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.

• Authors: Xiaolei Zhu, Michael T Nedelcovych, Ajit G Thomas, Yuto Hasegawa, Aisa Moreno-Megui, Wade Coomer, Varun Vohra, Atsushi Saito, Gabriel Perez, Ying Wu, Jesse Alt, Eva Prchalova, Lukáš Tenora, Pavel Majer, Rana Rais, Camilo Rojas, Barbara S Slusher, Atsushi Kamiya
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 44 Issue 4 Pg. 683-694 (03 2019) ISSN: 1740-634X [Electronic] England
• PMID: 30127344 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CD11b Antigen
• Itgam protein, mouse
• Prodrugs
• Diazooxonorleucine
• Glutaminase

Topics

• Animals
• Behavior, Animal (drug effects)
• CD11b Antigen
• Depression (etiology, prevention & control)
• Diazooxonorleucine (pharmacology)
• Disease Models, Animal
• Glutaminase (drug effects)
• Hippocampus (drug effects, immunology, metabolism)
• Inflammation (drug therapy, immunology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Prefrontal Cortex (drug effects, immunology, metabolism)
• Prodrugs (pharmacology)
• Signal Transduction
• Stress, Psychological (complications)