Dose Escalation in Pentylenetetrazol Kindling Detects Differences in Chronic Seizure Susceptibility

Abstract

Objective: 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 subconvulsive dose (35mg/kg) varies among different animal groups and experimental conditions due to factors such as species, age, sex, and genetic background. The objective of this study was to characterize a novel model of kindling, 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.

Methods: This study investigated the efficacy and validity of the PTZ-DE model by comparing its performance to the standard PTZ kindling approach across a series of conditions. First, the ability of the PTZ-DE model to produce the gradual increase in chronic seizure severity response characteristic of PTZ kindling was compared to the standard model across animal background characteristics (strain, sex). Next, the validity of this model was investigated by determining if the PTZ-DE model could replicate similar changes in chronic seizure susceptibility previously published using the standard approach after traumatic brain injury (TBI). Lastly, the PTZ-DE model's efficacy to detect seizure differences was measured in a condition (glyburide treatment) in which alterations to chronic seizure susceptibility were not detected with standard kindling.

Results: This study found that the PTZ-DE model corrects for background differences in PTZ susceptibility, replicates known differences in chronic seizure thresholds after TBI, and identifies new alterations in seizure threshold not detected with traditional kindling methods.

Significance: The PTZ-DE model may prove to be a superior tool to standard PTZ kindling for discovering new pathological mechanisms of epileptogenesis and for developing targeted therapies for chronic seizure management, as evidenced by its ability to detect subtle differences in seizure susceptibility across various experimental conditions.