catechol-O-methyltransferase Research Articles

Drosophila mutants lacking the glial neurotransmitter-modifying enzyme Ebony exhibit low neurotransmitter levels and altered behavior

Inhibitors of enzymes that inactivate amine neurotransmitters (dopamine, serotonin), such as catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), are thought to increase neurotransmitter levels and are widely used to treat Parkinson's disease and psychiatric disorders, yet the role of these enzymes in regulating behavior remains unclear. Here, we investigated the genetic loss of a similar enzyme in the model organism Drosophila melanogaster. Because the enzyme Ebony modifies and inactivates amine neurotransmitters, its loss is assumed to increase neurotransmitter levels, increasing behaviors such as aggression and courtship and decreasing sleep. Indeed, ebony mutants have been described since 1960 as "aggressive mutants," though this behavior has not been quantified. Using automated machine learning-based analyses, we quantitatively confirmed that ebony mutants exhibited increased aggressive behaviors such as boxing but also decreased courtship behaviors and increased sleep. Through tissue-specific knockdown, we found that ebony’s role in these behaviors was specific to glia. Unexpectedly, direct measurement of amine neurotransmitters in ebony brains revealed that their levels were not increased but reduced. Thus, increased aggression is the anomalous behavior for this neurotransmitter profile. We further found that ebony mutants exhibited increased aggression only when fighting each other, not when fighting wild-type controls. Moreover, fights between ebony mutants were less likely to end with a clear winner than fights between controls or fights between ebony mutants and controls. In ebony vs. control fights, ebony mutants were more likely to win. Together, these results suggest that ebony mutants exhibit prolonged aggressive behavior only in a specific context, with an equally dominant opponent.

Association of Polymorphism of the Enzyme Catechol-O-Methyltransferase with Fibromialgic Syndrome and its Clinical Repercussions

Objective: Fibromyalgia syndrome (FMS) is a clinical condition that mostly affects women, with chronic diffuse pain, physical disability, mood swings, anxiety, fatigue and insomnia. There are genetic contributions to its pathophysiology. Some single nucleotide polymorphisms (SNPs) can change the function of proteins that participate in pain modulation. Catechol-O-methyltransferase (COMT) is an enzyme responsible for the inactivation of catecholamines in the central nervous system, participating in descending nociceptive inhibitory pathways. This study verified the association of SNPs rs4680, rs6269, rs4633 and rs4818 of the COMT gene with clinical aspects in patients with FMS in Brazil. Methods: Forty-seven volunteers whith FMS were selected, in which the Fibromyalgia Impact Questionnaire, the Beck’s Depression and Anxiety Inventories, the Insomnia Severity Index and the Mini-Mental State Examination were applied. The DNA was extracted by salting out and the SPNs were evaluated by real time reverse transcription polymerase chain (RT-PCR). The association between clinic and SPNs was tested by the Fisher’s exact test. A 95% CI and p value < 0.05 were adopted. Results: The results showed that there was no association between such SNPs and the participants’ clinic regarding the tests used. Conclusions: This study showed that, although the disease has an important impact on patients’ daily lives, increasing the chances of depression, anxiety, insomnia and cognitive losses, it is not associated with the SNPs researched. Further investigations, with larger samples, are needed to assess these and other associations between genetics factors and FMS.

Influences of neurotransmission-related genetic polymorphisms on depression, anxiety and stress

Over 10% of the world population suffer from mental disorders. In particular, depression causes about 800,000 suicide cases annually, while anxiety is the most common mental disorder. Stresses from work, life, and health have been identified as the common triggers for the two mental disorders. Eventhough mental disorders are treatable and validated tools are available to diagnose, many individuals are left untreated due to different factors, such as a lack of trained personnel and stigma. Neuroscience research indicates that mental disorders could be hereditary, where genes involved in determining behavioural variants. Disturbance in brain communication, resulting from abnormalities in neurogenesis, neurotransmission, and enzymatic degradation, have led to negative emotional states. This mini-review will highlight some important genes in the neurotransmitter systems and explore the relationship between gene polymorphisms and emotional states (i.e., depression, anxiety, and stress). The genes that will be discussed in this mini-review include brain-derived neurotrophic factor (BDNF) which is involved in neuron development, serotonin-transporter-linked polymorphic region (5-HTTLPR) and 5-hydroxytryptamine receptor 1A (5-HT1A) which are involved in serotonin neurotransmitter action potential propagation, and monoamine oxidase A (MAOA) and catechol-O-methyltransferase (COMT), which are involved in neurotransmitter catabolism.

