efficacy of different nitric oxide-based strategies in preventing experimental cerebral malaria by plasmodium berghei anka的功效不同的氧化物氮策略防止鼠实验性脑型疟疾的安卡.pdfVIP

Efficacy of Different Nitric Oxide-Based Strategies in Preventing Experimental Cerebral Malaria by Plasmodium berghei ANKA 1,2 1,3 1 1,4 Yuri C. Martins *, Graziela M. Zanini , John A. Frangos , Leonardo J. M. Carvalho 1 Center for Malaria Research, La Jolla Bioengineering Institute, San Diego, California, United States of America, 2 Laboratory of Inflammation and Immunity, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 3 Parasitology Service, Evandro Chagas Clinical Research Institute, Fiocruz, Rio de Janeiro, Brazil, 4 Laboratory of Malaria Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil Abstract Background: Low nitric oxide (NO) bioavailability plays a role in the pathogenesis of human as well as of experimental cerebral malaria (ECM) caused by Plasmodium berghei ANKA (PbA). ECM is partially prevented by administration of the NO- donor dipropylenetriamine NONOate (DPTA-NO) at high concentration (1 mg/mouse), which also induces major side effects such as a sharp drop in blood pressure. We asked whether alternative strategies to improve NO bioavailability with minor side effects would also be effective in preventing ECM. Methodology/Principal Findings: Mice were infected with PbA and prophylactically treated twice a day with bolus injections of L-arginine, Nv-hydroxy-nor-Arginine (nor-NOHA), tetrahydrobiopterin (BH4), separately or combined, sodium nitrite, sildenafil or sildenafil plus DPTA-NO starting on day 0 of infection. L-arginine and BH4 supplementation, with or without arginase inhibition by nor-NOHA, increased plasma nitrite levels but failed to protect against ECM development. Accordingly, prophylact