Transdermal Glyceryl Trinitrate as an Effective Adjunctive Treatment with Artemether for Late-Stage Experimental Cerebral Malaria

Abstract

c Cerebral malaria (CM) is associated with low nitric oxide (NO) bioavailability, cerebrovascular constriction, occlusion, and hypoperfusion. Administration of exogenous NO partially prevents the neurological syndrome and associated vascular pathology in an experimental CM (ECM) mouse model. In this study, we evaluated the effects of transdermal glyceryl trinitrate in preventing ECM and, in combination with artemether, rescuing late-stage ECM mice from mortality. The glyceryl trinitrate and/or artemether effect on survival and clinical recovery was evaluated in C57BL/6 mice infected with P. berghei ANKA. NO synthase (NOS) expression in mouse brain was determined by Western blots. Mean arterial pressure (MAP) and pial arteriolar diameter were monitored using a tail-cuff blood pressure system and a cranial window preparation, respectively. Preventative administration of glyceryl trinitrate at 0.025 mg/h decreased ECM mortality from 67 to 11% and downregulated inducible NOS expression in the brain. When administered as adjunctive rescue therapy with artemether, glyceryl trinitrate increased survival from 47 to 79%. The adjunctive therapy caused a sustained reversal of pial arteriolar vasoconstriction in ECM mice, an effect not observed with artemether alone. Glyceryl trinitrate induced a 13% decrease in MAP in uninfected mice but did not further affect MAP in hypotensive ECM mice. Glyceryl trinitrate, when combined with artemether, was an effective adjunctive rescue treatment for ECM. This treatment ameliorated pial arteriolar vasospasm and did not significantly affect MAP. These results indicate that transdermal glyceryl trinitrate has potential to be considered as a candidate for adjunctive therapy for CM.

Endothelin-1 Treatment Induces an Experimental Cerebral Malaria–Like Syndrome in C57BL/6 Mice Infected with Plasmodium berghei NK65

“…Adjunctive treatment with the vasodilators nimodipine and glyceryl trinitrate improves survival in ECM mice. 12,14,38,39 As ET-1 is a potent vasoconstrictor, 40 we used intravital microscopy in mice implanted with chronic cranial windows to analyze the brain microvascular changes caused by the ET-1 during experimental malarial infection. PbA-infected mice and PbNinfected ET-1etreated mice displayed significant degrees of brain arteriolar constriction at 5 and 6 dpi ( Figure 5, A and B).…”

NO-Donor Dihydroartemisinin Derivatives as Multitarget Agents for the Treatment of Cerebral Malaria

“…10,11 We have also shown that administration of exogenous NO improves cerebral microcirculatory physiology in P. berghei infected mice 13–15 and that glyceryl trinitrate, a drug that generates NO, reverses cerebrovascular constriction and improves survival in mice with ECM. 16 Artemisinin derivatives are potent, fast-acting antimalarial drugs, and intravenous artesunate is the mainstay treatment for human cerebral malaria. 2 We hypothesized that the combination of artemisinin with NO-donors would bring together the potent antimalarial activity of the former with the vascular benefit of the latter and therefore be a more efficacious drug for treating cerebral malaria.…”

“…12 Administration of NO donors can prevent the neurological syndrome and the associated vascular dysfunction, 13–15 and more important, NO donors such as glyceryl trinitrate improve survival of mice with late-stage ECM and reverse ECM cerebrovascular constriction. 16 In a previous study we designed a new series of hybrid compounds in which amodiaquine, an established antimalarial drug included in the World Health Organization Model List of Essential Medicines, 17 was joined with NO-donor furoxan and nitrooxy (ONO 2 ) 18 moieties and studied them as potential anti SM/CM tools. All the amodiaquine-NO-donor hybrids were able to dilate rat aorta strips precontracted with phenylephrine with a NO-dependent mechanism and displayed high degree of activity against both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum .…”

Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria

“…Treatment with S-nitrosylated glutathione (GSNO), an endogenous, physiological NO donor, prevented ECM development while having milder effects on blood pressure (71). Glyceryl trinitrate (nitroglycerin; GTN) not only prevented ECM but also worked as adjunctive therapy with artemether, markedly increasing survival of mice with late-stage ECM compared to artemether alone (72). The benefit in survival was associated with reversal of cerebrovascular constriction, suggesting that the effect was due to improved brain perfusion.…”