Terrone, Gaetano (2017) New drugs and therapeutic strategies in pharmacoresistant epilepsy. [Tesi di dottorato]

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Epilepsy is a brain disorder characterized by an enduring predisposition to generate recurrent epileptic seizures and by the neurobiologic, cognitive, psychological and social consequences of this condition. Current antiepileptic drugs provide symptomatic relief from seizures, have multiple adverse effects, and fail to control seizures in up to 30% of people. This represents a major unmet clinical need. New anti-seizure treatments for epilepsy are unlikely to bridge this treatment gap. In order to develop such drugs, there is the need to understand the pathological processes occurring in the brain of people exposed to epileptogenic injuries, or with an established diagnosis of epilepsy. In this PhD thesis, I pointed my attention on the role of neuroinflammation in the mechanisms of epileptogenesis. Specific inflammatory molecules and pathways have been shown to significantly contribute to the mechanisms of seizure generation and progression in different experimental models. In particular, I have contributed to demonstrate for the first time that targeting oxidative stress with clinically tested drugs, for a limited time window post-injury, significantly delayed the onset of epilepsy, blocked disease progression and drastically reduced spontaneous seizures and long-term pathological consequences (cell loss, cognitive deficit). This intervention may be considered for patients exposed to potential epileptogenic insults as status epilepticus. Drug-induced reduction of oxidative stress prevented disulfide HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Moreover, my research work provided evidence supporting that monoacylglycerol lipase (MAGL) is a new potential target for drug development in epilepsy, in particular for the treatment of drug-refractory status epilepticus (SE). Inhibition of MAGL by a new potent and selective irreversible inhibitor (CPD-4645) protects mice against refractory SE and its therapeutic effects are potentiated by the ketogenic diet. In conclusion, all these experimental data contribute to better clarify the complex mechanisms underlying the pathophysiology of epilepsy, in order to identify new potential therapeutic targets. However, the major challenge will be represented by the translation of these experimental results into clinically effective human therapies.

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