Treatment for high blood pressure may deal a blow against leading cause of death from malaria

NYU Langone Medical Center reports on results in animal models that showed triple the survival rate in cerebral malaria when chloroquine was combined with one of two antihypertensive treatments

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NEW YORK—It’s not something we in the United States deal with very often, but some 216 million people each year still are infected globally with malaria, and hundreds of thousands die each year from the disease as well, mostly children in Sub-Saharan Africa. Researchers at NYU Langone Medical Center, having published study findings Sept. 19 in the Journal of Clinical Investigation, think they may have a way of reducing the mortality rates with the help of antihypertensive drugs.
The team focused on cerebral malaria, using mouse models in their work. About 1 percent of the people infected each year with malaria develop cerebral malaria (in which the parasite that causes the disease produces swelling and bleeding in the brain), and about 15 to 20 percent of those people die from the disease, making it the major cause of mortality among the 438,000 deaths last year from malaria.
“About one in five patients with cerebral malaria die within 48 hours of being admitted to the hospital, the time it takes for the parasite-killing drug to take effect," said senior study author Dr. Ana Rodriguez, an associate professor in the Department of Microbiology at NYU Langone. “If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”
And with that in mind, the NYU Langone researchers divided mice infected with cerebral malaria into groups either treated only with chloroquine, a drug commonly used to kill the parasite, or with chloroquine in combination with one of two antihypertensive treatments. While just 18 percent of mice treated only with chloroquine survived, 65 percent of mice also given irbersartan, an angiotensin receptor 1 blocker, survived, as did 73 percent of mice also treated with C21, an experimental drug that increases signaling through angiotensin receptor 2.
The team also found that infected mice treated with one of the two angiotensin-influencing drugs experienced fewer, smaller hemorrhages, and in most cases, fully recovered.
As NYU Langone notes, the researchers knew going in—as does anyone dealing with malaria research—that blood cells infected with malaria produce more of a protein that makes them stick to blood vessel walls, as well as the fact that malaria parasites multiply inside blood cells, which burst about two days later and release more parasites.
The NYU Langone study found that the bursting of infected blood cells, by showering their contents on the vessel walls they are stuck to, sends signals that interfere with the ability of wall-lining cells to cling to each other. Each cell in the wall holds on less tightly to its neighbors, opening gaps through which first blood serum and later whole blood can escape into brain tissue.
The research team used a genetically engineered version of the malaria parasite so that they could control the timing of blood cell bursts by adding a trigger molecule. Endothelial cell-cell junctions were normal before the blood cells burst, but compromised afterward, the researchers noted.
Some factor from the burst blood cells causes a protein called beta-catenin to break away from the complex that maintains the grip of one endothelial cell on its neighbors, according to the authors. Once free from its complex, beta-catenin travels to the nucleus to activate genes that cause a wall-lining cell to further detach from neighboring cells.
And this is where the antihypertensive drugs come in. Both therapeutics the researchers added to chloroquine treatments were able to prevent the activation of beta-catenin and thus prevented the blood vessel wall integrity from being compromised.
Angiotensin is a hormone that controls many factors related to blood pressure, sending its signal by fitting into receptor proteins on cells surfaces, like a lock into a key, as the authors and NYU Langone described it, and study author Dr. Julio Gallego-Delgado, one of the researchers in Rodriguez’s team, had seen a 2010 genetic study suggesting that biochemical pathways related to this hormone may be protective against cerebral malaria. And from that came the idea to test the combination of chloroquine and an antihypertensive drug.
The work doesn’t stop there, of course. Next on the team’s agenda is to determine the exact molecules coming from burst blood cells that signal to beta catenin in vessel walls, and then to conduct a clinical trial that tests the effects of the study drugs in human cerebral malaria patients.

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