Blood-brain Barrier Damage in the Pentylenetetrazole Generalized Seizure Model Mice Using Gadolinium-enhanced Magnetic Resonance Imaging

Abstract

Aims: Although epilepsy is a common disease, the pathological process has not been sufficiently elucidated. Previous studies have reported that blood-brain barrier (BBB) damage is involved in epileptogenesis. Our aim was to non-invasively and sequentially evaluate BBB damage in a mouse model of generalised seizure, using Gadolinium (Gd)-enhanced magnetic resonance imaging using T1 weighting (GdET1WI). In addition, we assessed whether or not valproate (VPA) could prevent BBB damage. Methods: Mice were kindled with the daily intraperitoneal administration of 40 mg/kg pentylenetetrazole (PTZ). After each PTZ injection, convulsive behaviours were observed, and seizures were scored from 0 to 5. Five consecutive scores of 4 or 5 were required to ensure kindling. We evaluated the changes in the BBB damage using the signal intensity (SI) ratio of GdET1WI. The SI was sequentially measured at baseline, score 1, score 3, PTZ-kindled, and 1-week post-kindled after PTZ withdrawal. In addition, the SI was measured in mice pretreated with VPA before PTZ injection. Results: The SI values (means±standard error of the mean) at score 1, score 3, PTZ-kindled, and post-kindled increased to 0.70%±0.22%, 7.17%±1.86%, 7.43%±1.60%, and 6.82%±1.27%, respectively, compared to baseline. All values (except at score 1) were significantly higher than those at baseline (p-value < 0.05). We did not observe significant differences between score 3 or post-kindled and PTZ-kindled. In VPA-pretreated mice, the SI significantly increased to 8.77%±1.57% compared to baseline, although convulsions were fully controlled. Conclusion: Our data suggest that BBB damage started before PTZ-induced kindling was acquired. The BBB damage was irreversible after PTZ-induced kindling. In addition, VPA prevented epileptic convulsive seizures but could not suppress BBB damage in PTZ-kindled mice.