An Overview of Animal Models and Symptomatic Treatment of Parkinson’s disease

The broad theory indicate that neurological ailment is caused by intricate interactions between environmental and genetic factors is supported using animal models to better understand the the cause and pathogenesis of Parkinson's disease (PD), as well as its cellular and molecular mechanisms. The more recent models use genetic manipulations that either introduce mutations similar to those found in familial cases of PD (a-synuclein, DJ-1, PINK1, Parkin, etc.) or selectively disrupt nigrostriatal neurons (MitoPark, Pitx3, Nurr1, etc.). "Classic" models are based on neurotoxins that specifically target catecholaminergic neurons. All of these together each model has its own benefits and drawbacks. The use of medication, deep brain stimulation, and physical therapy has been optimised for the symptomatic treatment of the motor symptoms of Parkinson disease (PD). L-dopa, several dopamine agonists, inhibitors of MAO-B and catechol-o-methyltransferase (COMT), and amantadine are among the pharmacotherapies available.

Dopamine receptors gene overexpression in the microenvironment of invasive gastric cancer and its potential implications.

Gastric cancer (GC) is the fifth most common cancer worldwide and the most commonly diagnosed cancer in Iran. The nervous system provides proximity to tumor cells by releasing neurotransmitters such as dopamine and presenting them to the corresponding receptor-bearing tumors. While nerve fibers infiltrate the tumor microenvironment, little is known about the expression levels of dopamine (DA), dopamine receptors (DRs), and catechol-O-methyltransferase (COMT) in GC patients. DRs and COMT expression were analyzed in 45 peripheral blood mononuclear cells (PBMCs) and 20 paired tumor and adjacent tissue of GC patients by quantitative polymerase chain reaction. DA was measured in plasma specimens using enzyme-linked immunosorbent assay. Protein-protein interaction analysis was carried out to identify GC-related hub genes. Increased expression of DRD1-DRD3 was found in tumor specimens compared with adjacent non-cancerous specimens (P < 0.05). A positive correlation was found between DRD1 and DRD3 expression (P = 0.009); DRD2 and DRD3 expression (P = 0.04). Plasma levels of dopamine were significantly lower in patients (1298 pg/ml) than in controls (4651 pg/ml). DRD1-DRD4 and COMT were up-regulated in PBMCs of patients compared with controls (P < 0.0001). Bioinformatic analyses showed 30 hub genes associated with Protein kinase A and extracellular signal-regulated kinase signaling pathways. The findings indicated dysregulation of DRs and COMT mRNA expression in GC and suggest that the brain- gastrointestinal axis may mediate gastric cancer development. Network analysis revealed that combination treatments could be considered for optimizing and improving the precision treatment of GC.

Synthesis and characterization of chemical engineered PLGA nanosphere: Triggering mechanism of Catechol-O-methyltransferase inhibition on in vivo neurodegeneration

Chemically engineered PLGA nanospheres are one of the emerging technologies for treating neurodegenerative disorders by inhibiting Catechol-O-methyltransferase (COMT). PLGA-MATPM nanospheres were chemically synthesized using PLGA and MATPM (N-allyl-N-(3-(m-tolyloxy)propyl) methioninate). The tailored PLGA nanospheres induce dose-dependent COMT inhibition in competitive kinetic mode. The interactions between COMT and PLGA nanosphere are explained by spectroscopic and molecular dynamics analysis. PLGA-MATPM NPs suppressed the growth of neuroblastoma cells due to the neurodegenerative toxicity of MPTP induction, demonstrating its potency as a cure for neurological disorders. PLGA-MATPM NPs cross the blood–brain barrier more effectively than those in the blood. Furthermore, PLGA nanospheres showed the most neurodegenerative recovery against MPTP-induced C57BL/6 mice. Using magnetic resonance imaging (MRI), it was validated for quality images of cerebral blood flow (CBF).

