Effects of oleuropein and hydroxytyrosol on brain renin-angiotensin system-regulating aminopeptidases in experimental glioma

Previous in vitro and in vivo studies have demonstrated that extra virgin olive oil polyphenols act against different pathologies, including several types of cancer such as glioma. Emerging therapies targeting the renin-angiotensin system (RAS) have shown therapeutic promise. Here we analyze the effects of the oral administration of oleuropein, hydroxytyrosol, and the mixture of both polyphenols in animals with gliomas to determine their effects on gliomagenesis and the regulatory proteolytic enzymes of the RAS of the aminopeptidase type, including the impact of sex differences. Gliomas were induced by the transplacental administration of N-ethyl-N-nitrosourea (ENU). Aminopeptidases were assayed fluorometrically using aminoacyl-ß-naphthylamides as substrates. Kaplan–Meier survival curves revealed that these treatments significantly improve survival rates, with notable sex differences. In addition, their effects on tumor number and volume showed sex differences. Regarding the RAS-regulating aminopeptidases, our results support the idea of an increased effect of angiotensin III (AngIII) on untreated animals. In contrast, the findings with polyphenol treatments allow us to infer a decrease in AngIII and an increase of angiotensin 1 – 7, also with sex differences. A putative role on glucose uptake facilitation mediated by insulin-regulated aminopeptidase is also hypothesized. Our results demonstrated that local RAS significantly participates in gliomagenesis induced by transplacental ENU administration. In summary, orally administered extra virgin olive oil polyphenols, mainly hydroxytyrosol, showed differential effects against glioma, acting through the RAS-regulating aminopeptidase activities, and such differences were further compounded by sex disparity.