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Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria

Abstract

The role of nitric oxide (NO) in the genesis of cerebral malaria is controversial. Most investigators propose that the unfortunate consequence of the high concentrations of NO produced to kill the parasite is the development of cerebral malaria. Here we have tested this high NO bioavailability hypothesis in the setting of experimental cerebral malaria (ECM), but find instead that low NO bioavailability contributes to the genesis of ECM. Specifically, mice deficient in vascular NO synthase showed parasitemia and mortality similar to that observed in control mice. Exogenous NO did not affect parasitemia but provided marked protection against ECM; in fact, mice treated with exogenous NO were clinically indistinguishable from uninfected mice at a stage when control infected mice were moribund. Administration of exogenous NO restored NO-mediated signaling in the brain, decreased proinflammatory biomarkers in the blood, and markedly reduced vascular leak and petechial hemorrhage into the brain. Low NO bioavailability in the vasculature during ECM was caused in part by an increase in NO-scavenging free hemoglobin in the blood, by hypoargininemia, and by low blood and erythrocyte nitrite concentrations. Exogenous NO inactivated NO-scavenging free hemoglobin in the plasma and restored nitrite to concentrations observed in uninfected mice. We therefore conclude that low rather than high NO bioavailability contributes to the genesis of ECM.

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Figure 1: Low rather than increased NO bioavailability contributes to ECM.
Figure 2: Administration of DPTA/NO donor inhibits vascular leak in brain and hypotension during ECM, and decreases MMP-9 and inflammatory biomarkers in blood.
Figure 3: Free hemoglobin in plasma and hypoargininemia contribute to low NO bioavailability during ECM.
Figure 4: Improving NO bioavailability through NO donor administration protects against the development of ECM.

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Acknowledgements

We thank N. Silvestrov and D. von Deutsch for analyzing the plasma arginine. This work was supported by grants from the US National Institutes of Health to J.A.F. (HL40696), M.I. (R24 HL643952), J.P.N. (EB003824) and H.C.v.d.H. (AI40667).

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Correspondence to Henri C van der Heyde.

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Supplementary information

Supplementary Fig. 1

Free oxyHb levels of mice on day 4, 6 and 9 of PbA infection and their clinical score (A). (PDF 355 kb)

Supplementary Table 1

Cytokines levels in plasma of mice with ECM. (PDF 63 kb)

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Gramaglia, I., Sobolewski, P., Meays, D. et al. Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria. Nat Med 12, 1417–1422 (2006). https://doi.org/10.1038/nm1499

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