Uterine Fibroid Diagnosed During Pregnancy: A Case Report

Uterine fibroids arise from the smooth muscle cells of the myometrium and contain large amounts of extracellular matrix. It is not uncommon for these tumours to be diagnosed during gestation and their volumetric changes remain a matter of debate. The fibroid can be a source of obstetric complications in pregnant women and pregnancy can influence the condition of the fibroid. The objective is to evaluate the behaviour of fibroids coexisting with pregnancy according to their genetic profile in order to determine the penetrance of the COMT gene in Senegalese patients. We analysed the variability of the COMT gene in 6 pregnancy patients with fibroids by PCR-sequencing. Molecular analyses of the COMT gene show an involvement of exon 4 of the said gene in this pathology.

Association of COMT Val158Met Polymorphism with Fibromyalgia in Khartoum State, Sudan.

Fibromyalgia (FM) is a disorder characterized by chronic musculoskeletal pain, fatigue, and cognitive problems. Neurotransmitters, mainly catecholamines, appear to be involved in regulating the etiology of FM. Catechol-O-methyltransferase (COMT) is involved in catabolizing catecholamines such as norepinephrine. The most common variant studied in the COMT gene is the valine (Val) to methionine (Met) substitution at codon 158. This is the first study in Sudan addressing FM cases and genetic susceptibility to the disease. We aimed in this study to investigate the frequency of COMT Val 158 Met polymorphism among patients with FM, rheumatoid arthritis, and in healthy individuals. Genomic DNA from forty female volunteers was analyzed: twenty were from primary and secondary FM patients, ten were from rheumatoid arthritis patients, and ten were from healthy control. FM patients' age was ranging from 25 years to 55 with a mean of 41.14 ± 8.90. The mean age of the rheumatoid arthritis patients and healthy individuals was 31.3 ± 7.5 and 38.6 ± 11.2, respectively. Samples were genotyped for COMT single nucleotide polymorphism rs4680 (Val158Met), using the amplification-refractory mutation system (ARMS-PCR). Genotyping data have been analyzed using the Chi-square and Fisher exact test. The most common genotype among the study participants was the heterozygous Val/Met found in all participants. It was the only genotype found in the healthy participants. The genotype Met/Met was found only in FM patients. The genotype Val/Val was found only in rheumatoid patients. Analyses have shown no association between the Met/Met genotype and FM, and this could be due to a small sample size. In a larger sample size, a significant association could be found as this genotype was shown only by FM patients. Moreover, the Val/Val genotype, which is shown only among rheumatoid patients, might protect them from developing FM symptoms.

CO109 Patient-Reported Improvements in “Off”-Time Quality, Non-Motor Fluctuation Severity, and Medication Satisfaction in the Real-World Opti-on Study of Opicapone in Parkinson’s Disease

Opicapone is an oral, once-daily, selective catechol-O-methyltransferase (COMT) inhibitor, approved as an adjunctive treatment to levodopa/carbidopa (LD/CD) in patients with Parkinson’s disease (PD) experiencing “OFF” episodes. OPTI-ON (OPicapone Treatment Initiation OpeN-Label Study) was a “real-world” study of opicapone use in the US that evaluated the characteristics, treatment patterns, and safety/tolerability of patients initiating opicapone treatment.

Association of polymorphisms rs4680 of the Catechol-O-Methyltransferase gene and rs6265 of the brain derived neurotrophic factor gene with the behavioral inhibition and behavioral activation systems

The Behavioral Inhibition System (BIS) comprises limbic circuitry implicated in avoidance behaviors. Its increased activation has been identified as a risk factor for anxiety and depressive disorders. In addition, both Catechol-O-Methyltransferase (COMT) and Brain Derived Neurotrophic Factor (BDNF) have been postulated as candidate genes that constitute a vulnerability for the onset of anxiety and depressive disorders. The aim of this study was to evaluate the possible association between the rs4680 polymorphism of the COMT gene and the rs6265 polymorphism of the BDNF gene with the BIS and the Behavioral Activation System (BAS) in a population sample from Colombia. Genetic information was obtained by extracting DNA from blood samples of 80 participants and using Taqman probes designed for each polymorphism. In addition, participants completed a BIS/BAS scale in order to establish a neuropsychological classification. The frequency of the Met allele of the BDNF gene was greater in the group with BIS sensitivity compared to the group with BAS sensitivity. On the contrary, the frequency of the Met allele of the COMT gen did not show a significant association with the BIS. The rs6265 polymorphism of BDNF gene is associated with the BIS which in turn constitutes a risk factor for anxiety and depression.

