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

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.

• Authors: Brittany A Riggle, Sanhita Sinharay, William Schreiber-Stainthorp, Jeeva P Munasinghe, Dragan Maric, Eva Prchalova, Barbara S Slusher, Jonathan D Powell, Louis H Miller, Susan K Pierce, Dima A Hammoud
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 51 Pg. E12024-E12033 (12 18 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 30514812 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Biomarkers
• Diazooxonorleucine
• Glutamine

Topics

• Adult
• Animals
• Antimalarials (therapeutic use)
• Biomarkers
• Blood-Brain Barrier (pathology)
• Brain (parasitology, pathology)
• Brain Edema (diagnostic imaging, pathology)
• Child
• Diazooxonorleucine (administration & dosage, antagonists & inhibitors, therapeutic use)
• Disease Models, Animal
• Disease Progression
• Female
• Glutamine (antagonists & inhibitors)
• Humans
• Magnetic Resonance Imaging (methods)
• Malaria, Cerebral (diagnostic imaging, drug therapy, parasitology, pathology)
• Malaria, Falciparum (diagnostic imaging, drug therapy, pathology)
• Mice
• Mice, Inbred C57BL
• Plasmodium falciparum (pathogenicity)