Antiepileptic effects of levetiracetam in a rodent neonatal seizure model

Abstract

Background: Neonatal seizures can result in chronic epilepsy and long-term behavioral and cognitive deficits. Levetiracetam (LeV), an antiepileptic drug that binds to the synaptic vesicle protein 2a (sV2a), has been increasingly used off-label for the therapy of neonatal seizures. Preclinical data regarding the acute or long-term efficacy of LeV are lacking. Methods:We tested the anticonvulsant efficacy of LeV in a rat model of hypoxia-induced neonatal seizures. In addition, we evaluated the protective effects of postnatal day (P)10 LeV treatment on later-life kainic acid (Ka)-induced seizure susceptibility and seizure-induced neuronal injury. Western blot and immunohistochemistry were used to assess the developmental regulation of sV2a in the rat and human brain. results: LeV pretreatment at P10 significantly decreased the cumulative duration of behavioral and electrographic seizures at both 25 and 50 mg/kg. at P40, Ka-induced seizures and neuronal loss were significantly diminished in rats previously treated with LeV. LeV target sV2a is present in both neonatal rat and human brain and increases steadily to adulthood. conclusion: LeV suppressed acute seizures induced by perinatal hypoxia and diminished later-life seizure susceptibility and seizure-induced neuronal injury, providing evidence for disease modification. These results support consideration of a clinical trial of LeV in neonatal seizures. n eonatal seizures can be refractory to conventional antiepileptic drugs (AEDs) (1,2), and recently, newer-generation drugs have been considered for off-label use and/or clinical trials for this indication. Levetiracetam ((S)-α-ethyl-2-oxo-1-pyrrolidine acetamide; LEV) is a newer AED with more than a 10-y history of US Food and Drug Administration approval for use as adjunctive therapy for partial epilepsy and is efficacious and safe as monotherapy in adult and pediatric epilepsy syndromes (3,4). LEV has a specific and unique binding target, the synaptic vesicle protein 2A (SV2A), which is involved in exocytosis of synaptic vesicles by interacting with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex (5). SV2A is widely expressed throughout all brain structures regardless of the neurotransmitter phenotype (6). LEV binding to SV2A impedes neurotransmitter exocytosis and can block the interaction of the SV2A protein with the actin cytoskeletal network involved in the synaptic vesicle trafficking (7). LEV has also been shown to modulate voltageoperated K + channels (8) and N-type high-voltage-activated Ca 2+ currents (9). Previous studies in adult animal models of chronic epilepsy demonstrate that LEV is a potent anticonvulsant with longlasting antiepileptogenic effects, even as a single dose (10-13). Unlike other conventional AEDs, LEV has no negative impact on cognition and memory formation in either normal or chronically epileptic rats (14). Taken together, these properties and its unique safety profile make LEV an attractive candidate drug for seizure suppression and antiepileptogen...

Profile of anticonvulsant action of levetiracetam, tiagabine and phenobarbital against seizures evoked by DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) in neonatal rats

“…Moreover, these findings demonstrate the preclinical efficacy of TGB in neonatal animals, and extend a prior report (Talos et al, 2013) regarding the efficacy of LEV in neonatal animals. Both drugs were effective at attenuating limbic motor seizures in neonatal rats.…”

“…The ED 50 in our present study also falls within the range of minimum active dose against pilocarpine and kainate in adult rats (17 to 54 mg/kg). In addition, the dose-response we found with LEV is similar to that previously described in a model of hypoxia-induced neonatal seizures (Talos et al, 2013). In the hypoxia-induced seizure model, LEV reduced the duration of electrographic seizures when administered at 25 or 50 mg/kg, but not at 10 mg/kg (Talos et al, 2013).…”

“…In addition, the dose-response we found with LEV is similar to that previously described in a model of hypoxia-induced neonatal seizures (Talos et al, 2013). In the hypoxia-induced seizure model, LEV reduced the duration of electrographic seizures when administered at 25 or 50 mg/kg, but not at 10 mg/kg (Talos et al, 2013). Here, we found anticonvulsant effects starting as low as 10 mg/kg.…”

“…Interestingly, in both the hypoxic model and in the present study LEV did not completely protect from seizure activity, with asymptotic protection seen between 25 and 50 mg/kg in the Talos study and 50 and 100 mg/kg in the present study. Levels of the binding target for LEV, SV2A, do not change significantly during the first two postnatal weeks, but increase significantly between P14 and P21 (Talos et al, 2013). Thus, while it remains to be tested, it is likely that the effect of LEV seen at P10 will be similar throughout the first two postnatal weeks.…”

“…Indeed, LEV appears to exert preferential action against partial seizures in experimental models (e.g., those triggered by kindling; Klitgaard et al, 1998; Löscher and Hönack, 1993). The only prior examination of LEV in neonatal animals utilized a hypoxic-ischemic model of seizures (Talos et al, 2013). Animals were tested at postnatal day (P) 10, and LEV significantly attenuated seizures at doses of 25 and 50 mg/kg, but not at 10 mg/kg.…”