title: Role of catechol-O-methyltransferase (COMT)-dependent processes in Parkinson's disease and L-DOPA treatment.
abstract: One of the most important enzymes in the catecholamine cycle, catecholamine-O-methyltransferase (COMT), plays a critical role in the extracellular metabolism of dopamine and norepinephrine both in the periphery and the central nervous system. COMT has attracted strong interest in regards to its role in dopamine-related pathologies, particularly Parkinson's disease. There are several mechanisms for the potential involvement of COMT-related processes in the pathophysiology of Parkinson's disease or the consequences of L-DOPA treatment. COMT-mediated metabolism of LDOPA in the periphery influences brain dopamine levels, while the product of central COMT-mediated dopamine metabolism, 3-methoxytyramine, can affect movement via interaction with Trace Amine-Associated Receptor 1 (TAAR1). COMT inhibitors have a long history of clinical use in the treatment of Parkinson's disease. Several clinical genetic studies have shown that variants of COMT gene contribute to the manifestations or treatment responses of this disorder. Here, we review the basic molecular mechanisms that could be involved in COMT-dependent processes in Parkinson's disease, the pharmacological properties of COMT inhibitors used in the treatment of this disorder and the clinical genetic observations involving COMT gene variants as modulators of pathological processes and responses to dopamine replacement therapies used in the treatment of the disorder.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Espinoza
authors.forename: Francesca
authors.initials: F
authors.lastname: Manago
authors.forename: Damiana
authors.initials: D
authors.lastname: Leo
authors.forename: Tatyana D
authors.initials: TD
authors.lastname: Sotnikova
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
mesh_terms: D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000494:pharmacology / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000095383:Trace Amine-Associated Receptors
chemical_list: D000978:Antiparkinson Agents; D002394:Catechol O-Methyltransferase; D065098:Catechol O-Methyltransferase Inhibitors; D004298:Dopamine; D007980:Levodopa; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors