Identification of a novel, fast-acting GABAergic antidepressant. Mol Psychiatry 2018 Feb;23(2):384-391
Date
03/23/2017Pubmed ID
28322281Pubmed Central ID
PMC5608625DOI
10.1038/mp.2017.14Scopus ID
2-s2.0-85015625674 (requires institutional sign-in at Scopus site) 30 CitationsAbstract
Current pharmacotherapies for depression exhibit slow onset, side effects and limited efficacy. Therefore, identification of novel fast-onset antidepressants is desirable. GLO1 is a ubiquitous cellular enzyme responsible for the detoxification of the glycolytic byproduct methylglyoxal (MG). We have previously shown that MG is a competitive partial agonist at GABA-A receptors. We examined the effects of genetic and pharmacological inhibition of GLO1 in two antidepressant assay models: the tail suspension test (TST) and the forced swim test (FST). We also examined the effects of GLO1 inhibition in three models of antidepressant onset: the chronic FST (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy (OBX). Genetic knockdown of Glo1 or pharmacological inhibition using two structurally distinct GLO1 inhibitors (S-bromobenzylglutathione cyclopentyl diester (pBBG) or methyl-gerfelin (MeGFN)) reduced immobility in the TST and acute FST. Both GLO1 inhibitors also reduced immobility in the cFST after 5 days of treatment. In contrast, the serotonin reuptake inhibitor fluoxetine (FLX) reduced immobility after 14, but not 5 days of treatment. Furthermore, 5 days of treatment with either GLO1 inhibitor blocked the depression-like effects induced by CMS on the FST and coat state, and attenuated OBX-induced locomotor hyperactivity. Finally, 5 days of treatment with a GLO1 inhibitor (pBBG), but not FLX, induced molecular markers of the antidepressant response including brain-derived neurotrophic factor (BDNF) induction and increased phosphorylated cyclic-AMP response-binding protein (pCREB) to CREB ratio in the hippocampus and medial prefrontal cortex (mPFC). Our findings indicate that GLO1 inhibitors may provide a novel and fast-acting pharmacotherapy for depression.
Author List
McMurray KMJ, Ramaker MJ, Barkley-Levenson AM, Sidhu PS, Elkin PK, Reddy MK, Guthrie ML, Cook JM, Rawal VH, Arnold LA, Dulawa SC, Palmer AAAuthors
Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - MilwaukeeJames M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee
MESH terms used to index this publication - Major topics in bold
AnimalsAntidepressive Agents
Depression
Depressive Disorder
Female
GABA Agents
Hindlimb Suspension
Hippocampus
Lactoylglutathione Lyase
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Prefrontal Cortex
Pyruvaldehyde
Swimming
