Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 119
Filtrar
1.
J Neural Transm (Vienna) ; 131(1): 25-30, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37798410

RESUMO

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.


Assuntos
Doença de Parkinson , Humanos , Masculino , Animais , Ratos , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Doença de Parkinson/tratamento farmacológico , Levodopa/efeitos adversos , Antiparkinsonianos/efeitos adversos , Emirados Árabes Unidos , Estudos Prospectivos , Qualidade de Vida , Inibidores de Catecol O-Metiltransferase/farmacologia , Inibidores de Catecol O-Metiltransferase/uso terapêutico
2.
CNS Spectr ; 29(3): 166-175, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38487834

RESUMO

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).


Assuntos
Inibidores de Catecol O-Metiltransferase , Catecol O-Metiltransferase , Cognição , Tolcapona , Humanos , Inibidores de Catecol O-Metiltransferase/farmacologia , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Cognição/efeitos dos fármacos , Catecol O-Metiltransferase/genética , Benzofenonas/farmacologia , Benzofenonas/uso terapêutico , Adulto , Memória de Curto Prazo/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Bioorg Chem ; 148: 107488, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38797066

RESUMO

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.


Assuntos
Dopamina , Inibidores da Monoaminoxidase , Monoaminoxidase , Doença de Parkinson , Animais , Camundongos , Dopamina/metabolismo , Relação Estrutura-Atividade , Monoaminoxidase/metabolismo , Estrutura Molecular , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/síntese química , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Catecol O-Metiltransferase/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Inibidores de Catecol O-Metiltransferase/farmacologia , Inibidores de Catecol O-Metiltransferase/química , Inibidores de Catecol O-Metiltransferase/síntese química , Humanos , Relação Dose-Resposta a Droga , Antiparkinsonianos/farmacologia , Antiparkinsonianos/química , Antiparkinsonianos/síntese química , Antiparkinsonianos/uso terapêutico
4.
Neurol Sci ; 45(5): 2035-2046, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38091213

RESUMO

BACKGROUND: Opicapone (OPC) is a third-generation, selective peripheral COMT inhibitor that improves peripheral L-DOPA bioavailability and reduces OFF time and end-of-dose motor fluctuations in Parkinson's disease (PD) patients. OBJECTIVES: In this study, we objectively assessed the effects of adding OPC to L-DOPA on bradykinesia in PD through kinematic analysis of finger movements. METHODS: We enrolled 20 treated patients with PD and motor fluctuations. Patients underwent two experimental sessions (L-DOPA, L-DOPA + OPC), separated by at least 1 week. In each session, patients were clinically evaluated and underwent kinematic movement analysis of repetitive finger movements at four time points: (i) before their usual morning dose of L-DOPA (T0), (ii) 30 min (T1), (iii) 1 h and 30 min (T2), and (iv) 3 h and 30 min after the L-DOPA intake (T3). RESULTS: Movement velocity and amplitude of finger movements were higher in PD patients during the session with OPC compared to the session without OPC at all the time points tested. Importantly, the variability of finger movement velocity and amplitude across T0-T3 was significantly lower in the L-DOPA + OPC than L-DOPA session. CONCLUSIONS: This study is the first objective assessment of the effects of adding OPC to L-DOPA on bradykinesia in patients with PD and motor fluctuations. OPC, in addition to the standard dopaminergic therapy, leads to significant improvements in bradykinesia during clinically relevant periods associated with peripheral L-DOPA dynamics, i.e., the OFF state in the morning, delayed-ON, and wearing-OFF periods.


Assuntos
Oxidiazóis , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Levodopa/efeitos adversos , Antiparkinsonianos/uso terapêutico , Hipocinesia/tratamento farmacológico , Hipocinesia/etiologia , Fenômenos Biomecânicos , Inibidores de Catecol O-Metiltransferase/farmacologia , Inibidores de Catecol O-Metiltransferase/uso terapêutico
5.
Biosci Biotechnol Biochem ; 88(6): 665-670, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38561637

RESUMO

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.


