Johns Hopkins Drug Discovery, 855 North Wolfe Street, Baltimore, MD, 21205, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Neuroimmune Pharmacol. 2019 Sep;14(3):391-400. doi: 10.1007/s11481-019-09859-w. Epub 2019 Jun 17.
HIV-associated neurocognitive disorders (HAND) have been linked to dysregulation of glutamate metabolism in the central nervous system (CNS) culminating in elevated extracellular glutamate and disrupted glutamatergic neurotransmission. Increased glutamate synthesis via upregulation of glutaminase (GLS) activity in brain immune cells has been identified as one potential source of excess glutamate in HAND. However, direct evidence for this hypothesis in an animal model is lacking, and the viability of GLS as a drug target has not been explored. In this brief report, we demonstrate that GLS inhibition with the glutamine analogue 6-diazo-5-oxo-L-norleucine (DON) can reverse cognitive impairment in the EcoHIV-infected mouse model of HAND. However, due to peripheral toxicity DON is not amenable to clinical use in a chronic disease such as HAND. We thus tested JHU083, a novel, brain penetrant DON prodrug predicted to exhibit improved tolerability. Systemic administration of JHU083 reversed cognitive impairment in EcoHIV-infected mice similarly to DON, and simultaneously normalized EcoHIV-induced increases in cerebrospinal fluid (CSF) glutamate and GLS activity in microglia-enriched brain CD11b + cells without observed toxicity. These studies support the mechanistic involvement of elevated microglial GLS activity in HAND pathogenesis, and identify JHU083 as a potential treatment option. Graphical Abstract Please provide Graphical Abstract caption.Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders .
HIV 相关神经认知障碍（HAND）与中枢神经系统（CNS）中谷氨酸代谢的失调有关，最终导致细胞外谷氨酸升高和谷氨酸能神经传递紊乱。脑免疫细胞中谷氨酰胺酶（GLS）活性的上调导致谷氨酸合成增加，被认为是 HAND 中谷氨酸过量的一个潜在来源。然而，该假说在动物模型中的直接证据尚缺乏，并且 GLS 作为药物靶点的可行性尚未得到探索。在本简要报告中，我们证明了用谷氨酰胺类似物 6-二氮-5-氧-L-正亮氨酸（DON）抑制 GLS 可以逆转 EcoHIV 感染的 HAND 小鼠模型中的认知障碍。然而，由于 DON 的外周毒性，它不适用于 HAND 等慢性疾病的临床应用。因此，我们测试了 JHU083，这是一种新型的、可穿透大脑的 DON 前药，预计具有更好的耐受性。JHU083 的系统给药类似于 DON 逆转了 EcoHIV 感染小鼠的认知障碍，同时使 EcoHIV 诱导的脑脊液（CSF）谷氨酸和小胶质细胞富集的脑 CD11b+细胞中的 GLS 活性恢复正常，而没有观察到毒性。这些研究支持了升高的小胶质细胞 GLS 活性在 HAND 发病机制中的机制参与，并确定了 JHU083 作为一种潜在的治疗选择。
