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.

Upregulation of the Glutaminase II Pathway Contributes to Glutamate Production upon Glutaminase 1 Inhibition in Pancreatic Cancer

“…However, given that inhibitors of GTK are not commercially available to combine with pharmacological GLS1 inhibition, an attempt to use glutamine antagonism was explored as proof‐of‐concept for improving therapeutic efficacy by blocking global metabolic pathways from glutamine utilization. Thus, we employed our previously reported global glutamine antagonist, termed JHU083 (ethyl 2‐(2‐amino‐4‐methylpentanamido)‐DON), a prodrug of 6‐diazo‐5‐oxo‐ l ‐norleucine (DON) . We generated patient‐derived pancreatic orthotopic tumors (JHU094), the same tumors used in our initial in vivo metabolomics analysis above, which were found to closely mimic the molecular, pathobiological, and clinical characteristics of PDAC .…”

Glutaminase 1 Regulates Neuroinflammation After Cerebral Ischemia Through Enhancing Microglial Activation and Pro-Inflammatory Exosome Release

“…in treating CNS disorders are currently under investigation. For instance, JHU-083, a prodrug of a classic GLS1 inhibitor L-DON, inhibits GLS1 activity in microglia to block inflammatory response and prevent depression-associated behaviors induced by chronic social defeat stress (39). Our study provided strong evidence that the inhibition of GLS1 by CB839 also alleviated neuroinflammation in acute brain injury, indicating bright prospects of GLS1 inhibitors in clinical application.…”

NV-5138 as a fast-acting antidepressant via direct activation of mTORC1 signaling

“…There are emerging links between CNS inflammation and glutamate signaling underlying depression (18). Furthermore, a recent study reported that pharmacological inhibition of microglial glutamate production ameliorates chronic stress-induced depressive-like behaviors (19). Considering that mTOR signaling also regulates the immune and inflammatory systems via modulation of NF-κB and STAT3 signaling pathways (ref.…”