Assuntos
Inibidores de Catecol O-Metiltransferase , Inibidores da Monoaminoxidase , Pólen , Animais , Austrália , Abelhas , Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/farmacologia , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Pólen/química
6.
Biochemistry ; 62(8): 1394-1405, 2023 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-36976271

RESUMO

Catechol-O-methyltransferase (COMT) is a key enzyme in the metabolism of catecholamines. Substrates of the enzyme include neurotransmitters such as dopamine and epinephrine, and therefore, COMT plays a central role in neurobiology. Since COMT also metabolizes catecholamine drugs such as L-DOPA, variation in COMT activity could affect pharmacokinetics and drug availability. Certain COMT missense variants have been shown to display decreased enzymatic activity. Additionally, studies have shown that such missense variants may lead to loss of function induced by impaired structural stability, which results in activation of the protein quality control system and degradation by the ubiquitin-proteasome system. Here, we demonstrate that two rare missense variants of COMT are ubiquitylated and targeted for proteasomal degradation as a result of structural destabilization and misfolding. This results in strongly reduced intracellular steady-state levels of the enzyme, which for the L135P variant is rescued upon binding to the COMT inhibitors entacapone and tolcapone. Our results reveal that the degradation is independent of the COMT isoform as both soluble (S-COMT) and ER membrane-bound (MB-COMT) variants are degraded. In silico structural stability predictions identify regions within the protein that are critical for stability overlapping with evolutionarily conserved residues, pointing toward other variants that are likely destabilized and degraded.


Assuntos
Catecol O-Metiltransferase , Complexo de Endopeptidases do Proteassoma , Catecol O-Metiltransferase/genética , Complexo de Endopeptidases do Proteassoma/genética , Tolcapona , Inibidores de Catecol O-Metiltransferase/farmacologia , Levodopa , Catecolaminas/metabolismo
7.
J Neural Transm (Vienna) ; 130(7): 925-930, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37036498

RESUMO

OBJECTIVE: To evaluate the long-term, real-life effects on non-motor symptoms (NMS) of opicapone compared to entacapone in levodopa-treated people with Parkinson's disease (PwP). METHODS: A retrospective data analysis, with pre- and post-opicapone initiation data of 17 PwP with motor fluctuations compared to a comparable group of 18 PwP introduced on entacapone. The primary outcome was changes in the NMS Scale (NMSS) total score after 1-year follow-up. Secondary outcomes included changes in the NMSS domains, and Parkinson's Disease Sleep Scale (PDSS) total and item scores after the same time span. RESULTS: Groups were comparable for baseline demographics and Parkinson's-related features (p ≥ 0.314) as well as duration of follow-up (1.33 ± 0.66 years for PwP on opicapone and 1.23 ± 0.49 years for those on entacapone; p = 0.858). PwP who were introduced on opicapone showed no changes in NMSS and PDSS total scores after 1 year (p = 0.605 and p = 0.507, respectively), whereas PwP who were introduced on entacapone showed significant worsening of NMSS and PDSS total scores at follow-up (p = 0.005 and p = 0.001, respectively). In neither group changes in individual NMSS domains from baseline to follow-up were observed (p ≥ 0.288 for entacapone and p ≥ 0.816 for opicapone, respectively). In PwP on entacapone significant worsening was seen in the distressing dreams, hallucinations, and limb numbness items of the PDSS (p ≤ 0.05). CONCLUSIONS: Introduction of opicapone in real-life PwP with motor fluctuations seems to stabilise NMS burden and aspects of sleep dysfunction, in contrast to entacapone where there was a worsening of NMS burden and PDSS scores over 1 year follow-up.


Assuntos
Levodopa , Doença de Parkinson , Humanos , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/efeitos adversos , Catecol O-Metiltransferase , Estudos Retrospectivos , Inibidores de Catecol O-Metiltransferase/farmacologia , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Nitrilas
8.
J Neural Transm (Vienna) ; 130(6): 847-861, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36964457

RESUMO

Inhibitors of monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) are major strategies to reduce levodopa degradation and thus to increase and prolong its effect in striatal dopaminergic neurotransmission in Parkinson's disease patients. While selegiline/rasagiline and tolcapone/entacapone have been available on the market for more than one decade, safinamide and opicapone have been approved in 2015 and 2016, respectively. Meanwhile, comprehensive data from several post-authorization studies have described the use and specific characteristics of the individual substances in clinical practice under real-life conditions. Here, we summarize current knowledge on both medication classes, with a focus on the added clinical value in Parkinson's disease. Furthermore, we outline practical considerations in the treatment of motor fluctuations and provide an outlook on ongoing studies with MAO-B and COMT inhibitors.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Monoaminoxidase/metabolismo , Catecol O-Metiltransferase/metabolismo , Levodopa/uso terapêutico , Inibidores de Catecol O-Metiltransferase/farmacologia , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico
9.
Eur J Neurol ; 30(10): 3132-3141, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37489574