0205 Catechol-O-methyltransferase Genotype, but not Dopamine Receptor D2 Genotype, Modulates Slow Wave Sleep

Abstract Introduction Slow wave sleep (SWS), a putative marker of sleep homeostasis, robustly increases following total sleep deprivation (TSD). The neurotransmitter dopamine is substantively involved in sleep-wake regulation. Single nucleotide polymorphisms (SNP) in the dopaminergic genes of dopamine receptor D2 (DRD2) and catechol-O-methyltransferase (COMT) have been found to alter dopamine availability primarily in the striatum and prefrontal cortex (PFC), respectively. Here, we investigate if these SNPs are associated with changes in SWS at baseline and following TSD. Methods N=105 healthy adults (ages 26.5±5.0; 55 females) completed one of three 4-day/3-night in-laboratory studies with 10h baseline sleep opportunity (22:00–08:00), 38h TSD period, and 10h recovery sleep opportunity. Sleep periods were recorded polysomnographically and visually scored according to AASM criteria. DNA isolated from whole blood was assayed for DRD2 (C957T, rs6277) and COMT (Val158Met, rs4680) genotypes using real-time PCR. For each genotype, SWS duration was analyzed using mixed-effects ANOVA with fixed effects for genotype, night (baseline vs. recovery), and their interaction, controlling for study, and a random effect over subjects on the intercept. Results DRD2 genotypes (25 C/C, 52 C/T, 28 T/T) and COMT genotypes (23 Val/Val, 58 Val/Met, 24 Met/Met) were in Hardy-Weinberg Equilibrium. As expected, SWS was substantially increased during recovery sleep compared to baseline. There was no main effect of DRD2 (F[2,102]=2.78, p=0.07), nor interaction of DRD2 by night (F[2,102]=1.45, p=0.24). However, there was a significant main effect of COMT on SWS duration (F[2,102]=3.20, p=0.04), without interaction of COMT by night (F[2,102]=1.43, p=0.24). Compared to Met allele carriers, Val homozygotes displayed reduced SWS duration during both baseline and recovery sleep. Conclusion The DRD2 T allele is associated with decreased dopamine D2 receptors and decreased dopaminergic signaling in the striatum relative to the C allele. The COMT Val allele is associated with increased enzymatic activity and decreased dopaminergic signaling in the PFC relative to the Met allele. Our results indicate that compared to striatal dopamine, PFC dopamine may be a more prominent mediator of SWS regulation, with less PFC dopamine corresponding to less SWS. This needs to be confirmed in a larger sample. Support (if any) CDMRP W81XWH1610319; USAMRDC W81XWH1810100; ONR N000141310302; NIH R21CA16769; ARO W911NF2210223.

COMT Val158Met Affects the Analgesic Response to Acupuncture Among Cancer Survivors With Chronic Pain

Catechol-O-methyltransferase (COMT) is the major enzyme involved in the catabolism of dopamine, a neurotransmitter in the brain’s reward system. The common COMT polymorphism Val158Met (rs4680 G>A) modulates pain response to opioids through a reward-motivated mechanism; however, its role in nonpharmacological pain medicine has not been clinically characterized. We genotyped 325 participants from a randomized controlled trial of cancer survivors with chronic musculoskeletal pain. We found that carrying methionine at position 158 (158Met) of COMT, encoded by the A allele, significantly increased the analgesic response to electroacupuncture (74% vs 50%; odds ratio [OR]: 2.79; 95% confidence interval [CI]: 1.31, 6.05; P < .01), but not to auricular acupuncture (68% vs 60%; OR: 1.43; 95% CI: .65, 3.12; P = .37) or usual care (24% vs 18%; OR: 1.46; 95% CI: .38, 7.24; P = .61) compared to Val/Val. These findings raise the possibility that COMT Val158Met might be an important predictor of analgesic response to electroacupuncture, providing novel insights into precision nonpharmacologic pain management tailored to individual genetic backgrounds. PerspectiveThis work suggests the modulating effects of the polymorphism in COMT Val158Met on the response to acupuncture. Further research needs to validate these findings, increase the mechanistic understanding of acupuncture, and guide further development of acupuncture as a precision pain management strategy.

