Biochemistry and Pharmacology of Catechol-O-Methyltransferase Inhibitors

Nissinen, Erkki; Männistö, Pekka T.

doi:10.1016/b978-0-12-381326-8.00005-3

Cited by 30 publications

(22 citation statements)

References 148 publications

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“…Furthermore, inflammation-linked COMT expression in mice and rats is tissue- and, in this case, brain region-specific. 35 At present, few studies have assessed how COMT expression is regulated, particularly in the brain. Genetic studies have predicted that promoters for the COMT gene contain binding motifs for transcription factors including Sp1, AP-2 and NF-D.…”

Section: Discussionmentioning

confidence: 99%

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Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation

Hartung

Eskew

Wong

et al. 2015

Brain, Behavior, and Immunity

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Nuclear factor-kappa B (NF-κB) is a ubiquitously expressed protein complex regulating the transcription of genes involved in inflammation and pain. Increased NF-κB activity in immune and nervous system cells is linked to several chronic pain conditions in humans as well as inflammation- and nerve injury-evoked pain in animals. A recent in vitro study further demonstrates that increased NF-κB activity in astrocytes decreases transcription of catechol-o-methyltransferase (COMT), an enzyme that inactivates catecholamines that cause pain. The purpose of the present study was to examine the relationship between systemic and astrocytic NF-κB activity, pain, and COMT expression in an animal model of inflammation. Results demonstrated that administration of the inflammatory stimulant complete Freund’s adjuvant (CFA) led to increased pain and decreased COMT protein expression in an NF-κB-dependent manner. Specifically, we found that rats and mice receiving intraplantar CFA exhibited increased behavioral responses to mechanical and thermal heat stimuli. CFA-evoked pain was blocked in rats receiving a pre-emptive systemic dose of the NF-κB inhibitor MG132 and exacerbated in IKKca mice with constitutive NF-κB activity in astrocytes. Furthermore, we observed NF-κB-linked reductions in COMT expression in midbrain at 6h and 1d following CFA in rats and at 1h and 1d in forebrain and midbrain following CFA in IKKca mice. Collectively, these results demonstrate that systemic and astrocytic NF-κB activity drive inflammatory pain and regulate the expression of COMT in forebrain and midbrain structures.

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, altered COMT expression in the forebrain has been associated with administration of mood stabilizing drugs, nutritional deficiencies, as well as a mechanism mediated by the estrogen receptor. 35 …”

Section: Discussionmentioning

confidence: 99%

Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation

Hartung

Eskew

Wong

et al. 2015

Brain, Behavior, and Immunity

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“…The clinical significance of 3-OMD as a competitive antagonist to LD is questionable 16,17. 3-OMD is considered as a biomarker of peripheral COMT inhibition 18. Currently, there are three COMT inhibitors that can be used in the treatment of PD, entacapone (ENT), tolcapone (TCP), and since its approval for medical use by the European Medicines Agency in June 2016, opicapone (OPC; Ongentys ® , developed by Bial-Portela & Ca.…”

Section: Introductionmentioning

confidence: 99%

Spotlight on opicapone as an adjunct to levodopa in Parkinson’s disease: design, development and potential place in therapy

Annus

Vécsei

2017

DDDT

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Parkinson’s disease (PD) is a progressive, chronic, neurodegenerative disease characterized by rigidity, tremor, bradykinesia and postural instability secondary to dopaminergic deficit in the nigrostriatal system. Currently, disease-modifying therapies are not available, and levodopa (LD) treatment remains the gold standard for controlling motor and nonmotor symptoms of the disease. LD is extensively and rapidly metabolized by peripheral enzymes, namely, aromatic amino acid decarboxylase and catechol-O-methyltransferase (COMT). To increase the bioavailability of LD, COMT inhibitors are frequently used in clinical settings. Opicapone is a novel COMT inhibitor that has been recently approved by the European Medicines Agency as an adjunctive therapy to combinations of LD and aromatic amino acid decarboxylase inhibitor in adult PD patients with end-of-dose motor fluctuations. We aimed to review the biochemical properties of opicapone, summarize its preclinical and clinical trials and discuss its future potential role in the treatment of PD.

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“…OCT1, OCT2 or extraneuronal monoamine transporter may mediate electrogenic uniport of a substrate or electroneutral exchange of two substrates (antiport). The OCTs are relatively resistant to the inhibitors of the neuronal transporters such as desipramine (Eisenhofer et al, 1991, Schömig et al, 2006, but are inhibited by steroids, such as corticosterone, and the O-methylated metabolites of catecholamines, like normetanephrine and metanephrine (Eisenhofer, 2001, Costa et al, 2009a, Nissinen and Männistö, 2010. Other compounds, like GF120918, were shown to inhibit extraneuronal monoamine transporter at low concentrations in isolated rat cardiomyocytes (Costa et al, 2009a).…”

Section: Catecholamine Extraneuronal Transportersmentioning

confidence: 99%

“…In the presynaptic terminals of the brain, no significant COMT is detected, but it is reported in some postsynaptic neurons and glial cells. The physiological substrates of COMT include L-3,4-dihydroxyphenylalanine, all three endogenous catecholamines (dopamine, NA, and ADR), their hydroxylated metabolites, catecholestrogens, ascorbic acid, and dihydroxyindolic intermediates of melanin (Mannisto andKaakkola, 1999, Nissinen andMännistö, 2010).…”

Section: Catechol-o-methyl Transferase Metabolismmentioning

confidence: 99%

Adrenaline and Noradrenaline: Partners and Actors in the Same Play"

Costa¹,

Carvalho²,

Bastos³

et al. 2012

Neuroscience - Dealing With Frontiers

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Biochemistry and Pharmacology of Catechol-O-Methyltransferase Inhibitors

Cited by 30 publications

References 148 publications

Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation

Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation

Spotlight on opicapone as an adjunct to levodopa in Parkinson’s disease: design, development and potential place in therapy

Adrenaline and Noradrenaline: Partners and Actors in the Same Play"

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Biochemistry and Pharmacology of Catechol-O-Methyltransferase Inhibitors

Cited by 30 publications

References 148 publications

Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation

Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation

Spotlight on opicapone as an adjunct to levodopa in Parkinson&rsquo;s disease: design, development and potential place in therapy

Adrenaline and Noradrenaline: Partners and Actors in the Same Play"

Contact Info

Product

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Spotlight on opicapone as an adjunct to levodopa in Parkinson’s disease: design, development and potential place in therapy