The novel ETA receptor antagonist HJP-272 prevents cerebral microvascular hemorrhage in cerebral malaria and synergistically improves survival in combination with an artemisinin derivative

Abstract

Aim To investigate the association between vasculopathy and survival during experimental cerebral malaria (ECM), and to determine whether targeting the endothelin-1 (ET-1) pathway alone or in combination with the anti-malaria drug artemether (a semi-synthetic derivative of artemisinin) will improve microvascular hemorrhage and survival. Main Methods C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) were randomly assigned to four groups: no treatment, artemether treated, ETA receptor antagonist (HJP-272) treated, or HJP-272 and artemether treated. The uninfected control mice were treated with HJP-272 and artemether. We analyzed survival, cerebral hemorrhage, weight change, blood glucose levels and parasitemia. Key Findings Our studies demonstrated decreased brain hemorrhage in PbA-infected (ECM) mice treated when HJP-272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one novel ETA receptor antagonist synthesized by our group, is used in conjunction with artemether, an anti-malarial agent. In addition, despite adversely affecting parasitemia and weight in non-artemether treated infected mice, HJP-272, seemed to confer some survival benefit when used as adjunctive therapy, though this did not reach significance. Significance Previous studies demonstrate that the endothelin pathway is associated with vasculopathy, neuronal injury and inflammation in ECM. As demonstrated here, components of the ET-1 pathway may be important targets for adjunctive therapy in ECM, and may help in preventing hemorrhage and in improving survival when used as adjunctive therapy during malaria infection. The data presented suggest that our novel agent, HJP-272, may ameliorate alterations in the vasculature which can potentially lead to inflammation, neurological dysfunction, and subsequent death in mice with ECM.

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

“…12,13,15,16 B6 mice infected with P. berghei NK65 (PbN) do not develop neurological signs, die after 12 days postinfection, and are widely accepted as a control infection model for the B6-PbA model. Endothelin-1 (ET-1) is thought to contribute to the pathogenesis of human CM.…”

“…Endothelin-1 (ET-1) is thought to contribute to the pathogenesis of human CM. 20,21 Our group recently demonstrated that ET-1 is involved in ECM vasculopathy 13,14 ; however, there are still significant gaps in understanding how ET-1 modulates brain vascular physiology during malaria infection. ET-1 is a potent regulator of the vascular tone, with mitogenic, apoptotic, and immunomodulatory properties.…”

Role of the Aryl Hydrocarbon Receptor in the Immune Response Profile and Development of Pathology during Plasmodium berghei Anka Infection

“…Moreover, the P. berghei Anka infection model also allows investigations into liver damage, as described in Plasmodium-infected humans (8,9). Observations from humans with CM due to P. falciparum, as well as those from the CM mouse model using P. berghei Anka, suggest that the pathogenesis of CM is multifactorial and includes sequestration of infected red blood cells (iRBCs), disruption of the blood-brain barrier (BBB), upregulation of the inflammatory pathways, and dysregulation of endothelin pathways (10)(11)(12)(13). Previously, we have demonstrated a crucial role for platelet-activating factor in experimental CM infection (10)(11)(12)(13).…”

“…Observations from humans with CM due to P. falciparum, as well as those from the CM mouse model using P. berghei Anka, suggest that the pathogenesis of CM is multifactorial and includes sequestration of infected red blood cells (iRBCs), disruption of the blood-brain barrier (BBB), upregulation of the inflammatory pathways, and dysregulation of endothelin pathways (10)(11)(12)(13). Previously, we have demonstrated a crucial role for platelet-activating factor in experimental CM infection (10)(11)(12)(13). Infection with P. berghei Anka results in a reduction in cerebral blood flow and neuronal dysfunction (14,15).…”

Potential Efficacy of Citicoline as Adjunct Therapy in Treatment of Cerebral Malaria

“…In the last 5 years, several novel compounds have been tested in animal models or in humans as adjunct therapy to prevent tissue and brain alterations during infection, including erythropoietin (EPO) (2,12), defibrotide (13), atorvastatin (14,15), the exogenous nitric oxide (NO) donor dipropylenetriamine-NONOate (16), and others (17,18). EPO, atorvastatin, and NO have undergone U.S. FDA review and been approved for other indications.…”