Epilepsia, 47(3):469–478, 2006 Blackwell Publishing, Inc. C  2006 International League Against Epilepsy Levetiracetam: Antiepileptic Properties and Protective Effects on Mitochondrial Dysfunction in Experimental Status Epilepticus ∗ Julie E. Gibbs, †Matthew C. Walker, and ∗ Hannah R. Cock ∗ Epilepsy Group, Centre for Clinical Neurosciences, St George’s, University of London, Tooting; and †Department of Clinical and Experimental Epilepsy, Institute of Neurology, UCL, London, England Summary: Purpose: To assess the anticonvulsant activity of the novel antiepileptic drug, levetiracetam (LEV) in a model of self-sustaining limbic status epilepticus, and to measure the consequence of LEV treatment on the pattern of mitochondrial dysfunction known to occur after status epilepticus (SE). Methods: The rat perforant pathway was stimulated for 2 h to induce self-sustaining status epilepticus (SSSE). Stimulated rats were assigned to one of three treatment groups, receiving in- traperitoneal injections of saline, 200 mg/kg LEV, or 1,000 mg/ kg LEV, 15 min into SSSE and at 3 times over the next 44-h period. All animals received diazepam after 3-h SSSE to ter- minate seizures. Forty-four hours later, the hippocampi were extracted and prepared for electrochemical high-performance liquid chromatography (HPLC), to measure reduced glutathione levels, and for spectrophotometric assays to measure activities of mitochondrial enzymes (aconitase, α-ketoglutarate dehydro- genase, citrate synthase, complex I, and complex II/III). These parameters were compared between treatment groups and with sham-operated rats. Results: LEV administration did not terminate seizures or have any significant effect on spike frequency, although rats that re- ceived 1,000 mg/kg LEV did exhibit improved behavioral seizure parameters. Significant biochemical changes occurred in saline- treated stimulated rats compared with shams: with reductions in glutathione, α-ketoglutarate dehydrogenase, aconitase, cit- rate synthase, and complex I activities. Complex II/III activi- ties were unchanged throughout. Rats that received 1,000 mg/ kg LEV had significantly improved biochemical parameters, in many instances, comparable to sham control levels. Conclusions: Despite continuing seizures, administration of LEV (1,000 mg/kg) protects against mitochondrial dys- function, indicating that in addition to its antiepileptic actions, LEV may have neuroprotective effects. Key Words: Levetiracetam—Status epilepticus—Perforant path- way stimulation—Mitochondria—Glutathione. Status epilepticus (SE) is a major medical emergency that can be defined as continuous seizure activity, or in- termittent seizure activity, lasting ≥30 min, during which time consciousness is not regained (1). This condition has a high mortality rate and considerable morbidity and is associated with the development of learning difficulties, focal neurologic deficits, and chronic epilepsy in survivors (2,3). First-line therapy for SE is the administration of benzodiazepines, usually either diazepam (DZP) or lo- razepam (4); however, this fails in ∼40% of cases (5). Fur- thermore, ∼30% of patients with SE experience seizures that do not respond to first- and second-line anticonvul- sant drug (AED) therapy, and this refractory SE is asso- ciated with an increased length of hospital stay and func- tional disability (6). Thus it is clear that additional, more Accepted November 4, 2005. Address correspondence and reprint requests to Dr. H. Cock at Epilepsy Group, Department of Cardiac & Vascular Sciences, St George’s, University of London, Cranmer Terrace, Tooting, London SW17 0RE, U.K. E-mail: hcock@sgul.ac.uk effective, well-tolerated treatments for SE are urgently required. It also is now well established that SE is associated with neuronal damage, particularly in the hippocampus (7). Both mitochondrial dysfunction and oxidative stress are considered critical determinants of the neuronal death associated with seizures (8–10) and may also play a role in subsequent epileptogenesis and in chronic epilepsy (11). We have previously reported, in an electrical stimulation model of SE, a specific pattern of biochemical change af- ter SE, consistent with the occurrence of oxidative stress and free radical production (12,13). These changes in- clude reductions in cellular levels of reduced glutathione (GSH; an antioxidant); reduced activity of complex I of the mitochondrial respiratory chain; and reduced activi- ties of enzymes susceptible to oxidative stress within the tricarboxylic acid cycle. On this background, we postu- late that drugs that can prevent, or reduce, this mitochon- drial dysfunction may exert neuroprotective effects and thus reduce seizure-associated brain damage. Levetirac- etam (LEV; (S)-α-ethyl-2-oxo-pyrrolidine acetamide) is 469