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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)391-400
Number of pages10
JournalJournal of Neuroimmune Pharmacology
Volume14
Issue number3
DOIs
StatePublished - Sep 15 2019

Keywords

  • 6-diazo-5-oxo-L-norleucine (DON)
  • EcoHIV
  • Glutaminase
  • HIV-associated neurocognitive disorders (HAND)
  • Microglia

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

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