Sex Differences in Opioid Response Linked to OPRM1 and COMT genes DNA Methylation/Genotypes Changes in Patients with Chronic Pain.

Analgesic-response variability in chronic noncancer pain (CNCP) has been reported due to several biological and environmental factors. This study was undertaken to explore sex differences linked to OPRM1 and COMT DNA methylation changes and genetic variants in analgesic response. A retrospective study with 250 real-world CNCP outpatients was performed in which data from demographic, clinical, and pharmacological variables were collected. DNA methylation levels (CpG island) were evaluated by pyrosequencing, and their interaction with the OPRM1 (A118G) and COMT (G472A) gene polymorphisms was studied. A priori-planned statistical analyses were conducted to compare responses between females and males. Sex-differential OPRM1 DNA methylation was observed to be linked to lower opioid use disorder (OUD) cases for females (p = 0.006). Patients with lower OPRM1 DNA methylation and the presence of the mutant G-allele reduced opioid dose requirements (p = 0.001), equal for both sexes. Moreover, COMT DNA methylation levels were negatively related to pain relief (p = 0.020), quality of life (p = 0.046), and some adverse events (probability > 90%) such as constipation, insomnia, or nervousness. Females were, significantly, 5 years older with high anxiety levels and a different side-effects distribution than males. The analyses demonstrated significant differences between females and males related to OPRM1 signalling efficiency and OUD, with a genetic-epigenetic interaction in opioid requirements. These findings support the importance of sex as a biological variable to be factored into chronic pain-management studies.

A Review of Biomarkers in Delirium Superimposed on Dementia (DSD) and Their Clinical Application to Personalized Treatment and Management.

Delirium superimposed on dementia (DSD) occurs when patients with pre-existing dementia develop delirium. This complication causes patients to become impaired, posing safety concerns for both hospital staff and patients. Furthermore, there is an increased risk of worsening functional disability and death. Despite medical advances, DSD provides both diagnostic and therapeutic challenges to providers. Identifying at-risk patients and providing personalized medicine and patient care can decrease disease burden in a time-efficient manner. This review delves into bioinformatics-based studies of DSD in order to design and implement a personalized medicine-based approach. Our findings suggest alternative medical treatment methods based on gene-gene interactions, gene-microRNA (miRNA) interactions, gene-drug interactions, and pharmacogenetic variants involved in dementia and psychiatric disorders. We identify 17 genes commonly associated with both dementia and delirium including apolipoprotein E(ApoE), brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT), butyrylcholinesterase (BChE), acetylcholinesterase(AChE), DNA methyltransferase 1 (DNMT1), prion protein (PrP), tumor necrosis factor (TNF), serine palmitoyltransferase long chain base subunit 1 (SPTLC1), microtubule-associated protein tau (MAPT), alpha-synuclein (αS), superoxide dismutase 1(SOD1), amyloid beta precursor protein (APP), neurofilament light (NFL), neurofilament heavy, 5-hydroxytryptamine receptor 2A (HTR2A), and serpin family A member 3 (ERAP3). In addition, we identify six main genes that form an inner concentric model, as well as their associated miRNA. The FDA-approved medications that were found to be effective against the six main genes were identified. Furthermore, the PharmGKB database was used to identify variants of these six genes in order to suggest future treatment options. We also looked at previous research and evidence on biomarkers that could be used to detect DSD. According to research, there are three types of biomarkers that can be used depending on the stage of delirium. The pathological mechanisms underlying delirium are also discussed. This review will identify treatment and diagnostic options for personalized DSD management.

