Statin Treatment Prevents Cerebral Malaria in Mouse Model

Addition of statins, drugs normally used to lower cholesterol levels, was found to prevent development of cerebral malaria in a mouse model of the human disease.

Cerebral malaria (CM) is the most severe manifestation of Plasmodium falciparum infection in children and nonimmune adults. Furthermore, previous studies have described a persistent cognitive impairment in children who survived an episode of CM.

Investigators at the University of Utah (Salt Lake City, USA) and their colleagues in Brazil worked with mice infected with P. berghei, a model of the human disease caused by P. falciparum. They added the drug lovastatin to the regular treatment regimen for the disease. Lovastatin is a member of the statin family of drugs. Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. In addition to their cholesterol-lowering activity statins also been implicated in modulating a variety of immune system responses.

In the current study, six days after infection with P. berghei mice that displayed clear signs of CM were treated with the classic anti-malaria drug chloroquine, or with a combination of chloroquine and lovastatin. Results published in the December 27, 2012, online edition of the journal PLOS Pathogens revealed that the combination of drugs decreased white blood cell accumulation and leakiness in blood vessels in the brains of the mice. Oxidative stress and key inflammatory chemokines and cytokines were reduced to noninfected control levels in animals treated with lovastatin. Fifteen days after infection, cognitive dysfunction was detected by a battery of cognition tests in animals rescued from CM by chloroquine treatment. In contrast, it was absent in animals treated with the lovastatin and chloroquine combination.

“Over 500,000 children develop cerebral malaria each year in sub-Saharan Africa, and persistent cognitive dysfunction in survivors is not only a major public health concern, but also a significant socioeconomic burden,” said contributing author Dr. Guy Zimmerman, professor of medicine at the University of Utah. “There is an urgent and unmet medical need for therapies that treat or prevent cognitive impairment in cerebral malaria.”

“The molecular mechanisms that give rise to cerebral malaria and subsequent cognitive dysfunction are not yet known,” said Dr. Zimmerman. “However, the fact that statin treatment decreases both injurious blood vessel inflammation and cognitive dysfunction suggests that a combination of vascular and inflammatory triggers leads to cerebral pathology and intellectual deficits.”

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