Development and validation of the maximal electro-shock seizure model in dogs

J Vet Pharmacol Ther. 2007 Dec;30(6):508-15. doi: 10.1111/j.1365-2885.2007.00906.x.

Abstract

The development and validation of the maximal electro-shock (MES) model using phenobarbital (Pb) as the positive control is described. This approach builds on previous work in rodent model systems, and has been adapted to dogs as a tool for pharmaceutical dose selection. Dogs, like rodents, exhibit generalized convulsions which manifest as progressive clinical signs in a dose (electrical current) dependent fashion. At the limit (300 mA, 200 msec) animals underwent clonic-tonic convulsions consistent with complete generalized (Grand Mal) seizures with a grade 3 clinical score (CS) and a menace response time of 98.5 +/- 24.4 sec (n = 8). Pretreatment of animals with Pb at 3, 10, and 30 mg/kg, in a 4-by-4 complete block crossover design (Latin-Square), resulted in a dose-dependant reduction in CS and menace response time. Estimates of plasma Pb concentration taken prior to MES induction showed a similar dose-dependent reduction in CS and menace response time with concentration. Using a cumulative logistic regression model, a predicted 50% probability of a CS = 1 was approximately 11.4 mg/kg. In addition, plasma Pb concentrations predicted a 50% probability of a CS = 1 occurs at plasma Pb concentration of approximately 16.0 mug/mL. Combined these data suggest that MES is a useful model for evaluating generalized convulsions in canines and may provide a tool for dose selection of novel pharmaceutical compounds.

Publication types

  • Validation Study

MeSH terms

  • Animals
  • Anticonvulsants / administration & dosage
  • Anticonvulsants / pharmacokinetics*
  • Anticonvulsants / therapeutic use
  • Area Under Curve
  • Disease Models, Animal*
  • Dog Diseases / physiopathology*
  • Dogs / metabolism*
  • Dose-Response Relationship, Drug
  • Electroshock / veterinary
  • Epilepsy, Tonic-Clonic / drug therapy
  • Epilepsy, Tonic-Clonic / physiopathology
  • Epilepsy, Tonic-Clonic / veterinary*
  • Male
  • Phenobarbital / administration & dosage
  • Phenobarbital / pharmacokinetics*
  • Phenobarbital / therapeutic use
  • Reproducibility of Results

Substances

  • Anticonvulsants
  • Phenobarbital