RESUMO

BACKGROUND AND PURPOSE: Motor fluctuations are a significant driver of healthcare resource utilization (HCRU) in people with Parkinson's disease (pwPD). A common management strategy is to include catechol-O-methyltransferase (COMT) inhibition with either opicapone or entacapone in the levodopa regimen. However, to date, there has been a lack of head-to-head data comparing the two COMT inhibitors in real-world settings. The aim of this study was to evaluate changes in HCRU and effect on sleep medications when opicapone was initiated as first COMT inhibitor versus entacapone. METHODS: In this retrospective cohort study, we assessed HCRU outcomes in pwPD naïve to COMT inhibition via UK electronic healthcare records (Clinical Practice Research Datalink and Hospital Episodes Statistics databases, June 2016 to December 2019). HCRU outcomes were assessed before (baseline) and after COMT inhibitor prescription at 0-6 months, 7-12 months and 13-18 months. Opicapone-treated pwPD were algorithm-matched (1:4) to entacapone-treated pwPD. RESULTS: By 6 months, treatment with opicapone resulted in 18.5% fewer neurology outpatient visits compared to entacapone treatment; this effect was maintained until the last follow-up (18 months). In the opicapone group, the mean levodopa equivalent daily dose decreased over the first year and then stabilized, whereas the entacapone-treated group showed an initial decrease in the first 6 months followed by a dose increase between 7 and 18 months. Neither COMT inhibitor had a significant impact on sleep medication use. CONCLUSIONS: This head-to-head study is the first to demonstrate, using 'real-world' data, that initiating COMT inhibition with opicapone is likely to decrease the need for post-treatment HCRU versus initiation of COMT inhibition with entacapone.


Assuntos
Doença de Parkinson , Humanos , Antiparkinsonianos/uso terapêutico , Catecol O-Metiltransferase , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Inibidores de Catecol O-Metiltransferase/farmacologia , Levodopa/uso terapêutico , Oxidiazóis/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Aceitação pelo Paciente de Cuidados de Saúde , Estudos Retrospectivos
10.
Bioorg Med Chem Lett ; 88: 129286, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-37054761

RESUMO

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.


Assuntos
Dopamina , Levodopa , Humanos , Dopamina/metabolismo , Levodopa/farmacologia , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Simulação de Acoplamento Molecular , Ligantes , Catecóis/farmacologia , Catecóis/química , Nitrilas/farmacologia , Inibidores Enzimáticos/farmacologia
11.
J Chem Inf Model ; 63(14): 4468-4476, 2023 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-37436881

RESUMO

A third-generation inhibitor of catechol O-methyltransferase (COMT), opicapone (1), has the 3-nitrocatechol scaffold as do the second-generation inhibitors such as entacapone (2) and tolcapone (3), but only 1 can sustainably inhibit COMT activity making it suitable for a once-daily regimen. These improvements should be attributed to the optimized sidechain moiety (oxidopyridyloxadiazolyl group) of 1 substituted at the 5-position of the 3-nitrocatechol ring. We analyzed the role of the sidechain moiety by solving the crystal structures of COMT/S-adenosylmethionine (SAM)/Mg/1 and COMT/S-adenosylhomocysteine (SAH)/Mg/1 complexes. Fragment molecular orbital (FMO) calculations elucidated that the dispersion interaction between the sidechains of Leu 198 and Met 201 on the ß6ß7-loop and the oxidopyridine ring of 1 were unique and important in both complexes. In contrast, the catechol binding site made a remarkable difference in the sidechain conformation of Lys 144. The ε-amino group of Lys 144 was outside of the catalytic pocket and was replaced by a water molecule in the COMT/SAH/Mg/1 complex. No nitrocatechol inhibitor has ever been reported to make a complex with COMT and SAH. Thus, the conformational change of Lys 144 found in the COMT/SAH/Mg/1 complex is the first crystallographic evidence that supports the role of Lys 144 as a catalytic base to take out a proton ion from the reaction site to the outside of the enzyme. The fact that 1 generated a complex with SAH and COMT also suggests that 1 could inhibit COMT twofold, as a typical substrate mimic competitive inhibitor and as a product-inhibition enhancer.


