Investigating Inflammatory Pathways as Therapeutic Targets and Biomarkers using Functional Imaging and Pharmacological Interventions in Epilepsy Models.

Abstract

Epilepsy is a neurological disorder that is characterised by spontaneous seizures. After various epileptogenic injuries, astrocytes become dysfunctional and experimental evidence indicates that these cells contribute to seizure mechanisms. The generation of inflammatory molecules in astrocytes appears to play a key pathogenic role in seizures. However, astrocytes may also contribute to repair the hyperexcitable neuronal networks underlying seizures. We focused our studies on understanding the role of astrocytes in epilepsy by (1) developing a new in vivo imaging method to monitor astrocytic cell activation during epileptogenesis and coupled this with their phenotypic characterization; (2) studying the role of Toll-like receptor 3 (TLR3) signaling in seizure mechanisms. We report that in vivo bioluminescence imaging is a powerful tool for monitoring astrocytic activation in diseased conditions. Characterization of astrocytic activation during epileptogenesis showed a rapid cell activation corresponding to their inflammatory phenotype while homeostatic (neuroprotective) mechanisms were activated with a delay. Moreover, we demonstrate that in vivo imaging of astrocyte activation allows to study the potential involvement of these cells in the therapeutic effects of anti-inflammatory drugs. We also show that priming TLR3 activation in astrocytes with the use of a synthetic agonist results in remarkable anti-inflammatory and anti-ictogenic effects. Mechanistic studies revealed that interferon regulatory factor (IRF)-3/Interferon-β mediated cascade is likely responsible for the inhibitory effects of TLR3 priming on seizures and neuronal excitability. In summary, astroglia activation during the critical epileptogenesis phase provides a potential target for interfering in a timely manner with the inflammatory phenotype of these cells contributing to seizures. Importantly, there are astrocytic cell functions that mediate decreased neuronal excitability and they should be carefully considered when developing treatments targeting these cells for therapeutic purposes