Transforming Growth Factor-β-Activated Kinase 1 (TAK1) Mediates Chronic Pain and Cytokine Production in Mouse Models of Inflammatory, Neuropathic, and Primary Pain

The origin of chronic pain is linked to inflammation, characterized by increased levels of proinflammatory cytokines in local tissues and systemic circulation. Transforming growth factor beta-activated kinase 1 (TAK1) is a key regulator of proinflammatory cytokine signaling that has been well characterized in the context of cancer and autoimmune disorders, yet its role in chronic pain is less clear. Here, we evaluated the ability of our TAK1 small-molecule inhibitor, takinib, to attenuate pain and inflammation in preclinical models of inflammatory, neuropathic, and primary pain. Inflammatory, neuropathic, and primary pain was modeled using intraplantar complete Freund’s adjuvant (CFA), chronic constriction injury (CCI), and systemic delivery of the catechol-O-methyltransferase (COMT) inhibitor OR486, respectively. Behavioral responses evoked by mechanical and thermal stimuli were evaluated in separate groups of mice receiving takinib or vehicle prior to pain induction (baseline) and over 12 days following CFA injection, 4 weeks following CCI surgery, and 6 hours following OR486 delivery. Hindpaw edema was also measured prior to and 3 days following CFA injection. Upon termination of behavioral experiments, dorsal root ganglia (DRG) were collected to measure cytokines. We also evaluated the ability of takinib to modulate nociceptor activity via in vitro calcium imaging of neurons isolated from the DRG of Gcamp3 mice. In all 3 models, TAK1 inhibition significantly reduced hypersensitivity to mechanical and thermal stimuli and expression of proinflammatory cytokines in DRG. Furthermore, TAK1 inhibition significantly reduced the activity of tumor necrosis factor (TNF)-primed/capsaicin-evoked DRG nociceptive neurons. Overall, our results support the therapeutic potential of TAK1 as a novel drug target for the treatment of chronic pain syndromes with different etiologies. PerspectiveThis article reports the therapeutic potential of TAK1 inhibitors for the treatment of chronic pain. This new treatment has the potential to provide a greater therapeutic offering to physicians and patients suffering from chronic pain as well as reduce the dependency on opioid-based pain treatments.

Consistent Effects of Once-Daily Opicapone 50 mg on COMT Activity Across Participants: A Pooled Post Hoc Analysis of Two Phase 1 Studies (P14-11.014)

<h3>Objective:</h3> To assess effects of adjunctive opicapone (OPC) 50 mg on catechol-O-methyltransferase (COMT) activity by participants’ baseline characteristics. <h3>Background:</h3> OPC is a once-daily COMT inhibitor approved as adjunctive treatment to carbidopa/levodopa (CD/LD) in patients with Parkinson’s disease (PD) experiencing “OFF”-episodes. In two Phase 3 trials, OPC reduced daily “OFF”-time in patients with PD and motor fluctuations. Phase 1 trials also showed that adding OPC 50 mg to CD/LD in healthy individuals and patients with PD decreased variability in plasma levodopa (LD) levels and COMT activity. However, the effects of participants’ baseline characteristics on COMT inhibition remain unknown. <h3>Design/Methods:</h3> This post hoc analysis included data from 2 open-label Phase 1 studies (Study 1: 16 patients with PD receiving immediate-release CD/LD; Study 2: 18 healthy participants receiving extended-release CD/LD) assessing the effect of OPC 50 mg on LD pharmacokinetics (PK). Blood samples to assess LD PK and soluble-COMT (S-COMT) activity were collected before and after 14–15 days of once-daily OPC 50 mg. Pooled data on S-COMT inhibition were analyzed by participants’ baseline characteristics: disease state (PD vs healthy), sex (male vs female), ethnicity (Hispanic/Latino vs non-Hispanic/Latino), body mass index (&lt;25 vs ≥25), and baseline S-COMT activity. <h3>Results:</h3> OPC added to CD/LD decreased mean (95% CI) S-COMT activity by ≥80% in patients with PD and healthy participants (Study 1: 83.0% [80.5–85.4%]; Study 2: 80.1% [78.5–81.8%]; Pooled: 81.4% [80.0–82.9%]). Mean percent reduction in S-COMT activity was 79–85% for all subgroups in individual and pooled studies, although some subgroups had small numbers of participants. Variability in S-COMT activity was lower in all participants after OPC compared to baseline. <h3>Conclusions:</h3> Adding once-daily OPC 50 mg to CD/LD resulted in substantial S-COMT inhibition with reduced variability regardless of baseline characteristics. In all participants, COMT inhibition shown by OPC with CD/LD leads to more consistent daily LD exposure. <b>Disclosure:</b> Gordon Loewen has received personal compensation for serving as an employee of Neurocrine. Gordon Loewen has received stock or an ownership interest from Neurocrine. Gordon Loewen has received intellectual property interests from a discovery or technology relating to health care. Kurt Olson has received personal compensation for serving as an employee of Neurocrine Biosciences Inc. Kurt Olson has stock in Neurocrine Biosciences Inc. Dr. Liang has received personal compensation for serving as an employee of Neurocrine Biosciences. Dr. Liang has stock in Neurocrine Biosciences. Dr. Klepitskaya has received personal compensation for serving as an employee of Neurocrine Biosciences, Inc.

