Identification of a novel, fast-acting GABAergic antidepressant

Abstract

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.

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…However, there was no difference in the remission rates and the response rate advantage of the combined administration of the drugs was lost when insomnia parameters were excluded from the depression score analysis, and there was no evidence for a faster acting antidepressant response of the combined SSRI and eszopiclone group [177]. Positive modulation of GABA A receptors through an increase of the glycolytic byproduct methylglyoxal [178], delivered via inhibition of the cytosolic enzyme lactoylglutathione lyase (GLO1), induces fast-onset antidepressant actions in animal tests [179]. In particular, a 5-day administration of two GLO1 inhibitors, S -bromobenzylglutathione cyclopentyl diester (pBBG) and methyl-gerfelin (MeGFN), reduced behavioral despair in the mouse forced-swim test and tail suspension test and it also blocked maladaptive phenotypes induced by chronic mild stress and ameliorated olfactory bulbectomy-induced locomotor hyperactivity [179]; see Table 1.…”

“…Positive modulation of GABA A receptors through an increase of the glycolytic byproduct methylglyoxal [178], delivered via inhibition of the cytosolic enzyme lactoylglutathione lyase (GLO1), induces fast-onset antidepressant actions in animal tests [179]. In particular, a 5-day administration of two GLO1 inhibitors, S -bromobenzylglutathione cyclopentyl diester (pBBG) and methyl-gerfelin (MeGFN), reduced behavioral despair in the mouse forced-swim test and tail suspension test and it also blocked maladaptive phenotypes induced by chronic mild stress and ameliorated olfactory bulbectomy-induced locomotor hyperactivity [179]; see Table 1. Additionally, administration of an alpha5-containing GABA A R positive allosteric modulator reduced behavioral deficits following chronic unpredictable mild stress, when injected 30 min prior to testing [180].…”

“…There is also considerable evidence showing increased BDNF levels following electroconvulsive shock in the hippocampus of rodents [237, 281, 302–309]. Finally, sub-chronic (5 days) administration of a 5-HT 2C antagonist [239], as well as partial activation of the GABA A receptor (via inhibition of GLO1) [179], increase BDNF protein levels in the mPFC and/or hippocampus of mice. In addition, administration of ketamine, GluN2-NMDAR antagonists, mGluR 2/3 antagonists and electroconvulsive shock reverse chronic stress-induced reduction in BDNF levels in the PFC [95, 198] and hippocampus [198, 310–312] of rodents, suggesting that BDNF induction could be considered as a marker of rapid antidepressant efficacy.…”

Glyoxalase (GLO1) inhibition or genetic overexpression does not alter ethanol’s locomotor effects: implications for GLO1 as a therapeutic target in alcohol use disorders

“…Pharmacological inhibition of GLO1 results in elevated MG levels in the brain, thus increasing GABAergic tone. Inhibition of GLO1 decreased binge-like ethanol drinking in mice during a drinking in the dark paradigm, as well as various anxiety-and depression-like behaviors (Distler et al, 2012, McMurray et al, 2017a, 2017b. In addition, transgenic overexpression of Glo1 increased ethanol drinking (McMurray et al, 2017a).…”

5’ UTR variants in the quantitative trait geneHnrnph1support reduced 5’ UTR usage and hnRNP H protein as a molecular mechanism underlying reduced methamphetamine sensitivity

“…Increasing methylglyoxal levels preclinically reduced alcohol drinking (18,19), induced a rapid antidepressantlike response (20), and reduced seizures (21). To summarize, mouse forward genetic studies have led to the identification and/or corroboration of several promising therapeutic targets for SUDs and other psychiatric disorders.…”