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J. Biol. Chem., Vol. 282, Issue 19, 14505-14514, May 11, 2007

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Magnetic Resonance Spectroscopy Reveals an Impaired Brain Metabolic Profile in Mice Resistant to Cerebral Malaria Infected with Plasmodium berghei ANKA^*

Marie-France Penet¹, Frank Kober, Sylviane Confort-Gouny, Yann Le Fur, Christiane Dalmasso, Nicolas Coltel, Agnès Liprandi^¶, Jean-Marc Gulian^||, Georges E. Grau, Patrick J. Cozzone, and Angèle Viola²

From the Centre de Résonance Magnétique Biologique et Médicale, Unité Mixte de Recherche (UMR) CNRS 6612, Facultéde Médecine la Timone, UniversitédelaMéditerranée, 27 Boulevard Jean Moulin, 13005 Marseille, the Unité des Rickettsies et des Pathogènes Emergents, UMR CNRS 6020, Institut Fédératif de Recherche, FacultédeMédecine la Timone, Universitédela Méditerranée, 13005 Marseille, the ^¶Service d'Anatomie Pathologique et de Neuropathologie, Hôpital la Timone, 13005 Marseille, and the ^||Laboratoire de Biochimie, Hôpital la Timone, 13005 Marseille, France

Malaria is a major cause of morbidity and mortality with an annual death toll exceeding one million. Severe malaria is a complex multisystem disorder, including one or more of the following complications: cerebral malaria, anemia, acidosis, jaundice, respiratory distress, renal insufficiency, coagulation anomalies, and hyperparasitemia. Using a combined in vivo/in vitro metabolic-based approach, we investigated the putative pathogenic effects of Plasmodium berghei ANKA on brain, in a mouse strain developing malaria but resistant to cerebral malaria. The purpose was to determine whether the infection could cause a brain dysfunction distinct from the classic cerebral syndrome. Mice resistant to cerebral malaria were infected with P. berghei ANKA and explored during both the symptomless and the severe stage of the disease by using in vivo brain magnetic resonance imaging and spectroscopy. The infected mice did not present the lesional and metabolic hallmarks of cerebral malaria. However, brain dysfunction caused by anemia, parasite burden, and hepatic damage was evidenced. We report an increase in cerebral blood flow, a process allowing temporary maintenance of oxygen supply to brain despite anemia. Besides, we document metabolic anomalies affecting choline-derived compounds, myo-inositol, glutamine, glycine, and alanine. The choline decrease appears related to parasite proliferation. Glutamine, myo-inositol, glycine, and alanine variations together indicate a hepatic encephalopathy, a finding in agreement with the liver damage detected in mice, which is also a feature of the human disease. These results reveal the vulnerability of brain to malaria infection at the severe stage of the disease even in the absence of cerebral malaria.

Received for publication, August 22, 2006 , and in revised form, February 7, 2007.

^* This work was supported in part by grants from CNRS, Programme National Imagerie du Petit Animal, and Action Concertée Incitative "Plateformes d'explorations fonctionnelles thématisées" (ACI 2003). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a doctoral fellowship from the Ministère de la Recherche (Institut Universitaire de France) and of a research fellowship from Association pour le Developpement des Recherches Biologiques et Médicales.

² To whom correspondence should be addressed: Tel.: 33-4-91-32-44-69; Fax: 33-4-91-25-65-39; E-mail: viola{at}medecine.univ-mrs.fr.

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