L‐arginine Supplementation and Thromboxane Synthase Inhibition Reverse Cerebral Ischemia in Murine Cerebral Malaria by Plasmodium berghei ANKA

Abstract

Cerebral malaria (CM) is one of the most severe and lethal complications of Plasmodium falciparum infection. The mainstay treatment for CM is intravenous artesunate, nevertheless 15–20% of the patients receiving this drug still die. Vascular dysfunction, with vasoconstriction, leads to decreased cerebral blood flow, ischemia, tissue hypoxia and death in CM. Nitric oxide (NO) and arachidonic acid metabolites are important regulators of physiological cerebral blood flow through their vasodilator or vasoconstrictive properties. The objective of this study was to determine the effects of L‐arginine supplementation and pharmacological inhibition of thromboxane A2 (TXA2) synthesis on the reversal of ischemia in experimental cerebral malaria (ECM). C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) and showing clinical signs of ECM were treated subcutaneously with the NO precursor L‐arginine (50mg/kg) and/or the thromboxane synthase inhibitor ozagrel (100mg/kg). Cerebral blood flow was measured by Laser Speckle Contrast Imaging (LSCI). The adjuvant effect of L‐arginine in combination with artesunate on survival of mice with late‐stage ECM was evaluated. Animals that developed ECM showed a significant decrease (25%) in cerebral blood flow compared to non‐infected control animals. L‐arginine induced a marked increase (22.5%) in cerebral blood flow in mice with ECM one hour after administration. The administration of ozagrel, which prevents the generation of the vasoconstrictor metabolite TXA2, also led to increased (16.5%) cerebral blood flow in animals with ECM, and this was consistent with decreased levels of brain TXA2 in ozagrel‐treated compared to saline‐treated animals. The combination of ozagrel and L‐arginine showed no synergistic effect on cerebral blood flow. Treatment of animals with late‐stage ECM with artesunate plus L‐arginine increased survival compared to artesunate plus saline. Conclusion: L‐arginine and ozagrel increase cerebral blood flow, and L‐arginine increase survival in mice with cerebral malaria and show potential as adjuvant therapy for this malaria complication.Support or Funding InformationCAPES, FAPERJ, IOC‐FiocruzThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.