@article{9ae6b8864cb148b9b8fff743c54571e2,
title = "JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress",
abstract = "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.",
author = "Xiaolei Zhu and Nedelcovych, {Michael T.} and Thomas, {Ajit G.} and Yuto Hasegawa and Aisa Moreno-Megui and Wade Coomer and Varun Vohra and Atsushi Saito and Gabriel Perez and Ying Wu and Jesse Alt and Eva Prchalova and Luk{\'a}{\v s} Tenora and Pavel Majer and Rana Rais and Camilo Rojas and Slusher, {Barbara S.} and Atsushi Kamiya",
note = "Funding Information: We are grateful for the commitment and involvement of Shota Iwaoka, Tomonori Matsushita, and Tiffany Green. We thank Dr. Hironori Kuga for advice on statistical analysis. We also thank Dr. Yan Jouroukhin and Chantelle Terrillion for technical support in the behavior tests that were performed at the Behavioral Core of the School of Medicine of Johns Hopkins University. We thank Mr. Kamal Abdi for providing support in animal maintenance throughout the study. This research was supported by multiple grants including R01DA041208 (A.K.), R21AT008547 (A.K.), P50MH094268 (A.K.), Catalyst award (A.K.), The Brain and Behavior Research Foundation (A.K., A.S.), P30MH075673 (B.S.S.), R01CA193895 (B.S.S.), Bloomberg Kimmel Institute for Cancer Immunotherapy (B.S.S.), R25MH080661 Pilot award (X.Z.), Postdoctoral Fellowship in Pharmacology/Toxicology from the PhRMA foundation (M. T.N.), and TEDCO Maryland Innovation Initiative grant award (B.S.S.) as well as the Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, v.v.i (RVO 61388963). Publisher Copyright: {\textcopyright} 2018, American College of Neuropsychopharmacology.",
year = "2019",
month = mar,
day = "1",
doi = "10.1038/s41386-018-0177-7",
language = "English (US)",
volume = "44",
pages = "683--694",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "4",
}