The Role of Endothelin in the Pathogenesis of Cerebral Malaria in a Mouse Model

Lay Summary

Using Imaging to Understand How Malaria Infection Causes Brain Dysfunction

Investigators will study animals infected with malaria to try to learn how this infectious disease sometimes produces damage,called “cerebral malaria,”  to the brain The investigators hypothesize that in some people malaria infection causes their blood vessels to constrict, resulting in a reduced blood flow to the brain, which then damages brain cells.

People with cerebral malaria develop seizures, unsteadiness, and confusion; occasionally they slip into a coma.  The investigators’ prior studies of cerebral malaria in a mouse model that they developed showed increased production of a protein called “endothelin” by cells that line blood vessels in the brain, and also by certain immune cells that participate in the immune inflammatory response.  Increased endothelin is known to cause blood vessels to constrict, which reduces blood flow to brain and damages brain cells.

Now the investigators will inhibit endothelin production in the cerebral malaria mouse model, and use MRI and MRS to image the animals’ brains.  This will enable the investigators to see whether the decreased endothelin levels correlate with functional and metabolic improvements in the animals’ brains.

Significance:  The research could lead to human studies designed to identify malaria-infected people who are at risk of developing brain damage.  The findings also may lead to development of preventative treatments to inhibit endothelin production to prevent cerebral malaria from occurring.

Abstract

The Role of Endothelin in the Pathogenesis of Cerebral Malaria in a Mouse Model

Cerebral malaria is an important cause of morbidity and mortality in many parts of the world, and children and pregnant women are particularly at risk. Preliminary observations from our laboratory using MRI indicate that in a murine model of cerebral malaria there is reduced cerebral blood flow and evidence of neuronal dysfunction. Endothelin-1is a potent vasoconstrictor, and our preliminary data indicate that components of the endothelin pathway are upregulated in the brain of a mouse with cerebral malaria and could provide an important mechanism for cerebral dysfunction. Quantitative magnetic resonance imaging and spectroscopy (MRI/MRS) are powerful tools to examine the functional and metabolic state of the brain in cerebral malaria, and thus we have employed this technology in our investigations of murine cerebral malaria.

We plan to directly evaluate the role of endothelin-1 in the mouse model by utilizing inhibitors of endothelin converting enzyme, endothelin receptor blockers, and mice in which the endothelin gene has been selectively deleted from endothelial cells. These findings will be correlated with functional /metabolic studies utilizing MRI of the brain. These studies will include detailed measurements of cerebral blood flow, water compartmentation, oxygen consumption and neuronal function.

The MR methods used in this proposal can be applied in clinical scanners operating at 1.5T or higher, which are common throughout the world. Furthermore, by obtaining a better understanding of the underlying physiological changes induced by cerebral malaria, these studies can direct optimal use of other blood flow and oxygenation sensitive methodologies such as transcranial Doppler or near infrared spectroscopy that can be used at the bedside. Detection of these physiological changes should help identify those individuals at risk for adverse neurological outcome and identifying a target population for additional treatment with endothelin inhibitors aimed at salvaging neural tissue.