A Novel Carbon Monoxide-Releasing Molecule Fully Protects Mice from Severe Malaria
| Autor: | Afonso Fernandes, Nuno Penacho, Rita Neres, Ana Pamplona, Ana Cristina Ruiz Peña, Carlos C. Romão, Maria M. Mota, Gonçalo J. L. Bernardes, João Seixas, Liliana Mancio-Silva |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Plasmodium berghei
Acute Lung Injury Plasmodium falciparum Malaria Cerebral Parasitemia Lung injury 010402 general chemistry Severity of Illness Index 01 natural sciences Thiogalactosides Antimalarials Mice 03 medical and health sciences chemistry.chemical_compound parasitic diseases Organometallic Compounds medicine Animals Humans Experimental Therapeutics Pharmacology (medical) Artemisinin 030304 developmental biology Pharmacology Carbon Monoxide 0303 health sciences biology Oxygen transport biology.organism_classification medicine.disease 3. Good health 0104 chemical sciences Mice Inbred C57BL Infectious Diseases Carboxyhemoglobin Gene Expression Regulation chemistry Mice Inbred DBA Cerebral Malaria Artesunate Immunology Heme Oxygenase-1 medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | Severe forms of malaria infection, such as cerebral malaria (CM) and acute lung injury (ALI), are mainly caused by the apicomplexan parasite Plasmodium falciparum . Primary therapy with quinine or artemisinin derivatives is generally effective in controlling P. falciparum parasitemia, but mortality from CM and other forms of severe malaria remains unacceptably high. Herein, we report the design and synthesis of a novel carbon monoxide-releasing molecule (CO-RM; ALF492) that fully protects mice against experimental CM (ECM) and ALI. ALF492 enables controlled CO delivery in vivo without affecting oxygen transport by hemoglobin, the major limitation in CO inhalation therapy. The protective effect is CO dependent and induces the expression of heme oxygenase-1, which contributes to the observed protection. Importantly, when used in combination with the antimalarial drug artesunate, ALF492 is an effective adjunctive and adjuvant treatment for ECM, conferring protection after the onset of severe disease. This study paves the way for the potential use of CO-RMs, such as ALF492, as adjunctive/adjuvant treatment in severe forms of malaria infection. |
| Databáze: | OpenAIRE |
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