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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

Zhu, Xiaolei
Autor Zhu, Xiaolei Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Nedelcovych, Michael T
Autor Nedelcovych, Michael T Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Thomas, Ajit G
Autor Thomas, Ajit G Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Hasegawa, Yuto
Autor Hasegawa, Yuto Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Moreno-Megui, Aisa
Autor Moreno-Megui, Aisa Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Coomer, Wade
Autor Coomer, Wade Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Vohra, Varun
Autor Vohra, Varun Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Saito, Atsushi
Autor Saito, Atsushi Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Perez, Gabriel
Autor Perez, Gabriel Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Wu, Ying
Autor Wu, Ying Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Neuropsychopharmacology. 2019 ; 44 (4) : 683-694. [pub] 20180813

ISSN 1740-634X
Medvik
Zdroj

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.

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