Alicia Comino Garcia Muñoz

Cerebral malaria (CM), a potentially lethal neurological complication of the infection by Plasmodium falciparum, affects mostly the pediatric population under 5 years old in sub-Saharan Africa. This clinical syndrome is characterized on anatomical brain imaging by microhemorrhages, parenchymal lesions and brain edema. Epidemiological studies based on sex or gender are rare and do not allow to draw any conclusions on a possible sexual dimorphism in CM. However, some regional data and genetic studies suggest a possible influence of sex on the susceptibility to this clinical syndrome and complications in surviving patients. The murine model of experimental cerebral malaria (ECM) in mice has proven to be a useful and reliable tool to study the pathogenic mechanisms and possible therapeutical approaches for CM. In this study, we used in vivo magnetic resonance imaging (MRI) to assess the differences linked to sex in the development of experimental CM in C57BL/6J mice infected with the murine parasite Plasmodium berghei ANKA. Our volumetric analysis reveals sex-dependent differences in brain swelling and lesion distribution, particularly microhemorrhages, as well as a regionalization of brain edema in ECM, with swelling-prone structures common to both sexes like the cortex and the pons, and others which show sex-specific alterations like the inferior and superior colliculi or the midbrain. Together, our results indicate that ECM is more severe in male than in female C57Bl/6J mice.

Cardiotoxicity, especially human ether-a-go-go–related gene (hERG)–related toxicity, is a leading cause of drug failure or market withdrawal. Reducing hERG binding to obviate potential cardiac toxicity is crucial. Nanotechnology has been applied to drug delivery for reducing drug toxicity and improving efficacy, but few studies have addressed hERG-related cardiotoxicity. We report the use of self-assembling dendrimer nanosystems for drug formulation and delivery, which effectively reduced hERG binding and associated toxicity while promoting therapeutic efficacy. Specifically, these dendrimer nanosystems efficiently encapsulated the antimalarial drug chloroquine, the anticancer agent doxorubicin, and the NUPR1 inhibitor ZZW115, all three having high affinity to hERG channels. These nanoformulations showed three- to eightfold reduced hERG binding affinity, which, in animal models, translated to abolished toxicity. These nanodrugs exhibited prolonged circulation, leading to enhanced accumulation at disease sites and improved treatment outcomes. This study highlights the potential of nanotechnology to reduce hERG binding and related toxicity while improving drug efficacy, offering valuable perspectives for drug development.

Cerebral malaria (CM), the most lethal clinical syndrome of Plasmodium falciparum infection, mostly affects children under 5 in sub-Saharan Africa. CM is characterized by seizures and impaired consciousness that lead to death in 15–20% of cases if treated quickly, but it is completely fatal when untreated. Brain magnetic resonance imaging (MRI) is an invaluable source of information on the pathophysiology of brain damage, but, due to limited access to scanners in endemic regions, only until very recently have case reports of CM patients studied with advanced MRI methods been published. The murine model of experimental cerebral malaria (ECM) shares many common features with the human disease and has been extensively used to study the pathogenic mechanisms of the neurological syndrome. In vivo MRI studies on this model, the first of which was published in 2005, have contributed to a better understanding of brain lesion formation in CM and identified disease markers that were confirmed by MRI studies published from 2013 onwards in pediatric patients from endemic areas. In this review, we recapitulate the main findings and critically discuss the contributions of MRI studies in the ECM model to the understanding of human CM.