Time- and region-dependent blood-brain barrier impairment in a rat model of organophosphate-induced status epilepticus

Pedro N. Bernardino, Brad A. Hobson, Sydney L. Huddleston, Peter M. Andrew, Jeremy A. MacMahon, Naomi H. Saito, Valerie A. Porter, Donald A. Bruun, Danielle J. Harvey, Joel R. Garbow, Angie Gelli, Abhijit J. Chaudhari, Pamela J. Lein

Research output: Contribution to journalArticlepeer-review

Abstract

Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication.

Original languageEnglish
Article number106316
JournalNeurobiology of Disease
Volume187
DOIs
StatePublished - Oct 15 2023

Keywords

  • Albumin
  • Blood-brain barrier impairment
  • Diisopropylfluorophosphate
  • Epilepsy
  • MRI
  • Organophosphate
  • Spontaneous recurrent seizures

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