Safety of opicapone after 5 years of post-marketing experience worldwide (P14-11.013)

<h3>Objective:</h3> Review the safety data of opicapone (OPC) after five years of marketing experience worldwide. <h3>Background:</h3> OPC is a once-daily catechol-O-methyltransferase (COMT) inhibitor proven to be effective in PD patients with motor fluctuations. OPC marketing authorisation was first granted on 24 June 2016 (EU). It was launched in October 2016 and is currently marketed in over 18 countries worldwide (including the US since September 2020). <h3>Design/Methods:</h3> Patient exposure to marketed OPC was estimated based on worldwide ex-factory sales cumulatively until 30 September 2021 (assuming the ex-factory amounts delivered were entirely dispensed and administered, and were used at the dosage of 1 hard capsule/day). From the first marketing authorisation until 30 September 2021, safety data was pooled and analysed from global post-marketing sources, including spontaneous, health authorities, literature reports, and non-interventional studies. Cumulative summary tabulations of adverse events arranged by primary System Organ Class (SOC) and preferred terms within each SOC were retrieved and sorted. <h3>Results:</h3> The estimated patient exposure was 1 413 624 patient-months during the period, corresponding to 117 802 patient-years. In the 5-year period, 4035 events were reported, 545 (13.5%) serious and 3490 (86.5%) non-serious. This corresponds to an incidence of 34.3 reports per 1000 patient-years. The 5 SOCs with the highest number of events were “Nervous system disorders”, “General disorders and administration site conditions”, “Psychiatric disorders”, “Gastrointestinal disorders” and “Surgical and medical procedures”. The 10 most frequently reported adverse events were “Dyskinesia”, “Muscle rigidity”, “Hallucination”, “Bradykinesia”, “Constipation”, “Tremor”, “Gait disturbance”, “Freezing phenomenon”, “Sleep disorder” and “Reduced facial expression”. <h3>Conclusions:</h3> Safety reports during 5 years of post-marketing experience with OPC were uncommon, and mostly refer to non-serious adverse events. Motor-symptoms of PD were among the most frequently reported adverse events. No new relevant safety concern was identified. OPC continues to have an adequate safety and tolerability profile with a favourable benefit-risk ratio. <b>Disclosure:</b> Mr. Guedes has received personal compensation for serving as an employee of BIAL - Portela &amp; C.ª, S.A.. Joana Graça has received personal compensation for serving as an employee of BIAL - Portela &amp; C.ª, S.A.. Ms. Sampaio has nothing to disclose. Mariana Vieira has received personal compensation for serving as an employee of Bial - Portela &amp; Cª, S.A.. Francisco Rocha has received personal compensation for serving as an employee of BIAL - Portela. Helena Gama has received personal compensation for serving as an employee of Bial-Portela &amp; Cª S.A..

Genetic bases of language control in bilinguals: Evidence from an EEG study.

