THE RATIONALE FOR NEUROPROTECTION IN EPILEPSY: STEPS FORWARD FOR NEW THERAPEUTIC AND PREVENTIVE STRATEGIES

Abstract

The growing number of research in epilepsy provides evidences regarding the progressive neuronal damage which occur as a result of recurrent brief seizures as well as prolonged seizures. Advances in understanding the neurobiology of epilepsy indicate that initial seizure injury triggers a sequence of adaptive molecular and cellular mechanisms that interact in a highly complex manner. These changes evolve over a period of time (up to years) and involve gene alteration, channel dysfunction, impaired inhibitory/excitatory balance tipped towards excitation, mitochondrial embarrassment, homeostatic alteration of cell essential elements and exhaustion of endogenous protective mechanisms. This results in long-lasting functional and structural neurobiological reorganization at different levels that contribute to neuronal hyperexcitability, excitotoxicity, apoptotic and necrotic cell death, gliosis, persistent epileptogenesis and spontaneous seizures later in life. Importantly, seizure is only one aspect of epilepsy, however, behavioral and cognitive deficits which occur as a result of seizures or its treatment can be more detrimental to an individual's overall function. The perspectives of beneficial neuroprotection in epilepsy aim not only to improve seizure control, but also to promote compensatory processes in repairing, modifying or blocking the active changes triggered by the initial injury. Recent evidences indicate that the current AEDs have some neuroprotective potentials. However, their limited capabilities against broader range of neurotoxic insults, differential effect on the brain during various stages of development and undesirable adverse effects, trigger the inspiration of new strategies. Speculative targets may include free radical scavengers/antioxidants, modifiers of mitochondrial dysfunction, antiapoptotics, immunomodulators, hormonotherapy and neurotrophic factors. For all, assessments of therapeutic time window, long-term neuroprotective potentials and adverse consequences are mandatory.