Blood–brain barrier damage, but not parenchymal white blood cells, is a hallmark of seizure activity

Abstract

It has long been held that chronic seizures cause blood-brain barrier (BBB) damage. Recent studies have also demonstrated that BBB damage triggers seizures. We have used the BBB osmotic disruption procedure (BBBD) to examine the correlation between BBB opening, pattern of white blood cells (WBCs) entry into the brain and seizure occurrence. These findings were compared to results from resected epileptic brain tissue from temporal lobe epilepsy (TLE) patients.We confirmed that a successful BBB osmotic opening (BBBD) leads to the occurrence of acute epileptiform discharges. Electroencephalography (EEG) and time-joint frequency analysis reveal EEG slowing followed by an increase in the 10-20 Hz frequency range. Using green fluorescent protein (GFP)-labeled WBCs (GFP-WBCs) suspended in Evans Blue we found that, at time of BBB-induced epileptiform discharges, WBCs populated the perivascular space of a leaky BBB. Similar results were obtained at time of pilocarpine seizure. No frank WBCs extravasation in the brain parenchyma was observed.In TLE brain specimens, CD45-positive leukocytes were detected only in the vascular and perivascular spaces while albumin and IgG extravasates were parenchymal. The pattern was similar to those observed in rats.Our data suggest that neither acute-induced nor chronic seizures correlate with WBC brain parenchymal migration while albumin and IgG brain leakage is a hallmark of acute and chronic seizures.

Brain Infiltration of Leukocytes Contributes to the Pathophysiology of Temporal Lobe Epilepsy

“…Furthermore, neutrophils are also involved, as shown by antibody-mediated suppression (Fabene et al, 2008), underscoring the importance of systemic inflammation for ictogenesis. Finally, extravasation of plasma proteins and K ϩ ions contributes to SRSs in pilocarpine-treated rodents (Marchi et al, 2007(Marchi et al, , 2010, in line with proepileptogenic effects of BBB disruption (Friedman et al, 2009). The color denotes the severity of the lesion, as depicted with a representative image in E (yellow, mild lesion; blue, moderate lesion; red, severe lesion).…”

Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers

“…[205][206][207][208][209][210] Additionally, barrier leakage itself triggers seizures, suggesting a pernicious feedback loop contributing to epilepsy progression. [210][211][212] In this regard, MMPs most likely degrade tight junction and ECM proteins, which potentially contribute to barrier leakage after seizures.…”

The Blood-Brain Barrier and Epilepsy

“…Such assessment can be improved by semiquantitative analysis of brain slices by fluorescence microscopy or by quantitative determination of the dye in brain homogenates (Ahishali et al, 2010;Cardosa et al, 2010;Uzüm et al, 2006;Ilbay et al, 2003;You et al 2011). Most tracers are labeled by a fluorescent dye or radioactive label that helps the quantification of the molecule (Marchi & Teng, 2010). To determine the limiting size for permeability, different molecular weight tracers can be used, such as fluorescent conjugated dextran (20-,10-and 4-kDa FITC-dextran), propidiumiodide (668 Da), and sodium fluorescein (376 Da).…”

“…Such markers of BBB opening can be detected in the blood in order to evaluate the permeability characteristics of the BBB. However, these methods do not offer spatial information, are invasive, may give false positive results in the presence of intracerebral hemorrhage and S100 levels may depend on the extent of injury or activation of brain astrocytes Marchi et al, 2010;Marchi et al, 2011a). …”

“…Spectral EEG analysis reveals slow (delta band) activity in regions showing BBB disruption. The usage of quantitative EEG analysis and the detection of abnormal BBB permeability may give information not only about the identification of the epilectic region, but also for targeting population at risk to develop epilepsy Mairinger et al, 2011;Marchi et al, 2010;Tomkins et al, 2007) A B Fig. 6.…”