Previous studies have debated whether the ability for bilinguals to mentally control their languages is a consequence of their experiences switching between languages or whether it is a specific, yet highly-adaptive, cognitive ability. The current study investigates how variations in the language-related gene FOXP2 and executive function-related genes COMT, BDNF, and Kibra/WWC1 affect bilingual language control during two phases of speech production, namely the language schema phase (i.e., the selection of one language or another) and lexical response phase (i.e., utterance of the target). Chinese-English bilinguals (N = 119) participated in a picture-naming task involving cued language switches. Statistical analyses showed that both genes significantly influenced language control on neural coding and behavioral performance. Specifically, FOXP2 rs1456031 showed a wide-ranging effect on language control, including RTs, F(2, 113) = 4.00, FDR p = .036, and neural coding across three-time phases (N2a: F(2, 113) = 4.96, FDR p = .014; N2b: F(2, 113) = 4.30, FDR p = .028, LPC: F(2, 113) = 2.82, FDR p = .060), while the COMT rs4818 (ts >2.69, FDR ps < .05), BDNF rs6265 (Fs >5.31, FDR ps < .05), and Kibra/WWC1 rs17070145 (ts > -3.29, FDR ps < .05) polymorphisms influenced two-time phases (N2a and N2b). Time-resolved correlation analyses revealed that the relationship between neural coding and cognitive performance is modulated by genetic variations in all four genes. In all, these findings suggest that bilingual language control is shaped by an individual's experience switching between languages and their inherent genome.

Synthesis and analysis of novel catecholic ligands as inhibitors of catechol-O-methyltransferase

l-DOPA, a dopamine precursor, is commonly used as a treatment for patients with conditions such as Parkinson’s disease. This therapeutic l-DOPA, as well as the dopamine derived from l-DOPA, can be deactivated via metabolism by catechol-O-methyltransferase (COMT). Targeted inhibition of COMT prolongs the effectiveness of l-DOPA and dopamine, resulting in a net increase in pharmacological efficiency of the treatment strategy. Following the completion of a previous ab initio computational analysis of 6-substituted dopamine derivatives, several novel catecholic ligands with a previously unexplored neutral tail functionality were synthesized in good yields and their structures were confirmed. The ability of the catecholic nitriles and 6-substituted dopamine analogues to inhibit COMT was tested. The nitrile derivatives inhibited COMT most effectively, in agreement with our previous computational work. pKa values were used to further examine the factors involved with the inhibition and molecular docking studies were performed to support the ab initio and experimental work. The nitrile derivatives with a nitro substituent show the most promise as inhibitors, confirming that both the neutral tail and the electron withdrawing group are essential on this class of inhibitors.

Genome-wide association study for single nucleotide polymorphism associated with mural and cumulus granulosa cells of PCOS (polycystic ovary syndrome) and non-PCOS patients

BackgroundThe genetic make-up of local granulosa cells and their function in the pathophysiology of polycystic ovary syndrome (PCOS) is crucial to a full comprehension of the disorder. The major purpose of this study was to compare the Single Nucleotide Polymorphism (SNP) of cumulus granulosa cells (CGCs) and mural granulosa cells (MGCs) between healthy individuals and women with PCOS using genome-wide association analysis (GWA). A case–control study was conducted in a total of 24 women diagnosed with PCOS and 24 healthy non-PCOS women of reproductive age aggregated into 4 samples of 6 patients each. GWA studies entail several processes, such as cell separation, cellular DNA extraction, library preparation followed by interpretation using bioinformatics databases. SNP locations were identified by reference gene also involves the use of Matrix-assisted laser desorption/ionisation-time of flight (MALDI-TOF) mass spectrometry (MS) (MALDI-TOF-MS) for the first sorting. Hybridization with the gene chip was followed by reading the SNP genotypes according to the publications in the literature. TASSEL (Trait Analysis by aSSociation, Evolution and Linkage) program and methods were used for GWA studies.ResultsAn aggregate of 21,039 SNP calls were obtained from our samples. Genes of autoimmune illnesses, obesity, inflammatory illnesses, nervous system diseases such as retinitis pigmentosa, autism, neural tube defects, and Alzheimer's disease; and various malignancies such as lung cancer, colorectal cancer, breast cancer were also identified in these cells. Gene ranking score reveals that granulosa cells carry key genes of neurological system and reproductive systems especially in brain and testis, respectively.ConclusionsMural and Cumulus Granulosa cells were shown to have the PCOS directly and indirectly related genes MMP9, PRKAA2, COMT and HP. We found that the expression of ARID4B, MUC5AC, NID2, CREBBP, GNB1, KIF2C, COL18A1, and HNRNPC by these cells may contribute to PCOS.Graphical abstract