Biomarkers of Epileptogenesis and Novel Therapeutic Approaches in Animal Models of Acquired Epilepsy

Di Sapia, Rossella (2023). Biomarkers of Epileptogenesis and Novel Therapeutic Approaches in Animal Models of Acquired Epilepsy. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00015f34

Abstract

Epilepsy is a chronic neurological disorder that affects over 50 million people worldwide. The current therapy is mainly based on symptomatic drugs acting on seizures but these drugs do not affect the underlying mechanisms of the disease. Moreover, despite more than 20 available antiseizure drugs, seizures remain uncontrolled in ~30% of patients. Hence, there is an urgent need to find novel therapeutics to improve the management of seizures and the neurological comorbidities. Epilepsy may occur after an acquired epileptogenic insult (e.g., traumatic brain injury, status epilepticus, CNS infections) and the risk of developing the disease varies among individuals exposed to similar injuries. Prevention of epilepsy is hampered by the lack of sensitive and specific prognostic biomarkers that may enable the identification of the individuals at risk of developing epilepsy. This prediction would greatly facilitate clinical trials of anti-epileptogenic treatments. Animal models are required to investigate the pathological mechanisms driving the transition from the epileptogenic insult to clinical onset and progression of epilepsy. These models are instrumental for discovering novel targets and developing effective treatments and biomarkers of epileptogenesis. Based on these clinical needs, we characterized two clinically relevant rodent models of epileptogenesis of differing etiology (traumatic brain injury, status epilepticus) with a 50-60% epilepsy incidence to identify potential biomarkers by performing EEG, MRI and behavioural measurements. Moreover, we studied the activation and the role of the IL-8 signaling in pharmacoresistant epilepsy using human temporal lobe epilepsy brain specimens and a wellestablished mouse model. This chemokine was reported to be increased in biospecimens of patients with drug-resistat seizures. Our studies provided evidence of prognostic biomarkers of epileptogenesis with clinical translatability, and a new druggable target for controlling pharmacoresistant seizures.