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  3. Targeting Epac1 to protect the blood brain barrier from inflammation-induced dysfunction: Evidence from an in vitro model

Targeting Epac1 to protect the blood brain barrier from inflammation-induced dysfunction: Evidence from an in vitro model

  • Life Sci. 2025 Oct 14:382:124022. doi: 10.1016/j.lfs.2025.124022.
Nuria Seoane 1,  Aitor Picos 2,  Dolores Viña 3,  Manuel Campos-Toimil 4
Affiliations

Affiliations

  • 1 Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Santiago de Compostela, Spain; Translational Research in Neurological Diseases (ITEN), Health Research Institute of Santiago de Compostela (IDIS), USC University Hospital Complex (CHUS), SERGAS, 15782 Santiago de Compostela, A Coruña, Spain. Electronic address: nuria.seoane@rai.usc.es.
  • 2 Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Santiago de Compostela, Spain; Translational Research in Neurological Diseases (ITEN), Health Research Institute of Santiago de Compostela (IDIS), USC University Hospital Complex (CHUS), SERGAS, 15782 Santiago de Compostela, A Coruña, Spain. Electronic address: aitor.picos@rai.usc.es.
  • 3 Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Santiago de Compostela, Spain; Translational Research in Neurological Diseases (ITEN), Health Research Institute of Santiago de Compostela (IDIS), USC University Hospital Complex (CHUS), SERGAS, 15782 Santiago de Compostela, A Coruña, Spain; Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain. Electronic address: mdolores.vina@usc.es.
  • 4 Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Santiago de Compostela, Spain; Translational Research in Neurological Diseases (ITEN), Health Research Institute of Santiago de Compostela (IDIS), USC University Hospital Complex (CHUS), SERGAS, 15782 Santiago de Compostela, A Coruña, Spain; Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain. Electronic address: manuel.campos@usc.es.
PMID: 41101634 DOI: 10.1016/j.lfs.2025.124022
Abstract

Aims: Exchange protein directly activated by cyclic AMP 1 (Epac1), a direct effector of cyclic AMP (cAMP), has been implicated in the regulation of endothelial permeability in peripheral tissues. However, its potential role in protecting the blood-brain barrier (BBB) under inflammatory conditions has not been previously explored. In this study, we evaluated for the first time the impact of selective Epac1 activation on BBB integrity using an in vitro model of brain microvascular endothelial cells (bEnd.3) exposed to lipopolysaccharide (LPS).

Materials and methods: Cells were cultured in Transwell systems and treated with selective activators or inhibitors of Epac1 and protein kinase A (PKA). Barrier function was assessed through transendothelial electrical resistance (TEER), tight junction protein expression and localization, Reactive Oxygen Species (ROS) production, pro-inflammatory gene expression, and macrophage adhesion assays.

Key findings: Our results show that Epac1 activation significantly prevented the LPS-induced decrease in TEER values, preserved claudin-5 expression, reduced oxidative stress, and stabilized cytoskeletal organization. PKA activation alone did not restore TEER or protect barrier integrity. However, both Epac1 and PKA were required to reduce macrophage adhesion and vascular cell adhesion molecule 1 (VCAM-1) expression, suggesting complementary roles in modulating inflammatory activation.

Significance: These findings identify Epac1 as a novel modulator of BBB integrity during inflammation and support the therapeutic potential of selectively targeting cAMP signaling pathways to preserve BBB function in neurodegenerative diseases associated with neuroinflammation.

Keywords

Blood brain barrier; Epac1; Inflammation; Neurodegenerative diseases; Transendothelial electrical resistence; cAMP pathway.

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