title: Levetiracetam: antiepileptic properties and protective effects on mitochondrial dysfunction in experimental status epilepticus.
abstract: OBJECTIVE
  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 intraperitoneal 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 terminate 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, alpha-ketoglutarate dehydrogenase, 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 received 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, alpha-ketoglutarate dehydrogenase, aconitase, citrate synthase, and complex I activities. Complex II/III activities 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 dysfunction, indicating that in addition to its antiepileptic actions, LEV may have neuroprotective effects.
authors.affiliation: Centre for Clinical Neurosciences, St George's, University of London, Tooting, London, England.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Gibbs
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walker
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Cock
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004569:Electroencephalography / Q000187:drug effects / Q000706:statistics & numerical data; D004827:Epilepsy / Q000188:drug therapy / Q000517:prevention & control*; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D000077287:Levetiracetam; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000378:metabolism / Q000517:prevention & control*; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D019580:Perforant Pathway / Q000378:metabolism / Q000502:physiology; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000927:Anticonvulsants; D018696:Neuroprotective Agents; D000077287:Levetiracetam; D002950:Citrate (si)-Synthase; D000154:Aconitate Hydratase; D005978:Glutathione; D010889:Piracetam