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

Evidence Implicating Blood-Brain Barrier Impairment in the Pathogenesis of Acquired Epilepsy following Acute Organophosphate Intoxication

“…In parallel, levels of reactive oxygen and nitrogen species are increased ( Puttachary et al, 2015 ; Pearson and Patel, 2016 ; Vanova et al, 2018 ; Guignet and Lein, 2019 ; Gage et al, 2021 ; Meyer et al, 2023 ). Interestingly, the spatiotemporal distribution of neuroinflammation observed in preclinical models of acute OP intoxication during the first week postexposure ( Flannery et al, 2016 ; Bar-Klein et al, 2017 ; Sisó et al, 2017 ) is very similar to that reported in a recent study of the regional characterization of BBB impairment ( Bernardino et al, 2023 ). However, no mechanistic or causal associations have yet been investigated between these two processes in the context of acute OP intoxication.…”

“…Critically, biomarkers of BBB dysfunction correlate with the development and progression of epilepsy in humans and in diverse preclinical models ( Tenreiro et al, 2016 ; Bar-Klein et al, 2017 ; Dadas and Janigro, 2019 ; Mendes et al, 2019 ; Nation et al, 2019 ), suggesting a potential antiepileptogenic benefit of protecting BBB function. Although this hypothesis has yet to be tested in models of acute OP intoxication, recent studies have reported BBB impairment following acute OP intoxication ( Abdel-Rahman et al, 2002 ; Song et al, 2004 ; Bar-Klein et al, 2017 ; Rojas et al, 2021 , 2022 ; Bernardino et al, 2023 ).…”

A longitudinal MRI and TSPO PET-based investigation of brain region-specific neuroprotection by diazepam versus midazolam following organophosphate-induced seizures

“…When combined with the evidence of microbleeds in the piriform cortex and hippocampus, these observations suggest dysfunction in the neurovascular unit (NVU), such as blood brain barrier (BBB) breakdown or frank compromise of vessel integrity (reviewed in Michinaga and Koyama, 2015 ). Exposure to OP pesticides at levels that did not produce acute cholinergic crisis in juvenile rats has been shown to impair the BBB ( Gupta et al, 1999 ; Song et al, 2004 ), and acute intoxication with OPs has been reported to cause leakage of albumin into brain parenchyma up to 48 h post exposure in rats ( Bernardino et al, 2023a ). Extravasation of circulating immune cells and/or plasma proteins into brain parenchyma may contribute to the persistent inflammation we observed by TSPO PET imaging ( Bernardino et al, 2023a ).…”

“…Exposure to OP pesticides at levels that did not produce acute cholinergic crisis in juvenile rats has been shown to impair the BBB ( Gupta et al, 1999 ; Song et al, 2004 ), and acute intoxication with OPs has been reported to cause leakage of albumin into brain parenchyma up to 48 h post exposure in rats ( Bernardino et al, 2023a ). Extravasation of circulating immune cells and/or plasma proteins into brain parenchyma may contribute to the persistent inflammation we observed by TSPO PET imaging ( Bernardino et al, 2023a ). Assessment of hippocampal volumes at 3 d post-DFP identified an increase in hippocampal volume consistent with swelling following NVU breakdown.…”

“…While it has been previously reported that administration of hyperosmolar therapies to attenuate vasogenic edema were ineffective in a mouse model of soman poisoning ( Carpentier et al, 2008 ), the intervention was limited to a single dose at 5 h post-soman intoxication. NVU dysfunction has been detected at one week ( Bernardino et al, 2023a ) and one month ( Bar-Klein et al, 2017 ) post OP intoxication; however the underlying mechanisms behind these effects and their time course remain largely limited to the first few days post OP intoxication ( Abdel-Rahman et al, 2002 ; Bernardino et al 2023a , 2023b ; Rojas et al, 2022 ). Additional studies are required to characterize the integrity of the NVU and its components, particularly pericytes, following acute OP intoxication.…”