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New malaria drugs could target host

Not only is cerebral malaria the deadliest form of malaria, it is also the most frequently-occurring, killing 1 to 3 million people each year, mostly children living in developing countries. So far, the most common medical approach has been to target the pathogen's infectious process. In the past twenty years, the appearance of strains resistant to classic anti-malarial drugs such as chloroquinine has led researchers to explore new therapeutic alternatives.

New malaria drugs could target host01


Cerebral angiograms obtained with magnetic resonance imaging of a healthy mouse (left) and a mouse with cerebral malaria (right). The angiogram of the diseased animal shows an important attenuation in the arterial-blood signal and major flow voids due to a compression of the cerebral arteries by a massive edema.

 “There are at least two components that participate in the development of cerebral malaria —one is due to the parasite, the other is due to the host” says immunopathologist Georges Grau,1 who studies the exaggerated immune response observed in lethal cases.
 In cerebral malaria, after the parasite has invaded the bloodstream, infected red blood cells accumulate against the walls of small vessels in the brain. This leads to obstruction, hemorrhage and oxygen starvation. In certain cases, the accumulation of red cells triggers an abnormally high inflammatory reaction, which further increases damage. “It is a combination of those two aspects that seems to be the cause of coma and death,” notes Grau, whose team recently led the first in vivo observation of cerebral malaria.2 
 Using magnetic resonance techniques, the researchers shed light on the anatomical and biochemical characteristics of the disease in infected mice. They not only found tissue damage and hemorrhages in several locations, but also confirmed the appearance of edema whose massive development leads to coma and death by compressing cerebral arteries.

 “This animal model of the pathology is very similar to what we've seen in children,” says biophysicist Angèle Viola,3 who participated in the study. “These results suggest it might be judicious to try anti-edema therapies on patients with cerebral malaria.” While anti-inflammatory drugs like aspirin and cortisone have proved inefficient in the battle, other compounds currently under investigation are promising, says Professor Grau. He cites the example of a synthetic molecule called LMP-420, which specifically targets the cause of the inflammation—the release of toxic cytokines into the bloodstream. The molecule LMP-420 has several advantages: it is easy to handle, cheaper than antibodies, and, according to a recent in vitro study led by professor Grau,4 can prevent the alteration of microvessels in cultures of human brain cells infected with Plasmodium falciparum. “We have to study its effects in vivo, but this could be a complementary therapy to conventional antimalarials,” says Grau. “The more mechanisms you target, the better.”

Clementine Wallace


Synthetic artemisinin to treat malaria

Artemisinin is extracted from a Chinese variety of wormwood that has been used to fight malaria for centuries in traditional Asian medicine. Appearance of strains of the parasite resistant to conventional anti-malarials, and heavy side effects of some of these drugs have raised interest , in Artemisinin and its derivatives. Moreover, the compound has not yet triggered resistance. But 300 tons of the drug would be required to treat the total number of yearly cases and only five to six tons are produced each year in South-East Asia. Cultivation conditions are so tricky that researchers have chosen to develop synthetic medications that mimic Artemisinin's mode of action, which is still being studied. Recently, a team of CNRS scientists demonstrated that a specific reaction between Artemisinin and the host's infected blood cells is what enables the drug to eliminate the parasite in mice.1 Interestingly, the compound does not react with “healthy” erythrocytes. But because polytherapy is recommended for all serious infections, research is currently underway to associate its active agent to that of medications with a longer half-life, such as chloroquine. This concept is called “covalent bitherapy.” “In synthetic drugs such as trioxaquines®, developed by Palumed in collaboration with Sanofi-Aventis, the trioxane of artemisinin is associated in a single molecule with the quinoline of chloroquine, ” explains CNRS team leader Anne Robert. “Combining two molecules is better than taking two separate pills, and the more complementary agents you associate, the more you reduce chances of the parasite finding ways to develop resistance.”

Clémentine Wallace

1. A. Robert et al., “The antimalarial drug artemisinin alkylates heme in infected mice” Proc Natl Acad Sci USA 102 (38): 13676-80. 2005.

Anne Robert
Laboratoire de Chimie de coordination, Toulouse

Notes :

1. Rickettsia and emerging pathogens unit (Unité des Rickettsies et pathogènes émergents). Joint lab: CNRS / Université Aix-Marseille.
2. M.F. Penet et al., “Imaging experimental cerebral malaria in vivo: significant role of ischemic brain edema,” J. Neurosci. 25 (32): 7352-8. 2005.
3. Biological and Medical Magnetic Resonance Center (Centre de résonance magnétique biologique et médicale). Joint lab: CNRS / Université Aix-Marseille-II
4. S. C. Wassmer et al., “Inhibition of Endothelial Activation: A New Way to Treat Cerebral Malaria?” PLoS Medicine, 2 (9): 1245. 2005.

Contacts :

Angèle Viola
Centre de résonance magnétique biologique et médicale, Marseille

Georges Grau
Laboratoire d'immunopathologie, Marseille


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