in the general population. The current study aimed to examine the associations of genetic variants in COMT and neurocognitive functioning in patients with SCD. PATIENTS AND METHODS: The Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort was used as a discovery cohort (n = 166). The genotypes for 5 SNPs (rs6269, rs4633, rs4818, rs4680, and rs165599) in COMT were extracted from whole genome sequencing data and analyzed using a dominant model. A polygenic score for COMT (PGSCOMT) integrating these 5 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (CSSCD, n = 156) and the Silent Cerebral Infarction Transfusion (SIT, n = 114) Trial were used as 2 independent replication cohorts. Due to previously reported sex differences, all analyses were conducted separately in males and females. The Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (q-value). RESULTS: In SCCRIP, 1 out of 5 SNPs (rs165599) was associated with IQ at q<0.05 in males but not females, and 2 other SNPs (rs4633 and rs4680) were marginally associated with sustained attention at p<0.05 in males only but did not maintain at q<0.05. PGSCOMT was negatively associated with IQ and sustained attention at p<0.05 in males only. Using 3 cohorts' data, 4 out of 5 SNPs (rs6269, rs4633, rs4680, rs165599) were associated with IQ (minimum q-value = 0.0036) at q<0.05 among male participants but not female participants. The PGSCOMT was negatively associated with IQ performance among males but not females across all cohorts. CONCLUSION: Select COMT SNPs are associated with neurocognitive abilities in males with SCD. By identifying genetic predictors of neurocognitive performance in SCD, it may be possible to risk-stratify patients from a young age to guide implementation of early interventions.

A randomized trial of the effects of COMT inhibition on subjective response to alcohol: Moderation by baseline COMT activity and mediation of alcohol self-administration.

BACKGROUND: Poor inhibitory control and enhanced subjective response to alcohol are interrelated risk factors for alcohol use disorder (AUD) that share underlying neural substrates, including dopamine signaling in the right prefrontal cortex, a potential target for pharmacological intervention. Cortical dopamine inactivation is primarily regulated by catechol-O-methyltransferase (COMT), an enzyme with large variation in activity as a function of the COMT rs4680 (val158met) single nucleotide polymorphism. In a previous randomized, placebo-controlled trial of the COMT inhibitor tolcapone (200 mg TID) in non-treatment-seeking participants with AUD, we found that tolcapone, relative to placebo, reduced alcohol self-administration only among rs4680 val-allele homozygotes, whose COMT activity is higher than in met-allele carriers. METHODS: We conducted secondary analyses of the effects of tolcapone and baseline COMT activity, as indexed by both rs4680 genotype and an enzymatic activity assay, on the subjective response to alcohol in a bar-laboratory paradigm among 60 participants in the previous trial. RESULTS: Tolcapone did not affect alcohol-induced stimulation or sedation more than placebo. However, baseline COMT activity moderated the effects of the drug on both outcomes, such that tolcapone-treated participants with higher baseline COMT activity had less stimulation (p = 0.008) and sedation (p = 0.053) than participants with lower baseline COMT activity and those treated with placebo. Additionally, alcohol-induced stimulation significantly mediated the interacting effects of baseline COMT activity and tolcapone on bar-laboratory self-administration. CONCLUSIONS: Tolcapone may reduce subjective response to alcohol more effectively among individuals with preexisting high COMT activity an effect that could account for the drug's reduction of alcohol consumption among these individuals.

Evaluation of the association COMT Val158Met variant and childhood trauma on aggression in Turkish SCZ patients.

