Related Experiment Video
Updated: Apr 11, 2026
In Vivo Tracking of Edema Development and Microvascular Pathology in a Model of Experimental Cerebral Malaria Using Magnetic Resonance Imaging
Published on: June 8, 2017
From METS to malaria: RRx-001, a multi-faceted anticancer agent with activity in cerebral malaria
Ozlem Yalcin1,2, Bryan Oronsky3, Leonardo J M Carvalho4,5
1Department of Bioengineering, University of California, 9500 Gilman Dr., La Jolla, San Diego, CA, 92093-0412, USA. ozlemyalcin@ku.edu.tr.
Background:
The survival of malaria parasites, under substantial haem-induced oxidative stress in the red blood cells (RBCs) is dependent on the pentose phosphate pathway (PPP). The PPP is the only source of NADPH in the RBC, essential for the production of reduced glutathione (GSH) and for protection from oxidative stress. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, therefore, increases the vulnerability of erythrocytes to oxidative stress. In Plasmodium, G6PD is combined with the second enzyme of the PPP to create a unique bifunctional enzyme, named glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (G6PD-6PGL). RRx-001 is a novel, systemically non-toxic, epigenetic anticancer agent currently in Phase 2 clinical development for multiple tumour types, with activity mediated through increased nitric oxide (NO) production and PPP inhibition. The inhibition of G6PD and NO overproduction induced by RRx-001 suggested its application in cerebral malaria (CM).
Methods:
Plasmodium berghei ANKA (PbA) infection in C57BL/6 mice is an experimental model of cerebral malaria (ECM) with several similar pathological features to human CM. This study uses intravital microscopy methods with a closed cranial window model to quantify cerebral haemodynamic changes and leukocyte adhesion to endothelial cells in ECM.
Results:
RRx-001 had both single agent anti-parasitic activity and significantly increased the efficacy of artemether. In addition, RRx-001 preserved cerebral perfusion and reduced inflammation alone or combined with artemether. RRx-001's effects were associated with inhibition of PPP (G6PD and G6PD-6PGL) and by improvements in microcirculatory flow, which may be related to the NO donating properties of RRx-001.
Conclusion:
The results indicate that RRx-001 could be used to potentiate the anti-malarial action of artemisinin, particularly on resistant strains, and to prevent infection.
Insights
RRx-001 shows promise in treating cerebral malaria by inhibiting the pentose phosphate pathway (PPP) and potentiating artemisinin, even against resistant strains. This drug preserves brain function and reduces inflammation during infection.
Area of Science:
- Malariology
- Parasitology
- Pharmacology
- Oncology
- Neuroscience
Background:
- The pentose phosphate pathway (PPP) is crucial for malaria parasite survival in red blood cells (RBCs) by producing NADPH for oxidative stress defense.
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency compromises erythrocyte defense against oxidative stress.
- Plasmodium species possess a unique bifunctional enzyme, G6PD-6-phosphogluconolactonase (G6PD-6PGL), integrating G6PD and 6-phosphogluconolactonase.
- RRx-001, an epigenetic anticancer agent, inhibits the PPP and increases nitric oxide (NO) production, suggesting potential in cerebral malaria (CM).
Purpose of the Study:
- To investigate the efficacy of RRx-001 as a single agent and in combination with artemether in a mouse model of cerebral malaria (CM).
- To evaluate the impact of RRx-001 on parasite burden, cerebral hemodynamics, and inflammation in experimental CM (ECM).
Main Methods:
- Utilized Plasmodium berghei ANKA (PbA) infection in C57BL/6 mice as a model for experimental cerebral malaria (ECM).
- Employed intravital microscopy with a closed cranial window to assess cerebral hemodynamic changes and leukocyte-endothelial cell interactions in ECM.
- Quantified anti-parasitic activity and combined efficacy with artemether.
Main Results:
- RRx-001 demonstrated single-agent anti-parasitic activity and synergistically enhanced artemether's efficacy.
- RRx-001 treatment preserved cerebral perfusion and reduced inflammation, both alone and in combination with artemether.
- Observed inhibition of the PPP (G6PD and G6PD-6PGL) and improved microcirculatory flow, potentially linked to RRx-001's NO-donating properties.
Conclusions:
- RRx-001 can potentiate the anti-malarial effects of artemisinin, particularly against resistant strains.
- RRx-001 shows potential for preventing malaria infection and treating cerebral malaria.
- The drug's mechanism involves PPP inhibition and NO-mediated improvements in microcirculation.
