Fig. 6

Vascular effects of malaria parasitized red blood cells. a. Malaria limits NO bioavailability and RRx-001 restores NO. Malaria is a disease of low NO bioavailability resulting from both low levels of production and high scavenging rates.[45] Red blood cell (RBC) lysis leads to the release of Hb and arginase: Acellular Hb scavenges NO and arginase degrades arginine, which is an NO precursor. The consequences of low NO bioavailability are: less deformable RBCs leading to occlusion, vasospasm and ischemia. As deoxyHb nitrite reductase catalyst, RRx-001 produces NO “on demand” in ischemic/ hypoxic areas, reversing the vascular defects. b. Proposed vascular status of malaria parasitized RBCs after treatment with RRx-001. Overview of direct and indirect therapeutic effects of RRx-001 on malarial pathogenesis. RRx-001 affects parasitized RBC directly by increasing of oxidative stress with resulting G6PD inhibition while indirectly treating vasculopathic sequelae due to low NO bioavailiability. c. G6PD in uninfected and infected RBCs. In uninfected erythrocytes, G6PD operates at a fraction of its capacity. Under increased oxidative stress, the NADPH is oxidized and G6PD becomes highly activated. Limiting G6PD lowers the ration NADPH/NADP, increasing G6PD activity. Under conditions of oxidative stress, known to be important for the action of anti-malarial drugs, cells with limited G6PD can only activate their G6PD activity to a small extent, under the risk of haemolytic anemia. RBCs and malaria parasites are equipped with antioxidant defense systems, glutathione (GSH) and thioredoxin (Trx) systems, which are both NADPH dependent. The GSH system reduced GSSG to GSH, using GSH reductase (GR), present in RBCs and malaria parasites. In addition, parasites have thioredoxin reductase (TR), which reduces Trx disulfide (Trx-S₂) to the Trx dithiol-form [Trx-(SH)₂]. The PPP is the only source of NADPH in erythrocytes, and most likely the major source of NADPH in the parasite