The holy grail of epilepsy prevention: Preclinical approaches to antiepileptogenic treatments
A variety of acute brain insults can induce epileptogenesis, a complex process that results in acquired epilepsy. Despite advances in understanding mechanisms of epileptogenesis, there is currently no approved treatment that prevents the development or progression of epilepsy in patients at risk. The current concept of epileptogenesis assumes a window of opportunity following acute brain insults that allows intervention with preventive treatment. Recent results suggest that injury-induced epileptogenesis can be a much more rapid process than previously thought, suggesting that the 'therapeutic window' may only be open for a brief period, as in stroke therapy. However, experimental data also suggest a second, possibly delayed process ("secondary epileptogenesis") that influences the progression and refractoriness of the epileptic state over time, allowing interfering with this process even after onset of epilepsy. In this review, both methodological issues in preclinical drug development and novel targets for antiepileptogenesis will be discussed. Several promising drugs that either prevent epilepsy (antiepileptogenesis) or slow epilepsy progression and alleviate cognitive or behavioral comorbidities of epilepsy (disease modification) have been described in recent years, using diverse animal models of acquired epilepsy. Promising agents include TrkB inhibitors, losartan, statins, isoflurane, anti-inflammatory and anti-oxidative drugs, the SV2A modulator levetiracetam, and epigenetic interventions. Research on translational target validity and on prognostic biomarkers that can be used to stratify patients (or experimental animals) at high risk of developing epilepsy will hopefully soon lead to proof-of-concept clinical trials with the most promising drugs, which will be essential to make prevention of epilepsy a reality.