Administration of the exogenous nitric oxide (NO) donor dipropylenetriamine-NONOate (DPTA-NO) to mice during Plasmodium berghei ANKA (PbA) infection largely prevents development of experimental cerebral malaria (ECM). However, a high dose (1 mg/mouse twice a day) is necessary and causes potent side effects such as marked hypotension. In the present study we evaluated whether an alternative, physiologically relevant NO donor, S-nitrosoglutathione (GSNO), was able to prevent ECM at lower doses with minimal side effects. Prophylactic treatment with high (3.5 mg), intermediate (0.35 mg) or low (0.035 mg) doses of GSNO decreased incidence of ECM in PbA-infected mice, decreasing also edema, leukocyte accumulation and hemorrhage incidence in the brain. The high dose inhibited parasite growth and also induced transient hypotension. Low and intermediate doses had no or only mild effects on parasitemia, blood pressure, and heart rate compared to saline-treated mice. PbA infection decreased brain total and reduced (GSH) glutathione levels. Brain levels of oxidized (GSSG) glutathione and the GSH/GSSG ratio were positively correlated with temperature and motor behavior. Low and intermediate doses of GSNO failed to restore the depleted brain total glutathione and GSH levels, suggesting that ECM prevention by GSNO was probably related to other effects such as inhibition of inflammation and vascular protection. These results indicate that ECM is associated with depletion of the brain glutathione pool and that GSNO is able to prevent ECM development in a wide range of doses, decreasing brain inflammation and inducing milder cardiovascular side effects.2030-01-01