Progress in neuroprotective strategies for preventing epilepsy

Abstract

Neuroprotection is increasingly considered as a promising therapy for preventing and treating temporal lobe epilepsy (TLE). The development of chronic TLE, also termed as epileptogenesis, is a dynamic process. An initial precipitating injury (IPI) such as the status epilepticus (SE) leads to neurodegeneration, abnormal reorganization of the brain circuitry and a significant loss of functional inhibition. All of these changes likely contribute to the development of chronic epilepsy, characterized by spontaneous recurrent motor seizures (SRMS) and learning and memory deficits. The purpose of this review is to discuss the current state of knowledge pertaining to neuroprotection in epileptic conditions, and to highlight the efficacy of distinct neuroprotective strategies for preventing or treating chronic TLE. Although the administration of certain conventional and new generation anti-epileptic drugs is effective for primary neuroprotection such as reduced neurodegeneration after acute seizures or the SE, their competence for preventing the development of chronic epilepsy after an IPI is either unknown or not promising. On the other hand, alternative strategies such as the ketogenic diet therapy, administration of distinct neurotrophic factors, hormones or antioxidants seem useful for preventing and treating chronic TLE. However, long-term studies on the efficacy of these approaches introduced at different time-points after the SE or an IPI are lacking. Additionally, grafting of fetal hippocampal cells at early time-points after an IPI holds considerable promise for preventing TLE, though issues regarding availability of donor cells, ethical concerns, timing of grafting after SE, and durability of graft-mediated seizure suppression need to be resolved for further advances with this approach. Overall, from the studies performed so far, there is consensus that neuroprotective strategies need to be employed as quickly as possible after the onset of the SE or an IPI for considerable beneficial effects. Nevertheless, ideal strategies that are capable of facilitating repair and functional recovery of the brain after an IPI and preventing the evolution of IPI into chronic epilepsy are still hard to pin down.

Introduction

Epilepsy is one of the oldest neurological conditions known to humankind. The term “epilepsy” is derived from Greek word “epilambanein”, which means “to seize upon” or “to attack”. In this modern era, epilepsy is the most frequent neurodegenerative disease after stroke. It afflicts more than 2 million Americans and 50 million people worldwide (Strine et al., 2005), and the temporal lobe epilepsy (TLE) is among the most frequent types of drug-resistant epilepsy (Engel, 2001, Litt et al., 2001, McKeown and McNamara, 2001). In a population of new patients presented with epilepsy, almost 30% of them have seizures originating from the temporal lobe of the brain (Manford et al., 1992). Individuals affected with TLE typically have comparable clinical description, including an initial precipitating injury (IPI) such as the status epilepticus (SE), head trauma, encephalitis or childhood febrile seizures (Harvey et al., 1997, Fisher et al., 1998, Cendes, 2002). There is usually a latent period of several years between this injury and the emergence of the chronic TLE characterized by spontaneous recurrent motor seizures (SRMS) originating from temporal lobe foci, and learning and memory impairments (Devinsky, 2004, Detour et al., 2005). Further, the TLE is frequently associated with hippocampal sclerosis, mainly exemplified by significant neurodegeneration in the dentate hilus (DH), and the CA1 and CA3c sub regions (Sloviter, 2005). Human studies suggest that the hippocampal sclerosis likely initiates or contributes to the generation of most TLEs (Engel, 1996). A significant number of people (∼25%) afflicted with epilepsy have seizures that cannot be controlled by anti-epileptic drugs (Litt et al., 2001, McKeown and McNamara, 2001). Moreover, anti-epileptic drugs (AEDs) merely provide symptomatic treatment without having any influence on the course of the disease. Thus, there is a pressing need to develop alternative therapeutic approaches that prevent the epileptogenesis after the SE or an IPI. From this perspective, identification of compounds or approaches that are efficacious for providing neuroprotection to the hippocampus after the onset of SE has great significance.