Possible new therapy against cerebral malaria

Teams from the "Alberto Sols" Biomedical Research Institute, the Autonomous University of Madrid (UAM) and the Higher Council for Scientific Research (CSIC) have shown that hypothyroidism protects against cerebral malaria, reducing neurological symptoms and significantly increasing survival in mice infected with the Plasmodium parasite . The results, published in the journal Science Advances , open the door to a possible new therapeutic target against cerebral malaria in childhood, a disease that annually kills several hundred thousand children in endemic areas.

A team of Spanish researchers has used an experimental mouse model of cerebral malaria that faithfully recapitulates the neurological symptoms and death caused by cerebral malaria in children to analyze the effect of thyroid status on cerebral malaria.

Specifically, the researchers compared the response to infection with the Plasmodium parasite of mice fed a normal diet with that of mice fed a low-iodine diet supplemented with anti-thyroid drugs for one month.

"Thus, we observed that hypothyroidism notably improved survival against the parasite and that, unlike normal mice, hypothyroid animals did not present severe neurological symptoms such as paralysis or coma," says the first author of the work, Diego Rodríguez Muñoz.

"In this way - adds the researcher - hypothyroidism prevented inflammation and compression of the brain and the consequent blockage of cerebral blood circulation, which are considered the main causes of death from cerebral malaria".

The results, published on April 6 in the journal Science Advances , have been presented by the teams of Ana Aranda and Susana Alemany from the "Alberto Sols" Biomedical Research Institute (IIBM) - a joint center of the Autonomous University of Madrid (UAM). ) and the Higher Council for Scientific Research (CSIC)—, in collaboration with other teams from the UAM, the Complutense University of Madrid (UCM) and the National Center for Cardiovascular Research (CNIC).

Possible therapeutic target

The results suggest that children living in iodine-deficient areas could be protected from cerebral malaria, and that the administration of anti-thyroid drugs could constitute a novel therapeutic approach to combat this disease.

However, this option is ruled out since thyroid hormones are necessary for proper brain development in childhood. However, during the study of the mechanisms by which hypothyroidism protects against cerebral malaria, it was shown that the activation of the Sirtuin 1 protein was involved in said protection.

"In fact, the administration of a drug that activates Sirtuin 1 was able to mimic the effects of hypothyroidism in normal infected animals, preventing the collapse of cerebral circulation, reducing neurological symptoms and increasing survival to infection", highlight the researchers. authors.

“Currently —they add— various clinical trials are being carried out with Sirtuin 1 activating drugs to treat different pathologies. If such drugs are shown to have no significant side effects, co-administration of such drugs with commonly used anti-malarial drugs to inhibit parasite replication could mean a breakthrough in the treatment of cerebral malaria in children."

Thus, the activation of the Sirtuin 1 protein could be a new therapeutic target against cerebral malaria in children and thus reduce the high mortality caused by Plasmodium .

Malaria is a serious disease that is transmitted to man through the bite of an Anopheles mosquito infected with the Plasmodium parasite .

Cerebral malaria, the most severe manifestation of the disease, mainly affects children under 5 years of age and annually kills several hundred thousand children in malaria-endemic areas, mainly located in developing countries.

In Africa, for example, these areas partially overlap with regions of iodine deficiency, and thus endemic hypothyroidism, because when iodine intake is low, the thyroid gland does not produce enough thyroid hormones.

Although both cerebral malaria and endemic hypothyroidism are serious health problems that still affect millions of people, it has not yet been studied whether iodine deficiency aggravates the development of cerebral malaria, resulting in increased morbidity and mortality, or if, on the contrary, it could improve its prognosis.

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Bibliographic reference:

Rodríguez-Muñoz, D., Sánchez, A., Pérez-Benavente, S., Contreras-Jurado, C., Montero-Pedrezuela, A., Toledo-Castillo, M., Gutiérrez, M., Rodrigues-Díez, R. ., Folgueira, C., Briones, AM, Sabio, G., Monedero, I., Chávez-Coira, I., Castejón-Ferrer, D., Fernández-Valle, E., Regadera, J., Bautista, JM , Aranda, A., Alemany, S. 2022. Hypothyroidism confers tolerance to Cerebral Malaria . Science Advances 8(14), doi: 10.1126/sciadv.abj7110

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Image: Cerebral circulation in an uninfected mouse, in a mouse infected with Plasmodium in which a strong decrease in blood flow is observed, and in an infected mouse treated with SRT1720, an activator of Sirtuin 1, which significantly recovers cerebral circulation / Rodríguez Muñoz et al.