Breaking the vicious cycle of epileptogenesis: Focus on brain inflammation and matrix metalloproteinases

Diede W. M. Broekaart

Research output: PhD ThesisPhD-Thesis - Research and graduation internal

Abstract

Epilepsy is a brain disease characterized by an enduring predisposition to generate epileptic seizures, currently affecting 65 million people worldwide. Patients mostly rely on drugs that reduce seizure frequency, but unfortunately, over 30% of people with epilepsy do not benefit from the available antiepileptic drugs. Moreover, treatments that prevent or cure epilepsy do not exist. Therefore, there is an urgent need for novel therapies aimed at targets that can reduce or even halt the development of epilepsy. The process that leads to the development of epilepsy and the progression of epilepsy after spontaneous seizures appear is called epileptogenesis. During that period multiple neurobiological changes take place resulting in a lower threshold for seizure activity. In this thesis, in order to find novel therapeutic targets, we aimed to investigate the involvement of two major processes that are thought to play a role in epileptogenesis: the activation of the inflammatory system and the dysregulation of the extracellular matrix (ECM). Taken together, this thesis shows that neuroinflammatory processes as well as ECM regulation play important roles in the development and progression of epilepsy. We identified several potential novel targets, such as the innate immune system, the (immuno)proteasome and ECM-degrading proteins called matrix metalloproteinases (MMPs). Furthermore, several therapeutic targets were evaluated using both in vitro and in vivo models. We identified the mTOR inhibitor rapamycin, microRNA155, microRNA146a and microRNA147b, and the MMP inhibitor IPR-179 as promising novel therapeutic strategies to be further explored in preclinical and clinical settings.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • University of Amsterdam
Supervisors/Advisors
  • Aronica, Eleonora, Supervisor
  • van Vliet, Erwin, Co-supervisor
Award date28 May 2020
Print ISBNs9789082787191
Publication statusPublished - 2020

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