Childhood trauma is a serious form of stress that makes individuals more vulnerable to developing Schizophrenia (SCZ). Many studies have predicted the association between the catechol-O-methyltransferase (COMT) gene Val158Met variant and aggressive attack. We aimed to investigate the association the COMT variant and childhood trauma on aggression in Turkish SCZ patientsThis study included 89 patients diagnosed with SCZ. Childhood Trauma Questionnaire (CTS) and Overt Aggression Scale (OAS) were used to assess childhood trauma and aggression. COMT Val158Met variant was analyzed by PCR-RFLP method from isolated DNAs.There was no statistically significant difference in comparing the COMT genotype distribution and clinical characteristics including suicide attempts, self-destructive behavior, crime history, substance, alcohol and tobacco use. When we evaluate Spearman's rank correlation coefficients between CTQ and OAS, the correlation between the OAS and CTQ scores of the patients was statistically significant except for the sexual abuse subgroup of the CTQ. In the univariate logistic regression analysis, in which the dichotomized OAS score was accepted as the dependent variable, it was found that age, suicide attempt, substance abuse, and CTQ total score significantly predicted the higher OAS scores. In the multivariate logistic regression analysis, which included the variables that predicted OAS significantly, age, suicide attempt, and total CTQ score were determined as independent variables predicting OAS.Because of the phenotypic complexity in SCZ, it is difficult to draw strong conclusions about COMT and to highlight a definitive relationship. Larger-scale studies are needed to examine the multifactorial inheritance pattern of schizophrenia in different dimensions.

To Each His Own Fear: Gender-Related Association of Anxiety, Substance Use, and Eating Disorders in a Representative Birth Cohort Sample of Young Adults with Either COMT Val158Met allele.

INTRODUCTION: The role of catechol-O-methyltransferase (COMT) in catecholamine neurotransmitter metabolism has led to the investigation of variants of the corresponding gene in the etiology of different psychiatric disorders, but the results are inconclusive. METHODS: We have examined the relationship between COMT Val158Met single nucleotide polymorphism (rs4680) and the occurrence of psychiatric disorders in a highly representative birth cohort sample of young adults in the Estonian Children Personality Behaviour and Health Study (original n = 1,238). The lifetime occurrence of psychiatric disorders at the age of 25 years was assessed with the Mini-International Neuropsychiatric Interview. RESULTS: Both Val- and Met-alleles of the COMT Val158Met were associated with specific psychiatric disorders. Met-allele carriers had a significantly higher occurrence of agoraphobia (3.2% vs. 0.5%; χ2 = 4.10; p < 0.05) compared to Val/Val homozygotes. Also, the occurrence of panic disorder was significantly higher in female Met-allele carriers than in Val/Val homozygote females (10.2% vs. 3.6%; χ2 = 4.62 p = 0.03). In contrast, the occurrence of generalized anxiety disorder was higher in Val/Val females when compared to Met-allele carriers (12.7% vs. 6.8%; χ2 = 4.16; p = 0.04). Also, female Val/Val homozygotes (15.5%) had a higher occurrence of eating disorders than Met-allele carriers (6.1%) of the COMT Val158Met polymorphism (χ2 = 10.39; p = 0.002). In the whole sample, Met-allele homozygotes had a higher occurrence of alcohol use and substance use disorders than Val-allele carriers (χ2 = 3.62 and 3.68, respectively; p < 0.05). CONCLUSION: In a regional highly birth cohort representative sample, either COMT rs4680 variant was observed in association with specific psychiatric disorders.

A 12-month prospective real-life study of opicapone efficacy and tolerability in Emirati and non-White subjects with Parkinson's disease based in United Arab Emirates.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, and the condition is complicated by the emergence of wearing off/motor fluctuations with levodopa treatment after a variable period. COMT inhibitors when used as adjunct therapy to levodopa tend to smoothen out these wearing off fluctuations by enhancing delivery of levodopa and increasing its bioavailability to the brain. The study was conducted to investigate the motor and nonmotor effect, safety and tolerability of the third generation once-daily COMT inhibitor (opicapone), as add-on, adjuvant therapy to levodopa and at 6 and 12 months follow-up in a real-life cohort of consecutive Emirati and non-White PD patients. A real-life observational analysis using tolerability parameters as used previously by Rizos et al. and Shulman et al. based on clinical database of cases rat Kings College Hospital Dubai Parkinson care database. This was a prospective, single-arm follow-up clinical evaluation study that evaluated the effectiveness of opicapone 50 mg once-daily regime in 50 patients diagnosed with idiopathic neurodegenerative disorder. All patients were assessed with scales used in clinical pathway and include motor Unified Parkinson's Disease Rating Scale (UPDRS), nonmotor symptom scale (NMSS), quality of life (PDQ8) Parkinson's fatigue scale (PFS16) and King's Parkinson's Pain Scale (KIPS). Out of 50 patients treated with opicapone (72% male, mean age 66.9 years (SD 9.9, range 41-82 years) and mean duration of disease 5.7 years (SD 2.5 range (2-11), there was significant statistical improvements shown in motor function-UPDRS part 3: baseline 40.64 ± 2.7, at 6 months 32.12 ± 3.14 and after 12 months 33.72 ± 3.76. Nonmotor burden NMSS: 107.00 ± 21.86, at 6 months 100.78 ± 17.28 and 12 months 96.88 ± 16.11. Reduction in dyskinesias (UPDRS part 4): baseline 8.78 ± 1.07, at 6 months 7.4 ± 0.81 and 12 months 6.82 ± 0.75. Opicapone provides beneficial motor and nonmotor effects in Emirati and other non-White Parkinson's patients, resident in UAE, proving its efficacy across different racial groups as COMT activity may vary between races.

