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.

中文翻译：

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JHU-083 选择性地阻断大脑 CD11b+ 细胞中的谷氨酰胺酶活性，并防止由慢性社交失败压力引起的抑郁相关行为。

对于与压力相关的精神疾病，包括重度抑郁症 (MDD)，有许多临床有效的治疗方法。尽管如此，许多患者表现出对一线干预的抗拒，需要基于病理机制的新型干预。越来越多的证据表明 MDD 病理生理学中谷氨酸信号的改变，表明调节谷氨酸信号级联可能提供新的治疗潜力。在这里，我们报告 JHU-083，我们最近开发的谷氨酰胺酶抑制剂 6-diazo-5-oxo-L-norleucine (DON) 的前体药物，可改善遭受慢性社交失败压力 (CSDS) 的小鼠的社交回避和快感缺乏样行为。JHU-083 使 CSDS 诱导的谷氨酰胺酶活性增加正常化，特别是在从前额叶皮层和海马体分离的富含小胶质细胞的 CD11b+ 细胞中。JHU-083 治疗还可以逆转 CSDS 诱导的 CD11b+ 细胞炎症激活。这些结果支持改变谷氨酸信号在 CSDS 模型中观察到的行为异常中的重要性，并将富含小胶质细胞的 CD11b+ 细胞中的谷氨酰胺酶鉴定为与应激相关精神疾病（如 MDD）的病理生理学有关的药物治疗靶点。