International journal of molecular sciences · 2022
Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling.
СтатьяНазвание и аннотация: Перевод в очереди
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Stahl Stephen M, De Martin Sara, Mattarei Andrea, Bettini Ezio, Pani Luca, Guidetti Clotilde, Folli Franco, de Somer Marc, Traversa Sergio, Inturrisi Charles E, Pappagallo Marco, Gentilucci Marco, Alimonti Andrea, Fava Maurizio, Manfredi Paolo L
Аннотация
This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.