title: Profile of retigabine-induced neuronal apoptosis in the developing rat brain.
abstract: OBJECTIVE
  Acute neonatal exposure to some, but not all, anticonvulsant drugs induces a profound increase in neuronal apoptosis in rats. Phenobarbital and phenytoin induce apoptosis at a therapeutically relevant dose range, lamotrigine and carbamazepine do so only at supratherapeutic doses or in polytherapy, and valproate does so even at subtherapeutic doses. Levetiracetam is devoid of pro-apoptotic effects. Retigabine, a new-generation drug, acts uniquely by enhancing the M-type potassium current. Because its safety profile in developing animals is unstudied, we sought to determine if retigabine would induce apoptosis.
  
  
  METHODS
  Postnatal day (P) 7 rat pups were treated with retigabine (5-30 mg/kg), vehicle (saline), or comparator drugs (phenobarbital, lamotrigine, levetiracetam, or carbamazepine). Cell death was assessed using amino-cupric-silver staining. A separate group of animals was treated repeatedly (three times over 24 h) with retigabine (15 mg/kg) or vehicle. To establish a pharmacokinetic profile for retigabine, we measured plasma and brain levels after drug treatment.
  
  
  RESULTS
  Consistent with prior studies from our group and others, we found phenobarbital-induced cell death throughout thalamus, nucleus accumbens, and several neocortical areas. By contrast, levetiracetam, lamotrigine, and carbamazepine were found to have no appreciable apoptotic effect on the aforementioned structures. Acute (single) exposure to retigabine, even at doses of 30 mg/kg, was also without effect on apoptosis. However, repeated (three times) exposure to retigabine triggered apoptosis in a subset of brain areas. The half-life of retigabine in plasma was 2.5 h, with appreciable concentrations reached in the brain within 1 h of administration.
  
  
  CONCLUSIONS
  These data demonstrate that retigabine, like many other anticonvulsant drugs, is capable of triggering neuronal apoptosis in the developing rat brain. Unlike other drugs, repeated dosing of retigabine was necessary to induce this effect. This may be due to its shorter half-life as compared to other drugs, such as phenobarbital.
authors: Department of Pharmacology & Physiology, Georgetown University School of Medicine, Washington, District of Columbia, U.S.A.
authors: Lindsay
authors: L
authors: Brown
authors: Department of Pharmacology & Physiology, Georgetown University School of Medicine, Washington, District of Columbia, U.S.A.
authors: Samuel
authors: S
authors: Gutherz
authors: Department of Pharmacology & Physiology, Georgetown University School of Medicine, Washington, District of Columbia, U.S.A.
authors: Catherine
authors: C
authors: Kulick
authors: Department of Pharmacology & Physiology, Georgetown University School of Medicine, Washington, District of Columbia, U.S.A.
authors: Colin
authors: C
authors: Soper
authors: Department of Pharmacology & Physiology, Georgetown University School of Medicine, Washington, District of Columbia, U.S.A.
authors: Alexei
authors: A
authors: Kondratyev
authors: Department of Pharmacology & Physiology, Georgetown University School of Medicine, Washington, District of Columbia, U.S.A.
authors: Patrick A
authors: PA
authors: Forcelli
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology; D002219:Carbamates / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010655:Phenylenediamines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; C101866:ezogabine
keywords: Cell death; Gestational; Neonatal; Teratogen