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

Brittany A. Riggle, Sanhita Sinharay, William Schreiber-Stainthorp, Jeeva P. Munasinghe, Dragan Maric, Eva Prchalova, Barbara Slusher, Jonathan Powell, Louis H. Miller, Susan K. Pierce, Dima A. Hammoud

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)E12024-E12033
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number51
DOIs
StatePublished - Dec 18 2018

Fingerprint

Cerebral Malaria
Glutamine
Diazooxonorleucine
Pathology
Fatal Outcome
Brain Edema
Prodrugs
Antimalarials
Plasmodium falciparum
Malaria
Disease Progression
Edema
Therapeutics
Drug Therapy
Mortality
Brain
Infection

Keywords

  • Cerebral malaria
  • Experimental cerebral malaria
  • Glutamine antagonist
  • MRI
  • Plasmodium falciparum

ASJC Scopus subject areas

  • General

Cite this

Riggle, B. A., Sinharay, S., Schreiber-Stainthorp, W., Munasinghe, J. P., Maric, D., Prchalova, E., ... Hammoud, D. A. (2018). MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice. Proceedings of the National Academy of Sciences of the United States of America, 115(51), E12024-E12033. https://doi.org/10.1073/pnas.1812909115

MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice. / Riggle, Brittany A.; Sinharay, Sanhita; Schreiber-Stainthorp, William; Munasinghe, Jeeva P.; Maric, Dragan; Prchalova, Eva; Slusher, Barbara; Powell, Jonathan; Miller, Louis H.; Pierce, Susan K.; Hammoud, Dima A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 51, 18.12.2018, p. E12024-E12033.

Research output: Contribution to journalArticle

Riggle, BA, Sinharay, S, Schreiber-Stainthorp, W, Munasinghe, JP, Maric, D, Prchalova, E, Slusher, B, Powell, J, Miller, LH, Pierce, SK & Hammoud, DA 2018, 'MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 51, pp. E12024-E12033. https://doi.org/10.1073/pnas.1812909115
Riggle, Brittany A. ; Sinharay, Sanhita ; Schreiber-Stainthorp, William ; Munasinghe, Jeeva P. ; Maric, Dragan ; Prchalova, Eva ; Slusher, Barbara ; Powell, Jonathan ; Miller, Louis H. ; Pierce, Susan K. ; Hammoud, Dima A. / MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 51. pp. E12024-E12033.
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