Associations between Catechol-O-methyltransferase (COMT) polymorphisms and cognitive impairments, psychiatric symptoms and tardive dyskinesia in schizophrenia.

INTRODUCTION: Catechol-O-methyltransferase (COMT) is a crucial enzyme involved in dopamine metabolism and has been implicated in the etiology of tardive dyskinesia (TD). We aimed to investigate the associations between COMT gene polymorphisms and the occurrence and severity of TD in a Chinese population, as well as the impact on the psychiatric symptoms and cognitive impairments observed in TD patients. METHODS: A total of 216 chronic schizophrenia patients, including 59 TD patients and 157 NTD patients, were recruited for this study. Three SNPs of the COMT gene (rs4680, rs165599 and rs4818) were selected and genotyped using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). TD severity, psychopathology and cognitive functioning were assessed using the Abnormal Involuntary Movement Scale (AIMS), the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively. RESULTS: In TD patients, total AIMs scores were higher in carriers of the rs4680 AA genotype than in carriers of the AG and GG genotypes (p = 0.01, 0.006), carriers of the rs4818 GC and CC genotypes had higher orofacial scores than in GG genotypes (p = 0.032, 0.002). In male TD patients, carriers of the rs165599 GA genotype scored lower in the extremities and trunk scores than AA genotype carriers (p = 0.015). Moreover, in male TD patients, COMT rs4818 was associated with cognition, since the C allele carriers had significantly higher immediate memory (p = 0.043) and verbal function (p = 0.040) scores than the G allele carriers. In addition, rs165599 genotype interacted with TD diagnosis on depressed factor (p = 0.031). CONCLUSION: Within the Chinese population, COMT gene polymorphisms could potentially serve as biomarkers for the symptoms and prognosis of TD patients.

A preliminary study on the association of single nucleotide polymorphisms and methylation of dopamine system-related genes with psychotic symptoms in patients with methamphetamine use disorder.

Methamphetamine use disorder (MAUD) can substantially jeopardize public security due to its high-risk social psychology and behaviour. Given that the dopamine reward system is intimately correlated with MAUD, we investigated the association of single nucleotide polymorphisms (SNPs), as well as methylation status of dopamine receptor type 4 (DRD4), catechol-O-methyltransferase (COMT) genes, and paranoid and motor-impulsive symptoms in MAUD patients. A total of 189 MAUD patients participated in our study. Peripheral blood samples were used to detect 3 SNPs and 35 CpG units of methylation in the DRD4 gene promoter region and 5 SNPs and 39 CpG units in the COMT gene. MAUD patients with the DRD4 rs1800955 C allele have a lower percentage of paranoid symptoms than those with the rs1800955 TT allele. Individuals with paranoid symptoms exhibited a reduced methylation degree at a particular DRD4 CpG2.3 unit. The interaction of the DRD4 rs1800955 C allele and the reduced DRD4CpG2.3 methylation degree were associated with a lower occurrence of paranoid symptoms. Meanwhile, those with the COMT rs4818 CC allele had lower motor-impulsivity scores in MAUD patients but greater COMT methylation levels in the promoter region and methylation degree at the COMT CpG 51.52 unit. Therefore, based only on the COMT rs4818 CC polymorphism, there was a negative correlation between COMT methylation and motor-impulsive scores. Our preliminary results provide a clue that the combination of SNP genotype and methylation status of the DRD4 and COMT genes serve as biological indicators for the prevalence of relatively high-risk psychotic symptoms in MAUD patients.

