Identification of a novel, fast-acting GABAergic antidepressant.
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.
Committee on Neurobiology, University of Chicago, Chicago, IL, USA.|Department of Human Genetics, University of Chicago, Chicago, IL, USA.
K M J
KMJ
McMurray
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
M J
MJ
Ramaker
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
A M
AM
Barkley-Levenson
Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
P S
PS
Sidhu
Department of Chemistry, University of Chicago, Chicago, IL, USA.
P K
PK
Elkin
Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
M K
MK
Reddy
Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
M L
ML
Guthrie
Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
J M
JM
Cook
Department of Chemistry, University of Chicago, Chicago, IL, USA.
V H
VH
Rawal
Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
L A
LA
Arnold
Committee on Neurobiology, University of Chicago, Chicago, IL, USA.|Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.|Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
S C
SC
Dulawa
Department of Human Genetics, University of Chicago, Chicago, IL, USA.|Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.|Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.|Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
A A
AA
Palmer
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D018682:GABA Agents / Q000494:pharmacology; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000187:drug effects; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000187:drug effects; D011765:Pyruvaldehyde / Q000494:pharmacology*; D013550:Swimming
D000928:Antidepressive Agents; D018682:GABA Agents; D011765:Pyruvaldehyde; C000624928:Glo1 protein, mouse; D007791:Lactoylglutathione Lyase