Abstracts

Rationale: Blood-brain barrier (BBB) disruption is a key element in the pathogenesis of epilepsy. Previous studies have shown that BBB disruption allows immune cells, inflammatory mediators, and albumin to infiltrate the brain parenchyma, lower the seizure threshold, and promote epileptogenesis. However, the mechanisms underlying the complex interplay between BBB disruption and brain inflammation, and subsequent effects on seizure susceptibility and progression, remain unclear. Methods: In this study, we use a GABA inhibitor, flurothyl, to determine whether seizure-induced BBB permeability and inflammation affect the seizure threshold and seizure progression. BBB integrity was assessed using Evans blue dye (EBD), a tracer for serum albumin. Immunohistochemistry of fixed brain tissue was used to assess neuronal activity, cell death, and astroglial activation. Results: Our results show that the BBB remains intact during flurothyl-induced myoclonic jerks (MJ), but is disrupted upon reaching generalized tonic-clonic seizures (GTCS) (p<0.05, n≥12). We observe an increase in neuronal activity, cell death, and astroglial activation following flurothyl-induced GTCS (p<0.05, n≥8). In addition, increased BBB permeability contributes to seizure progression, but does not correlate with changes in seizure threshold. Treatment with an FDA-approved drug, Losartan, inhibits BBB disruption, leading to an increased latency to GTCS and slower seizure progression (p<0.05, n≥6). Losartan-treated mice also show a decrease in neuronal activity, cell death, and reactive astrogliosis. Conclusions: Altogether, these results suggest that inflammation and neuronal excitability due to an increase in BBB disruption occurring between the first MJ and GTCS contribute to seizure progression. This study is supported by Northwestern University Feinberg School of Medicine. Funding: No funding