Experimental cerebral malaria induces cerebral vascular dysfunction and cognitive impairment via endothelin a receptor signaling

Abstract

Cerebral malaria (CM) is the deadliest complication of Plasmodium falciparum (P. falciparum) infection. Despite extensive research, 20% of CM patients die, and of those that survive one in every four develop long-term neurological sequelae. The potent vasoactive peptide, endothelin-1 (ET-1), which is thought to be involved in CM, mediates blood brain barrier (BBB) permeability, inflammation, and vascular tone. Researchers propose that elevated levels of ET-1 during severe P. falciparum infection may contribute to cerebrovascular dysfunction ultimately impairing neurocognition. Previous studies showed that increased levels of ET-1 are associated with reduced cerebral blood flow (CBF) and brain microvascular hemorrhage in an experimental CM (ECM) model. However, the underlying mechanism of ET-1 in the pathogenesis of CM is not fully understood. We hypothesize that increased levels of ET-1 mediate vascular and cognitive dysfunction in the P. berghei ANKA (PbA) ECM model. This thesis work focused on characterizing the effects of ET-1 on cerebral vascular integrity and neurocognitive function.;Human and experimental models of CM are associated with long-term neurological deficits despite successful antimalarial treatment. Visual memory deficits represent one of the long-term neurological sequelae that greatly diminish the quality of life of those with CM. We utilized P. berghei NK65 (PbN) infected animals to evaluate the development of visual memory deficits, as they typically do not develop ECM. As expected, there were no changes in visual memory performance in PbN-infected animals upon performing cognitive testing. However, exogenous administration of ET-1 induced visual memory deficits in PbN-infected mice, similar to those that occur in the PbA ECM model, suggesting that the vasoactive peptide directly contribute to the development of neurological deficits. We found that ET-1 was increased in the brains of PbA-infected mice contributed to BBB disruption, cerebral vasoconstriction, and neuroinflammation, which contribute to the development of visual deficits. Treatment with an ETA receptor blocker (ETARB) also reduced brain endothelial activation concomitantly diminishing brain microvascular congestion. Furthermore, we determined that ETARB adjunctive therapy prevented visual memory impairments in PbA-infected mice by attenuating cerebral vasoconstriction, BBB disruption, and vascular congestion.;We propose that the cerebrovascular and cognitive dysfunction associated with ECM is mediated by activation of c-Jun N terminal kinase (JNK), a downstream substrate of ET-1 signaling. JNK is associated with cognitive impairment, cerebral vasospasms and is important in the development of ECM. Here, we demonstrated that ET-1 induced the expression of JNK phosphorylation in the brains of PbN-infected mice, while ETARB prevented increased JNK phosphorylation in PbA-infected animals. Our findings indicate that cerebrovascular disturbances and cognitive impairments in ECM are due, in part, to ET-1 mediated signaling. We therefore conclude that therapeutic strategies targeting the ET-1 signaling-axis as an adjunct therapy may reduce cerebrovascular dysfunction, contributing to the abrogation of neurological sequelae in patients with CM.