2. Academic Validation
  3. MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice

MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice

  • Proc Natl Acad Sci U S A. 2018 Dec 18;115(51):E12024-E12033. doi: 10.1073/pnas.1812909115.
Brittany A Riggle 1,  Sanhita Sinharay 2,  William Schreiber-Stainthorp 2,  Jeeva P Munasinghe 3,  Dragan Maric 4,  Eva Prchalova 5 6,  Barbara S Slusher 5 6,  Jonathan D Powell 7,  Louis H Miller 8,  Susan K Pierce 1,  Dima A Hammoud 9
Affiliations

Affiliations

  • 1 Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
  • 2 Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
  • 3 Magnetic Resonance Imaging Research Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
  • 4 Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
  • 5 Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205.
  • 6 Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205.
  • 7 Department of Oncology, Sidney Kimmel Comprehensive Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
  • 8 Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852 [email protected] [email protected].
  • 9 Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892; [email protected] [email protected].
PMID: 30514812 DOI: 10.1073/pnas.1812909115
Abstract

The deadliest complication of Plasmodium falciparum Infection is cerebral malaria (CM), with a case fatality rate of 15 to 25% in African children despite effective antimalarial chemotherapy. No adjunctive treatments are yet available for this devastating disease. We previously reported that the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) rescued mice from experimental CM (ECM) when administered late in the Infection, a time by which mice had already suffered blood-brain barrier (BBB) dysfunction, brain swelling, and hemorrhaging. Herein, we used longitudinal MR imaging to visualize brain pathology in ECM and the impact of a new DON prodrug, JHU-083, on disease progression in mice. We demonstrate in vivo the reversal of Disease markers in symptomatic, infected mice following treatment, including the resolution of edema and BBB disruption, findings usually associated with a fatal outcome in children and adults with CM. Our results support the premise that JHU-083 is a potential adjunctive treatment that could rescue children and adults from fatal CM.

Keywords

MRI; Plasmodium falciparum; cerebral malaria; experimental cerebral malaria; glutamine antagonist.

Figures
Products