Efficacy of different nitric oxide-based strategies in preventing experimental cerebral malaria by Plasmodium berghei ANKA.

Abstract

BACKGROUND:

Low nitric oxide (NO) bioavailability plays a role in the pathogenesis of human as well as of experimental cerebral malaria (ECM) caused by Plasmodium berghei ANKA (PbA). ECM is partially prevented by administration of the NO-donor dipropylenetriamine NONOate (DPTA-NO) at high concentration (1 mg/mouse), which also induces major side effects such as a sharp drop in blood pressure. We asked whether alternative strategies to improve NO bioavailability with minor side effects would also be effective in preventing ECM.

METHODOLOGY/PRINCIPAL FINDINGS:

Mice were infected with PbA and prophylactically treated twice a day with bolus injections of L-arginine, Nω-hydroxy-nor-Arginine (nor-NOHA), tetrahydrobiopterin (BH4), separately or combined, sodium nitrite, sildenafil or sildenafil plus DPTA-NO starting on day 0 of infection. L-arginine and BH4 supplementation, with or without arginase inhibition by nor-NOHA, increased plasma nitrite levels but failed to protect against ECM development. Accordingly, prophylactic treatment with continuous delivery of L-arginine using osmotic pumps also did not improve survival. Similar outcomes were observed with sodium nitrite sildenafil (aimed at inhibiting phosphodiesterase-5) or with DPTA-NO. However, sildenafil (0.1 mg/mouse) in combination with a lower dose (0.1 mg/mouse) of DPTA-NO decreased ECM incidence (82 ± 7.4% mortality in the saline group and 38 ± 10.6% in the treated group; p<0.05). The combined prophylactic therapy did not aggravate anemia, had delayed effects in systolic, diastolic and mean arterial blood pressure and induced lower effects in pulse pressure when compared to DPTA-NO 1 mg/mouse.

CONCLUSIONS/SIGNIFICANCE:

These data show that sildenafil lowers the amount of NO-donor needed to prevent ECM, resulting also in lesser side effects. Prophylactic L-arginine when given in bolus or continuous delivery and bolus BH4 supplementation, with or without arginase inhibition, were able to increase NO bioavailability in PbA-infected mice but failed to decrease ECM incidence in the doses and protocol used.

• Authors: Yuri C Martins, Graziela M Zanini, John A Frangos, Leonardo J M Carvalho
• Journal: PloS one (PLoS One) Vol. 7 Issue 2 Pg. e32048 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22348145 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Nitric Oxide Donors
• Piperazines
• Purines
• Sulfones
• Nitric Oxide
• Arginine
• Sildenafil Citrate

Topics

• Animals
• Arginine (administration & dosage, pharmacology, therapeutic use)
• Chemoprevention (methods)
• Drug Therapy, Combination
• Malaria, Cerebral (parasitology, prevention & control)
• Mice
• Nitric Oxide
• Nitric Oxide Donors (adverse effects, therapeutic use)
• Piperazines (administration & dosage, pharmacology, therapeutic use)
• Plasmodium berghei
• Purines (administration & dosage, pharmacology, therapeutic use)
• Sildenafil Citrate
• Sulfones (administration & dosage, pharmacology, therapeutic use)