- Epigenetic and pharmacological targeting of neuroinflammation as novel therapeutic interventions for epilepsy
- Award date
- 9 January 2018
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Epilepsy is a neurological disease characterized by recurrent unprovoked seizures due to aberrant and synchronized firing of groups of neurons. A major clinical need for pharmaco-resistant epilepsy is to develop novel therapeutic approaches with anti-epileptogenic or disease-modifying properties for either suppressing or preventing seizures. Histopathological and molecular analyses of brain tissue of refractory epilepsy patients and rodents with seizures, and pharmacological studies in animal models, suggest that neuroinflammation plays a key role in the pathogenesis of seizures, cell loss and comorbidities.
We showed the contribution of the innate immunity Toll-like receptors 4 (TLR4) and Receptors for Advanced Glycation End Products to seizure mechanisms and for mediating the ictogenic effects of the danger signal High Mobility Group Box 1.
A novel epigenetic intervention in a murine model of acquired epilepsy, using a synthetic miR-146a mimic, which inhibits Interleukin-1 Receptor 1 (IL-1R1)/TLR4 intracellular signaling, and a novel combination of anti-inflammatory drugs, which prevent IL-1β biosynthesis and block TLR4, reduced chronic seizure recurrence and prevented epilepsy progression.
The activation of IL-1β/IL-1R1 signaling increased NMDA-dependent neurotransmission and seizure susceptibility in a mouse model of Creutzfeldt-Jacob disease, an incurable brain disorder caused by alterations in prion protein structure. Blocking IL-1β receptors with anakinra, the human recombinant IL-1 receptor antagonist, normalized hippocampal neurotransmission and reduced seizures susceptibility.
In summary, seizures and epilepsy severity can be drastically reduced by targeting specific neuroinflammatory mechanisms, thus providing an innovative therapeutic approach for significantly improving the disease course.
Thesis (complete) (Embargo up to and including 01 January 2020)
Chapter 7: Priming of TLR3 signaling in astrocytes mediates anti-inflammatory and anticonvulsive effects: The role of IFN-β and AHR-mediated signaling (Embargo up to and including 01 January 2020)
Chapter 8: General discussion and summary (Embargo up to and including 01 January 2020)
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