Prospects of levetiracetam as a neuroprotective drug against status epilepticus, traumatic brain injury, and stroke

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Prospects of levetiracetam as a neuroprotective drug against status epilepticus, traumatic brain injury, and stroke

Ashok K. Shetty^1,2,3*

• ¹Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott & White, Temple, TX, USA
• ²Research Service, Olin E. Teague Veterans Affairs Medical Center, Central Texas Veterans Health Care System, Temple, TX, USA
• ³Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA

Levetiracetam (LEV) is an anti-epileptic drug commonly used for the treatment of partial onset and generalized seizures. In addition to its neuromodulatory and neuroinhibitory effects via its binding to the synaptic vesicle protein SV2A, multiple studies have suggested neuroprotective properties for LEV in both epileptic and non-epileptic conditions. The purpose of this review is to discuss the extent of LEV-mediated protection seen in different neurological conditions, the potential of LEV for easing epileptogenesis, and the possible mechanisms that underlie the protective properties of LEV. LEV has been found to be particularly beneficial for restraining seizures in animal models of spontaneous epilepsy, acute seizures, and status epilepticus (SE). However, its ability for easing epileptogenesis and cognitive dysfunction following SE remains controversial with some studies implying favorable outcomes and others reporting no beneficial effects. Efficacy of LEV as a neuroprotective drug against traumatic brain injury (TBI) has received much attention. While animal studies in TBI models have showed significant neuroprotection and improvements in motor and memory performance with LEV treatment, clinical studies suggest that LEV has similar efficacy as phenytoin in terms of its ability to prevent post-traumatic epilepsy. LEV treatment for TBI is also reported to have fewer adverse effects and monitoring considerations but electroencephalographic recordings suggest the presence of increased seizure tendency. Studies on stroke imply that LEV is a useful alternative to carbamazepine for preventing post-stroke seizures in terms of efficacy and safety. Thus, LEV treatment has promise for restraining SE-, TBI-, or stroke-induced chronic epilepsy. Nevertheless, additional studies are needed to ascertain the most apt dose, timing of intervention, and duration of treatment after the initial precipitating injury and the mechanisms underlying LEV-mediated beneficial effects.

Introduction

Levetiracetam [LEV; 2S-(oxo-1-pyrrolidinyl) butanamide] is an anti-epileptic drug (AED) often utilized for the treatment of partial onset and generalized seizures (1, 2). LEV has both anti-seizure and anti-epileptogenic properties. It has been also proposed that LEV is an attractive AED for managing post-traumatic seizures (PTSs) owing to its beneficial pharmacokinetic attributes, including excellent bioavailability, linear kinetics, minimal plasma protein binding, and rapid achievement of steady state concentrations (2–4). The underlying mechanisms by which LEV facilitates anti-epileptic and anti-epileptogenic effects are different from classic AEDs. Studies insinuate that LEV bestows its effects mainly through the inhibition of the synaptic vesicle protein 2A (1). Additional investigations have also revealed that LEV can inhibit HVA-Ca² channels (N-type), negate the inhibition of negative allosteric modulators such as zinc and β-carbolines of γ-aminobutyric acid (GABA)- and glycine-gated currents, and diminish the calcium release from intraneuronal stores (1, 5).

Moreover, a multitude of studies have proposed that LEV has considerable neuroprotective properties in both epileptic and non-epileptic disorders (2, 6–9). The capability of LEV to augment the manifestation of glial glutamate transporters EAAT1/GLAST and EAAT2/GLT-1 has been proposed as one of the foremost mechanisms through which LEV mediates its neuroprotective properties (2, 10). This hypothesis fits well with one of the conspicuous changes detected following most brain insults, which is increased concentration of glutamate in the extracellular areas causing enhanced activation of N-methyl-d-aspartate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on neurons and culminating in significant neurodegeneration (2, 11, 12). The efficacy of LEV as a neuroprotective compound has been examined in several brain injury and neurodegenerative disease prototypes. These include brain damage resulting from status epilepticus (SE) or acute seizures, spontaneous epilepsy, closed head trauma, subarachnoid hemorrhage (SAH), hypoxic-ischemia, and stroke. The goal of this review is to confer the extent of LEV-mediated neuroprotection observed in different brain injury models, the potential of LEV for easing epileptogenesis, and the possible mechanisms that underlie neuroprotective properties of LEV in different neurological conditions.

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