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  • Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders.

Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders.

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology (2019-06-19)
Michael T Nedelcovych, Boe-Hyun Kim, Xiaolei Zhu, Lyndah E Lovell, Arena A Manning, Jennifer Kelschenbach, Eran Hadas, Wei Chao, Eva Prchalová, Ranjeet P Dash, Ying Wu, Jesse Alt, Ajit G Thomas, Rana Rais, Atsushi Kamiya, David J Volsky, Barbara S Slusher
ANOTACE

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 .

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Sigma-Aldrich
6-Diazo-5-oxo-L-norleucine, crystalline
SAFC
Hanks′ Balanced Salt solution, HBSS Modified, with phenol red, without calcium, without magnesium, liquid
SAFC
Hanks′ Balanced Salt solution, HBSS Modified, with calcium, with magnesium, without phenol red, liquid, suitable for cell culture