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ORIGINAL RESEARCH ARTICLE

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

María Jesús Ramírez-Expósito1 ,  Cristina Cueto-Ureña1 ,  María Pilar Carrera-González1 ,  José Manuel Martínez-Martos1*
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1 Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, School of Health Sciences, University of Jaén, Jaén, Spain
CP, 7943
Submitted: 18 December 2024 | Revised: 14 February 2025 | Accepted: 3 March 2025 | Published: 19 March 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

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.

Keywords
Glioma
Oleuropein
Hydroxytyrosol
Sex
Aspartyl aminopeptidase
Aminopeptidase A
Aminopeptidase N
Aminopeptidase B
Insulin-regulated aminopeptidase
Funding
This research was funded by JUNTA DE ANDALUCÍA (grant number CTS1029), CONSEJERÍA DE INNOVACIÓN, CIENCIA Y EMPRESA (grant number CVI09-4957M), UNIVERSIDAD DE JAÉN (grant number CTS1039_2021), and INSTITUTO DE ESTUDIOS GIENNENSES (grant number IEG09).
Conflict of interest
The authors declare they have no competing interests.
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