Dose escalation in pentylenetetrazol kindling detects differences in chronic seizure susceptibility.

Abstract

Pentylenetetrazol (PTZ) kindling is a widely used model for inducing epileptogenesis and evaluating long-term seizure susceptibility differences among animals. This model is typically performed by chronic, repetitive exposures to a constant subconvulsive PTZ dose. However, the effectiveness of the commonly used dose (35 mg/kg) varies among different animal groups due to factors such as species, age, sex, and genetic background. This study characterizes a novel kindling approach, the PTZ Dose Escalation (PTZ-DE) model, which assesses chronic seizure threshold with enhanced sensitivity by empirically determining the minimally effective dose to induce PTZ kindling for specific experimental conditions. The efficacy and validity of the PTZ-DE model were compared to the standard PTZ kindling approach. First, the characteristic increase in chronic seizure response was compared between PTZ-DE and the standard model across animal characteristics (strain, sex). Next, the PTZ-DE model's validity was assessed by determining whether PTZ-DE could replicate the increased chronic seizure susceptibility previously reported using the standard approach after traumatic brain injury (TBI). Lastly, the PTZ-DE model's effectiveness in detecting seizure differences was measured in a condition (glyburide treatment) where alterations to chronic seizure susceptibility were not detected with standard kindling. This study observed that, compared to the standard model, the PTZ-DE model corrects for background differences in PTZ susceptibility, replicates known alterations in chronic seizure thresholds, and uncovers changes in seizure threshold previously unidentified by the standard approach. The PTZ-DE model may be a superior approach for discovering new pathological mechanisms of epileptogenesis and for developing targeted therapies for seizure management.