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|Title:||Carbon monoxide and brain sequestration of Plasmodium berghei ANKA in experimental cerebral malaria|
|Author:||Pena, Ana Catarina Dias|
Zilhão, Rita Maria Pulido Garcia
Teses de mestrado
|Abstract:||Resumo alargado em português disponível no documento|
Malaria is a major infectious disease worldwide, causing ~1 million deaths each year due to severe complications, one of the most lethal being cerebral malaria (CM). Thereby, understanding CM pathogenesis is of vital importance for developing effective therapies against it. The experimental cerebral malaria (ECM) model of C57BL/6 mice infected with P. berghei ANKA (PbA) shares many similarities with human CM. However, whereas in humans a critical event is sequestration of Plasmodium-infected red blood cells (iRBCs) in the brain microvasculature, in rodents is mostly leukocyte sequestration that occurs. Thereby, the pathologic significance of iRBCs brain sequestration during ECM is controversial and remains to be clarified. Recently, it was shown that heme-oxygenase-1 (HO-1) plays a crucial role in protection against ECM, which appears to be mediated by carbon monoxide (CO) production, an end-product of its enzymatic activity. In fact, administration of CO by inhalation rescues all C57BL/6 PbA-infected mice from developing ECM. The present study shows that CO protection comprises the reduction of iRBC brain sequestration in infected mice, supporting the importance of this process in ECM pathogenesis and the relevance of C57BL/5 PbA-infected mouse model to study CM. Moreover, our results indicate that CO has a therapeutic potential as a molecule with anti-inflammatory and anti-chemotaxis effects. We also demonstrate that CORM-2, a CO-relasing molecule (CORM-2), mimics CO protection against ECM, suppressing neuroinflammation and parasite sequestration in the brain. Importantly, CORM-2 does not induce formation of carboxyhemoblogin, circumventing CO inhalation toxicity. Moreover, CORM-2 inhibits platelet aggregation and loss of RBC deformability, which likely contributes to prevent disease development. Additionally, CORM-2 also leads to an arrest in parasite load, which origin and relevance is not clear. Altogether, these results indicate that CO-RMs seem to represent a novel class of drugs with therapeutic potential to protect the host from cerebral malaria.
|Description:||Tese de mestrado, Biologia (Biologia Celular e Biotecnologia), 2009, Universidade de Lisboa, Faculdade de Ciências|
|Appears in Collections:||FC - Dissertações de Mestrado|
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