Assuntos
Inibidores de Catecol O-Metiltransferase , Catecol O-Metiltransferase , Inibidores de Catecol O-Metiltransferase/farmacologia , Inibidores de Catecol O-Metiltransferase/química , Catecol O-Metiltransferase/metabolismo , Tolcapona , Oxidiazóis/farmacologia
12.
Bioorg Chem ; 139: 106673, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37354660

RESUMO

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).


Assuntos
Catecol O-Metiltransferase , Nanosferas , Camundongos , Animais , Catecol O-Metiltransferase/metabolismo , Nanosferas/química , Camundongos Endogâmicos C57BL , Inibidores de Catecol O-Metiltransferase/farmacologia , Metilação
13.
Int J Neurosci ; 133(5): 532-543, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-33980110

RESUMO

Purpose: Levodopa formulations are the workhorses of the labor against motor symptoms management in Parkinson's disease (PD). Progression of PD on levodopa inevitably leads to motor fluctuations. It is important to understand the safety and efficacy of opicapone, the most recent addition to the clinician's armamentarium against these fluctuations.Materials and methods: We review the development of COMT inhibitors in the treatment of PD as well as the efficacy and safety data reported in the currently published literature of opicapone in PD. The "currently published literature" is defined as all published, PubMed indexed trials including the word "opicapone." Finally, we compare opicapone to the competitor pharmaceuticals on the market to treat symptom fluctuations in PD and share our opinion of opicapone's place in clinical practice.Results: From the reported results of phase 3 and 4 trials of opicapone in PD, it is a safe and efficacious option to combat motor fluctuations for our PD patients taking levodopa. A reduction of "off" time by up to 1 h per day can be expected, increasing "on" time with fewer dyskinesias. Opicapone is not generally hepatotoxic, and the most reported side-effects-dyskinesia, dry mouth, dizziness, diarrhea, and constipation-were seen in only 1.4% of the OPTIPARK (a large phase 4 clinical trial) study population.Conclusions: One should consider utilizing opicapone, perhaps in combination with other augmenting medications with different mechanisms of action, to help treat motor and non-motor fluctuations in PD.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Levodopa/efeitos adversos , Antiparkinsonianos/efeitos adversos , Inibidores de Catecol O-Metiltransferase/farmacologia , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Oxidiazóis/efeitos adversos , Ensaios Clínicos Fase IV como Assunto
14.
Molecules ; 28(3)2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36770999

RESUMO

Calendula officinalis is commonly known as marigold and its flowers are used in herbal medicines, cosmetics, perfumes, dyes, pharmaceutical preparations, and food products. However, the utility of its leaves has not been studied in depth. The purpose of the present study was to identify the major compounds in C. officinalis leaves and to determine the inhibitory properties of the isolated compounds toward human catechol-O-methyltransferase (COMT), a key neurotransmitter involved in Parkinson's disease and depression. We isolated and identified ten compounds, including two phenylpropanoids and seven flavonoids, from C. officinalis leaf extracts, of which four flavonoids were identified from C. officinalis leaves for the first time. Eight compounds exhibited COMT inhibitory activities with IC50 values of less than 100 µM. Our results indicate that compounds in C. officinalis leaves are potentially effective for preventing Parkinson's disease and depression. Thus, C. officinalis leaves may hold promise as dietary supplements.


Assuntos
Calendula , Doença de Parkinson , Humanos , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase , Doença de Parkinson/tratamento farmacológico , Flavonoides/farmacologia , Extratos Vegetais/farmacologia
15.
PLoS Biol ; 17(3): e2007050, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30856169

RESUMO

We present a selection design that couples S-adenosylmethionine-dependent methylation to growth. We demonstrate its use in improving the enzyme activities of not only N-type and O-type methyltransferases by 2-fold but also an acetyltransferase of another enzyme category when linked to a methylation pathway in Escherichia coli using adaptive laboratory evolution. We also demonstrate its application for drug discovery using a catechol O-methyltransferase and its inhibitors entacapone and tolcapone. Implementation of this design in Saccharomyces cerevisiae is also demonstrated.


