Molecular Targets on Antiepileptogenic Therapy Research: Deconstructing the Network for Translational Purposes

Abstract

Abbreviations: AED, antiepileptic drugs; PSD, post-synaptic density; LTP, long term potentiation; AMPAR, α-amino-3-hydroxy--5-methyl-4-isoxazole propionate receptor; NMDAR, n-methyl-d-aspartate receptor; GABA A R, γ-aminobutyric acid receptor A; PSD-95, post-synaptic density protein-95; ERK, extracellular-signal-regulated kinase; MAPK, mitogen-activated protein kinase; CREB, cAMP response element-binding protein; IL, interleukin; TNF, tumor necrosis factor; ATL, anterior temporal lobectomy; LTP, long term potentiation; TLR4, toll-like receptor-4; TBI, traumatic brain disorders; TLE, temporal lobe epilepsy; GFAP, glial fibrillary acidic protein IntroductionEpilepsy is the second most common neurological disorder, affecting more than 50million people worldwide.1 Although new therapies in the epilepsy treatment have been introduced as a result of the preclinical research over the last two decades, seizures are not yet controlled in all patients. Current pharmacological approaches on Epilepsy are mostly seizure suppressing and the associated comorbidities suppose a serious withdrawal for patients, burdening their life quality.2 To address this, a greater attention has been given on research focusing epileptogenesis. This mechanism is defined as the process whereby a neuronal network develops recurrent spontaneous epileptic seizures and at the same time, the cause of seizures becoming more severe and frequent in chronic epilepsy.3 On this regard, it has been recently proposed an alternative terminology to define the current therapeutical approaches on Epilepsy and to be differenced from the classical designation of AED, 'antiepileptic drugs' on the symptomatic treatment. The term 'anti-seizure drugs', describe those compounds with an active intervention on the disease development and that have shown a sustained modulatory effect on the predisposition to generate spontaneous recurrent seizures in vivo and in vitro experimental models. 4 Herein, there are summarized the main potential molecular targets, extracted from these research models and proposed to play a key role on the epileptogenic process. These studies have the ultimate goal of the development of disease biomarkers on future experimental designs that would allow for the identification of patients at risk of developing epilepsy or for monitoring disease progression and prognosis on treatment outcome. DiscussionThe need of disassembling the network for the upgrade on epilepsy therapeuticsThe classic traditional approach on epilepsy treatment has always focused on restoring the normal function on epileptic networks. Seizures occur in groups of neurons and involve complex interactions across several regions. Targeting recurrent hyperexcitability and thus stopping the number and intensity of episodes that utterly accelerate the development of disease, would also delay its direct consequences on appearance of disease comorbidities.3 Electrical brain stimulation, including the novel responsive stimulation (RNS), is used to control seizures and achieve modulation o...