COMT Val/Met, stressful life events and externalizing behaviors in youth: A longitudinal study from the ABCD sample.

Early adolescence is a crucial time for understanding and detecting the risk factors that may influence youth externalizing/disruptive behaviors and disorders. Previous literature reported evidence that risk factors for disruptive behaviors include catechol-O-methyltransferase (COMT) Val158Met (rs4680) polymorphism and environmental influences. An unanswered question is whether there is a change in these risk factors over stages of youth development. This longitudinal study examines the interaction effect of Val158Met and stressful life events (SLE) on youth externalizing behaviors from ages 9-11. Participants were 2363 children of European ancestry recruited as part of the Adolescent Brain Cognitive Development study. Repeated measures linear mixed models were used to examine the effect of the interaction between Val158Met and SLE (G × E) on disruptive behaviors over development. Externalizing behaviors were analyzed at both baseline and two-year follow-up. Both Val158Met genotype and SLE scores demonstrated significant main effects on disruptive behaviors in youth, and those effects were consistent at both time points. G × E was not associated with externalizing behaviors. Youth who carried the Val allele and/or were exposed to higher SLE consistently had increased externalizing behavior scores. To our knowledge, this is the first study to longitudinally examine the interaction effects of Val158Met and SLE on externalizing behaviors in youth. The results highlight the importance of understanding the genetic and environmental factors underlying externalizing behaviors for better detection of at-risk youth, helping further with early prevention efforts. The findings propose that COMT Val158Met genotype may act as a biomarker for development of novel treatment strategies for disruptive behaviors.

Interaction between vitamin E intake and a COMT gene variant on colorectal cancer risk among Korean adults: a case-control study.

OBJECTIVES: Previous human trials have not supported the anticarcinogenic effect of vitamin E despite biological plausibility and considerable epidemiological evidence. A possible explanation for this inconsistency is the interactive effect of the catechol-O-methyltransferase (COMT) gene and supplemental vitamin E on cancer. We examined whether a COMT gene variant modulates the effect of dietary vitamin E intake on colorectal cancer (CRC) risk. METHODS: In this case-control study of Korean adults (975 cases and 975 age- and sex-matched controls), dietary vitamin E density (mg/1,000 kcal) was measured using a semiquantitative food frequency questionnaire, COMT single nucleotide polymorphism (SNP) rs740603 (A>G) was genotyped, and CRC was verified histologically. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models with adjustments for potential confounders. RESULTS: Higher vitamin E density was associated with a lower risk of CRC (highest vs. lowest quartiles: OR, 0.72; 95% CI, 0.55 to 0.96; p-for-trend=0.002). When stratified by COMT SNP rs740603 genotype, the inverse association between vitamin E density and CRC risk was confined to those with at least 1 A allele (≥median vs.

Stalevo® : A pioneering treatment for OFF periods in Parkinsons disease.

Enzymatic metabolism is the key determinant of the overall bioavailability, brain penetration, and efficacy of levodopa in the treatment of Parkinsons disease (PD). Enzyme inhibitors in the form of peripheral dopa-decarboxylase inhibitors and monoamine oxidase type-B inhibitors have been successfully employed to maximize the utility of levodopa in both early- and late-stage PD. However, another major pathway of the peripheral metabolism of levodopa through catechol-O-methyltransferase (COMT) remains unchecked by those measures. Consequently, this becomes a major factor in determining the extent of delivery to the brain. The introduction of tolcapone as a potent and effective peripheral and central COMT inhibitor was frustrated by the emergence of hepatic toxicity. Only with the subsequent introduction of entacapone as an effective inhibitor of peripheral COMT activity has it become possible to fully control the peripheral metabolism of levodopa and to optimize its delivery to the brain. At a single-dose level of 200 mg, the efficacy of entacapone in reducing OFF time and increasing ON time has led to its widespread use for the treatment of "wearing off". To maximize the efficacy of entacapone and to time-lock its pharmacokinetic profile to that of levodopa, a triple combination of levodopa, carbidopa, and entacapone in the form of Stalevo® that allowed for flexibility in levodopa dosing was introduced early in the 21st century. This pioneering development has been successfully used worldwide for the past 20 years. This review considers the role of all three classes of enzyme inhibitors in PD medicine.