Assuntos
S-Adenosilmetionina/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecóis/farmacologia , Metilação , Metiltransferases/metabolismo , Nitrilas/farmacologia , Tolcapona/farmacologia
16.
Nutr Neurosci ; 25(3): 462-471, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32441567

RESUMO

Background: Lactoferrin (bLF) is an iron-binding multifunctional protein that is abundant in milk. In mice, it inhibits catechol-O-methyltransferase (COMT) activity and increases blood levodopa levels. However, the clinical effects are unknown.Objective: The objective of this study was to determine the effect of bLF on the kinetics of levodopa in blood.Design: The effects of the concomitant administration of a combined formulation of levodopa and an aromatic amino acid decarboxylase inhibitor and bLF on the concentration of levodopa in blood and its metabolism were assessed in eight healthy subjects. In addition, we analyzed the association with clinical factors and evaluated whether clinical factors affected the COMT inhibitory activity of bLF in vitro.Results: Although not statistically significant, the peak plasma concentration (Cmax) of levodopa increased by 18.5%. From the results of the stratified analysis of total cholesterol, a relationship with ΔCmax was predicted. Therefore, bLF was reacted with cholesterol in the presence of lecithin and sodium deoxycholate in vitro to evaluate COMT inhibitory activity, and an increase in inhibitory activity was observed. By contrast, the ester compound cholesteryl oleate had no effect. The inhibitory activity of free fatty acids, which are known to interact with bLF, was also enhanced.Conclusion: The COMT inhibitory activity of bLF is not effective in elevating blood levodopa levels. However, in humans with high lipid levels, such as cholesterol, interactions may enhance the inhibitory effect, resulting in the enhanced absorption of levodopa.Trial registration: ID, UMIN000026787, registered 30 March 2017; URL, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000030749Trial registration: UMIN Japan identifier: UMIN000026787.


Assuntos
Lactoferrina , Levodopa , Animais , Antiparkinsonianos/farmacologia , Catecol O-Metiltransferase/química , Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/química , Inibidores de Catecol O-Metiltransferase/farmacologia , Voluntários Saudáveis , Humanos , Lactoferrina/química , Lactoferrina/metabolismo , Levodopa/farmacocinética , Lipídeos , Camundongos
17.
Molecules ; 27(9)2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35566171

RESUMO

Two analogues of tolcapone where the nitrocatechol group has been replaced by a 1-hydroxy-2(1H)-pyridinone have been designed and synthesised. These compounds are expected to have a dual mode of action both beneficial against Parkinson's disease: they are designed to be inhibitors of catechol O-methyl transferase, which contribute to the reduction of dopamine in the brain, and to protect neurons against oxidative damage. To assess whether these compounds are worthy of biological assessment to demonstrate these effects, measurement of their pKa and stability constants for Fe(III), in silico modelling of their potential to inhibit COMT and blood-brain barrier scoring were performed. These results demonstrate that the compounds may indeed have the desired properties, indicating they are indeed promising candidates for further evaluation.


Assuntos
Inibidores de Catecol O-Metiltransferase , Doença de Parkinson , Benzofenonas , Catecol O-Metiltransferase , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecóis/farmacologia , Quelantes , Inibidores Enzimáticos/farmacologia , Compostos Férricos , Humanos , Nitrofenóis , Doença de Parkinson/tratamento farmacológico , Piridonas
18.
J Cogn Neurosci ; 33(9): 1753-1765, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33054556

RESUMO

The contents of working memory must be maintained in the face of distraction, but updated when appropriate. To manage these competing demands of stability and flexibility, maintained representations in working memory are complemented by distinct gating mechanisms that selectively transmit information into and out of memory stores. The operations of such dopamine-dependent gating systems in the midbrain and striatum and their complementary dopamine-dependent memory maintenance operations in the cortex may therefore be dissociable. If true, selective increases in cortical dopamine tone should preferentially enhance maintenance over gating mechanisms. To test this hypothesis, tolcapone, a catechol-O-methyltransferase inhibitor that preferentially increases cortical dopamine tone, was administered in a randomized, double-blind, placebo-controlled, within-subject fashion to 49 participants who completed a hierarchical working memory task that varied maintenance and gating demands. Tolcapone improved performance in a condition with higher maintenance requirements and reduced gating demands, reflected in a reduction in the slope of RTs across the distribution. Resting-state fMRI data demonstrated that the degree to which tolcapone improved performance in individual participants correlated with increased connectivity between a region important for stimulus response mappings (left dorsal premotor cortex) and cortical areas implicated in visual working memory, including the intraparietal sulcus and fusiform gyrus. Together, these results provide evidence that augmenting cortical dopamine tone preferentially improves working memory maintenance.


