Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies

Abstract

The prevalence of epilepsy is estimated 5-10 per 1000 population and around 70% of patients with epilepsy can be sufficiently controlled by antiepileptic drugs (AEDs). Epileptogenesis is the process responsible for converting normal into an epileptic brain and mechanisms responsible include among others: inflammation, neurodegeneration, neurogenesis, neural reorganization and plasticity. Some AEDs may be antiepileptiogenic (diazepam, eslicarbazepine) but the correlation between neuroprotection and inhibition of epileptogenesis is not evident. Antiepileptogenic activity has been postulated for mTOR ligands, resveratrol and losartan. So far, clinical evidence gives some hope for levetiracetam as an AED inhibiting epileptogenesis in neurosurgical patients. Biomarkers for epileptogenesis are needed for the proper selection of patients for evaluation of potential antiepileptogenic compounds.

Anti-Epileptogenic Effects of Antiepileptic Drugs

“…Three separate stages of epileptogenesis may be distinguished: initial insult (for example SE), latent period without seizure activity and finally, chronic epilepsy with recurrent seizure activity [8]. There are apparently acute (from hours to weeks, including transcriptional events, neurodegeneration and activation of inflammatory pathways) and chronic processes (mainly from weeks to months, embracing neurogenesis, mossy fiber sprouting, neuronal circuit reorganization and gliosis) which lead to and sustain epileptogenesis [8].…”

Antagonistic interaction of lacosamide with carbamazepine and valproate in the mouse tonic-clonic seizure model

“…Since induction, propagation and amplification of seizures are complex processes and, unfortunately, not fully understood, seizure suppression often requires medicating with various AEDs [4,13]. Undoubtedly, various AEDs with diverse molecular mechanisms of action should synergistically cooperate in terms of seizure suppression [12].…”

Metaloproteinaza macierzy pozakomórkowej 9 i epileptogeneza – kluczowa rola enzymu i strategie zmierzające do zapobiegania rozwojowi choroby

“…It is widely known that level of MMPs is increased during neuropathological diseases that are accompanied by an inflammatory component, so, reasonably, the starting point of investigations were bound to MMP-9s aggravation of immune response and its epileptogenic consequences [38]. On other hand, an alternative view on MMP-9 role in epileptic brain has also been proposed based on unique MMP-9 functions at the synapse leading to epilepsy circuity establishment [6]. In the following chapters will be reviewing scientific evidence dealing with different aspects of MMP-9 engagement into epileptogenesis.…”

“…Aberrant synaptogenesis on the contrary, that occurs days to weeks after initial insult, is not associated with spine pruning, but rather with an increase in spine number. Seizure-related changes in spines are believed to represent a mechanistic basis for cognitive deficits in epilepsy [6].…”

“…Clearly comprehending this processes and establishing its key players, we shall be able to develop tools to interfere and prevent the epilepsy advancement. The prevention, delay or seizure modification may be considered as a clinically relevant endpoint for antiepiletogenesis studies [3,6,7].…”