Role of Nitric oxide synthase II in cognitive impairment due to experimental cerebral malaria

Abstract

The role of nitric oxide (NO) in the pathogenesis of cerebral malaria and its cognitive sequelae remains controversial. Cerebral malaria is still the worst complication of Plasmodium falciparum infection, which is characterized by high rates of morbidity and mortality. Even after recovery from infection due to antimalarial therapy, the development of cognitive impairment in survivors reinforces the need to seek new therapies that demonstrate efficacy in preventing long-lasting sequelae. During disease pathogenesis, reactive oxygen and nitrogen species (RONS) are produced after the established intense inflammatory response. Increased expression of the enzyme inducible nitric oxide synthase (iNOS) seems to contribute to tissue injury and the onset of neurological damage. Elevated levels of NO developed by iNOS can induce the production of highly harmful nitrogen-reactive intermediates such as peroxynitrite. To address this, we performed biochemical and behavioral studies in C57BL6 mice, aminoguanidine (specific pharmacological inhibitor of the enzyme iNOS) treated and iNOS−/−, infected with Plasmodium berghei ANKA (PbA), with the aim of clarifying the impact of iNOS on the pathogenesis of cerebral malaria. Our findings underscore the effectiveness of both strategies in reducing cerebral malaria and providing protection against the cognitive impairment associated with the disease. Here, the absence or blockade of the iNOS enzyme was effective in reducing the signs of cerebral malaria detected after six days of infection. This was accompanied by a decrease in the production of pro-inflammatory cytokines and reactive oxygen and nitrogen species. In addition, nitrotyrosine (NT-3), a marker of nitrosative stress, was also reduced. Futher, cognitive dysfunction was analyzed fifteen days after infection in animals rescued from infection by chloroquine treatment (25 mg/kg bw). We observed that both interventions on the iNOS enzyme were able to improve memory and learning loss in mice. In summary, our data suggest that the iNOS enzyme has the potential to serve as a therapeutic target to prevent cognitive sequelae of cerebral malaria.