Assuntos
Dopamina , Memória de Curto Prazo , Catecol O-Metiltransferase , Inibidores de Catecol O-Metiltransferase/farmacologia , Método Duplo-Cego , Humanos , Imageamento por Ressonância Magnética , Tolcapona
19.
Neuroimage ; 234: 117999, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33789133

RESUMO

Dopamine has direct and complex vasoactive effects on cerebral circulation. Catechol-O-methyltransferase (COMT) regulates cortical dopamine, and its activity can be influenced both genetically and pharmacologically. COMT activity influences the functional connectivity of the PFC at rest, as well as its activity during task performance, determined using blood oxygen level-dependent (BOLD) fMRI. However, its effects on cerebral perfusion have been relatively unexplored. Here, 76 healthy males, homozygous for the functional COMT Val158Met polymorphism, were administered either the COMT inhibitor tolcapone or placebo in a double-blind, randomised design. We then assessed regional cerebral blood flow at rest using pulsed arterial spin labelling. Perfusion was affected by both genotype and drug. COMT genotype affected frontal regions (Val158 > Met158), whilst tolcapone influenced parietal and temporal regions (placebo > tolcapone). There was no genotype by drug interaction. Our data demonstrate that lower COMT activity is associated with lower cerebral blood flow, although the regions affected differ between those affected by genotype compared with those altered by acute pharmacological inhibition. The results extend the evidence for dopaminergic modulation of cerebral blood flow. Our findings also highlight the importance of considering vascular effects in functional neuroimaging studies, and of exercising caution in ascribing group differences in BOLD signal solely to altered neuronal activity if information about regional perfusion is not available.


Assuntos
Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Circulação Cerebrovascular/fisiologia , Imageamento por Ressonância Magnética/métodos , Imagem de Perfusão/métodos , Marcadores de Spin , Adolescente , Adulto , Circulação Cerebrovascular/efeitos dos fármacos , Dopamina/metabolismo , Humanos , Masculino , Tolcapona/farmacologia , Adulto Jovem
20.
Neuroimage ; 242: 118472, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34390874

RESUMO

The cognitive effects of pharmacologically enhancing cortical dopamine (DA) tone are variable across healthy human adults. It has been postulated that individual differences in drug responses are linked to baseline cortical DA activity according to an inverted-U-shaped function. To better understand the effect of divergent starting points along this curve on DA drug responses, researchers have leveraged a common polymorphism (rs4680) in the gene encoding the enzyme catechol-O-methyltransferase (COMT) that gives rise to greater (Met allele) or lesser (Val allele) extracellular levels of cortical DA. Here we examined the extent to which changes in resting cortical perfusion following the administration of two mechanistically-distinct dopaminergic drugs vary by COMT genotype, and thereby track predictions of the inverted-U model. Using arterial spin labeling (ASL) and a double-blind, within-subject design, perfusion was measured in 75 healthy, genotyped participants once each after administration of tolcapone (a COMT inhibitor), bromocriptine (a DA D2/3 agonist), and placebo. COMT genotype and drug interacted such that COMT Val homozygotes exhibited increased prefusion in response to both drugs, whereas Met homozygotes did not. Additionally, tolcapone-related perfusion changes in the right inferior frontal gyrus correlated with altered performance on a task of executive function. No comparable effects were found for a genetic polymorphism (rs1800497) affecting striatal DA system function. Together, these results indicate that both the directionality and magnitude of drug-induced perfusion change provide meaningful information about individual differences in response to enhanced cortical DA tone.


Assuntos
Catecol O-Metiltransferase/genética , Dopamina/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Adulto , Bromocriptina/farmacologia , Inibidores de Catecol O-Metiltransferase/farmacologia , Corpo Estriado/metabolismo , Agonistas de Dopamina/farmacologia , Método Duplo-Cego , Função Executiva/fisiologia , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Tolcapona/farmacologia , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA