Selected Molecular Targets for Counteracting Epileptogenesis: What Do We Know About Its Effective Inhibition?

Abstract

Epilptogenesis is a long-term process that involves the transformation of a healthy brain into a seizure-producing brain. Since approximately 30% of epilepsy patients suffer from drug-resistant seizures, the concept of inhibiting the epileptogenesis process and thus preventing seizures has emerged. The search for effective methods of inhibiting epileptogenesis is possible thanks to animal models, which include kindled seizures; models based on the induction of status epilepticus resulting in subsequent spontaneous recurrent seizures, or brain trauma; and genetic models. Blood–brain barrier dysfunction, inflammatory processes in the brain, and oxidative stress appear to play a major role in epileptogenesis. This prompted testing of a number of anti-inflammatory agents and antioxidants in the epileptogenic process. One noteworthy finding was that losartan (an antihypertensive drug), as a TGF-β antagonist, proved effective in inhibiting epileptogenesis due to blood–brain barrier damage. Due to the many mechanisms involved in the process of epileptogenesis, it seems that the use of a combination of drugs will be an effective method of inhibiting it. The most promising combination includes levetiracetam (a second-generation antiseizure drug), atorvastatin, and ceftriaxone (a beta-lactam antibiotic), which effectively inhibits spontaneous seizures in animals experiencing status epilepticus. Any clinical trials on the inhibition of epileptogenesis must take into account the fact that a small percentage of patients develop epileptic seizures after stroke or brain injury. Recently suggested markers predicting a high probability of epileptic seizures after brain damage may facilitate appropriate patient selection for studies on inhibition of epileptogenesis.