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A novel carbon monoxide-releasing molecule fully protects mice from severe malaria.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2012 Mar; Vol. 56 (3), pp. 1281-90. Date of Electronic Publication: 2011 Dec 12. - Publication Year :
- 2012
-
Abstract
- 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.
- Subjects :
- Acute Lung Injury metabolism
Acute Lung Injury microbiology
Animals
Antimalarials pharmacology
Antimalarials therapeutic use
Carboxyhemoglobin metabolism
Gene Expression Regulation
Heme Oxygenase-1 genetics
Heme Oxygenase-1 metabolism
Humans
Malaria, Cerebral metabolism
Malaria, Cerebral microbiology
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Organometallic Compounds pharmacology
Organometallic Compounds therapeutic use
Plasmodium berghei physiology
Plasmodium falciparum drug effects
Plasmodium falciparum physiology
Severity of Illness Index
Thiogalactosides pharmacology
Thiogalactosides therapeutic use
Acute Lung Injury drug therapy
Antimalarials chemical synthesis
Carbon Monoxide metabolism
Malaria, Cerebral drug therapy
Organometallic Compounds chemical synthesis
Plasmodium berghei drug effects
Thiogalactosides chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 56
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 22155828
- Full Text :
- https://doi.org/10.1128/AAC.05571-11