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JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress
X. Zhu, MT. Nedelcovych, AG. Thomas, Y. Hasegawa, A. Moreno-Megui, W. Coomer, V. Vohra, A. Saito, G. Perez, Y. Wu, J. Alt, E. Prchalova, L. Tenora, P. Majer, R. Rais, C. Rojas, BS. Slusher, A. Kamiya,
Language English Country Great Britain
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
P50 MH094268
NIMH NIH HHS - United States
R01 CA193895
NCI NIH HHS - United States
P50MH094268
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) - International
P30 MH075673
NIMH NIH HHS - United States
R21AT008547
U.S. Department of Health & Human Services | NIH | National Center for Complementary and Integrative Health (NCCIH) - International
K01 MH086050
NIMH NIH HHS - United States
R21 AT008547
NCCIH NIH HHS - United States
R01 MH110246
NIMH NIH HHS - United States
R01DA041208
U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) - International
P30MH075673
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) - International
R01 CA229451
NCI NIH HHS - United States
R25 MH080661
NIMH NIH HHS - United States
R01CA193895
U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) - International
R01 DA041208
NIDA NIH HHS - United States
NLK
Free Medical Journals
from 1994 to 1 year ago
PubMed Central
from 2010 to 1 year ago
Europe PubMed Central
from 2010 to 1 year ago
ProQuest Central
from 2000-01-01 to 1 year ago
Open Access Digital Library
from 1994-01-01
Health & Medicine (ProQuest)
from 2000-01-01 to 1 year ago
Psychology Database (ProQuest)
from 2000-01-01 to 1 year ago
- MeSH
- CD11b Antigen * MeSH
- Behavior, Animal drug effects MeSH
- Depression etiology prevention & control MeSH
- Diazooxonorleucine * pharmacology MeSH
- Glutaminase drug effects MeSH
- Hippocampus drug effects immunology metabolism MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Prefrontal Cortex drug effects immunology metabolism MeSH
- Prodrugs * pharmacology MeSH
- Stress, Psychological complications MeSH
- Signal Transduction MeSH
- Inflammation drug therapy immunology metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
There are a number of clinically effective treatments for stress-associated psychiatric diseases, including major depressive disorder (MDD). Nonetheless, many patients exhibit resistance to first-line interventions calling for novel interventions based on pathological mechanisms. Accumulating evidence implicates altered glutamate signaling in MDD pathophysiology, suggesting that modulation of glutamate signaling cascades may offer novel therapeutic potential. Here we report that JHU-083, our recently developed prodrug of the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) ameliorates social avoidance and anhedonia-like behaviors in mice subjected to chronic social defeat stress (CSDS). JHU-083 normalized CSDS-induced increases in glutaminase activity specifically in microglia-enriched CD11b+ cells isolated from the prefrontal cortex and hippocampus. JHU-083 treatment also reverses the CSDS-induced inflammatory activation of CD11b+ cells. These results support the importance of altered glutamate signaling in the behavioral abnormalities observed in the CSDS model, and identify glutaminase in microglia-enriched CD11b+ cells as a pharmacotherapeutic target implicated in the pathophysiology of stress-associated psychiatric conditions such as MDD.
References provided by Crossref.org
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