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 Slusher

Research output: Contribution to journalArticle

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)
JournalJournal of Neuroimmune Pharmacology
DOIs
StatePublished - Jan 1 2019

Fingerprint

Glutaminase
Glutamine
Norleucine
Glutamic Acid
HIV
Diazooxonorleucine
Brain
Prodrugs
Microglia
Synaptic Transmission
Cerebrospinal Fluid
Chronic Disease
Up-Regulation
Central Nervous System
Animal Models
Neurocognitive Disorders
Pharmaceutical Preparations

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

Cite this

Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders. / Nedelcovych, Michael T.; Kim, Boe Hyun; Zhu, Xiaolei; Lovell, Lyndah E.; Manning, Arena A.; Kelschenbach, Jennifer; Hadas, Eran; Chao, Wei; Prchalová, Eva; Dash, Ranjeet P.; Wu, Ying; Alt, Jesse; Thomas, Ajit G.; Rais, Rana; Kamiya, Atsushi; Volsky, David J.; Slusher, Barbara.

In: Journal of Neuroimmune Pharmacology, 01.01.2019.

Research output: Contribution to journalArticle

Nedelcovych, Michael T. ; Kim, Boe Hyun ; Zhu, Xiaolei ; Lovell, Lyndah E. ; Manning, Arena A. ; Kelschenbach, Jennifer ; Hadas, Eran ; Chao, Wei ; Prchalová, Eva ; Dash, Ranjeet P. ; Wu, Ying ; Alt, Jesse ; Thomas, Ajit G. ; Rais, Rana ; Kamiya, Atsushi ; Volsky, David J. ; Slusher, Barbara. / Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders. In: Journal of Neuroimmune Pharmacology. 2019.
@article{3d400160d34e4404b967daafd5edf1a5,
title = "Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders",
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.]",
keywords = "6-diazo-5-oxo-L-norleucine (DON), EcoHIV, Glutaminase, HIV-associated neurocognitive disorders (HAND), Microglia",
author = "Nedelcovych, {Michael T.} and Kim, {Boe Hyun} and Xiaolei Zhu and Lovell, {Lyndah E.} and Manning, {Arena A.} and Jennifer Kelschenbach and Eran Hadas and Wei Chao and Eva Prchalov{\'a} and Dash, {Ranjeet P.} and Ying Wu and Jesse Alt and Thomas, {Ajit G.} and Rana Rais and Atsushi Kamiya and Volsky, {David J.} and Barbara Slusher",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s11481-019-09859-w",
language = "English (US)",
journal = "Journal of NeuroImmune Pharmacology",
issn = "1557-1890",
publisher = "Springer New York",

}

TY - JOUR

T1 - Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders

AU - Nedelcovych, Michael T.

AU - Kim, Boe Hyun

AU - Zhu, Xiaolei

AU - Lovell, Lyndah E.

AU - Manning, Arena A.

AU - Kelschenbach, Jennifer

AU - Hadas, Eran

AU - Chao, Wei

AU - Prchalová, Eva

AU - Dash, Ranjeet P.

AU - Wu, Ying

AU - Alt, Jesse

AU - Thomas, Ajit G.

AU - Rais, Rana

AU - Kamiya, Atsushi

AU - Volsky, David J.

AU - Slusher, Barbara

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.]

AB - 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.]

KW - 6-diazo-5-oxo-L-norleucine (DON)

KW - EcoHIV

KW - Glutaminase

KW - HIV-associated neurocognitive disorders (HAND)

KW - Microglia

UR - http://www.scopus.com/inward/record.url?scp=85068066620&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068066620&partnerID=8YFLogxK

U2 - 10.1007/s11481-019-09859-w

DO - 10.1007/s11481-019-09859-w

M3 - Article

C2 - 31209775

AN - SCOPUS:85068066620

JO - Journal of NeuroImmune Pharmacology

JF - Journal of NeuroImmune Pharmacology

SN - 1557-1890

ER -