Peri-infarct blood-brain barrier dysfunction facilitates induction of spreading depolarization associated with epileptiform discharges

TY - JOUR

T1 - Peri-infarct blood-brain barrier dysfunction facilitates induction of spreading depolarization associated with epileptiform discharges

AU - Lapilover, E G

AU - Lippmann, Kristina

AU - Salar, Seda

AU - Maslarova, Anna

AU - Dreier, Jens P

AU - Heinemann, U

AU - Friedman, Ariella A

N1 - Copyright © 2012 Elsevier Inc. All rights reserved.

PY - 2012/12

Y1 - 2012/12

N2 - Recent studies showed that spreading depolarizations (SDs) occurs abundantly in patients following ischemic stroke and experimental evidence suggests that SDs recruit tissue at risk into necrosis. We hypothesized that BBB opening with consequent alterations of the extracellular electrolyte composition and extravasation of albumin facilitates generation of SDs since albumin mediates an astrocyte transcriptional response with consequent disturbance of potassium and glutamate homeostasis. Here we show extravasation of Evans blue-albumin complex into the hippocampus following cortical photothrombotic stroke in the neighboring neocortex. Using extracellular field potential recordings and exposure to serum electrolytes we observed spontaneous SDs in 80% of hippocampal slices obtained from rats 24 h after cortical photothrombosis. Hippocampal exposure to albumin for 24 h through intraventricular application together with serum electrolytes lowered the threshold for the induction of SDs in most slices irrespective of the pathway of stimulation. Exposing acute slices from naive animals to albumin led also to a reduced SD threshold. In albumin-exposed slices the onset of SDs was usually associated with larger stimulus-induced accumulation of extracellular potassium, and preceded by epileptiform activity, which was also observed during the recovery phase of SDs. Application of ifenprodil (3 μM), an NMDA-receptor type 2 B antagonist, blocked stimulus dependent epileptiform discharges and generation of SDs in slices from animals treated with albumin in-vivo. We suggest that BBB opening facilitates the induction of peri-infarct SDs through impaired homeostasis of K+.

AB - Recent studies showed that spreading depolarizations (SDs) occurs abundantly in patients following ischemic stroke and experimental evidence suggests that SDs recruit tissue at risk into necrosis. We hypothesized that BBB opening with consequent alterations of the extracellular electrolyte composition and extravasation of albumin facilitates generation of SDs since albumin mediates an astrocyte transcriptional response with consequent disturbance of potassium and glutamate homeostasis. Here we show extravasation of Evans blue-albumin complex into the hippocampus following cortical photothrombotic stroke in the neighboring neocortex. Using extracellular field potential recordings and exposure to serum electrolytes we observed spontaneous SDs in 80% of hippocampal slices obtained from rats 24 h after cortical photothrombosis. Hippocampal exposure to albumin for 24 h through intraventricular application together with serum electrolytes lowered the threshold for the induction of SDs in most slices irrespective of the pathway of stimulation. Exposing acute slices from naive animals to albumin led also to a reduced SD threshold. In albumin-exposed slices the onset of SDs was usually associated with larger stimulus-induced accumulation of extracellular potassium, and preceded by epileptiform activity, which was also observed during the recovery phase of SDs. Application of ifenprodil (3 μM), an NMDA-receptor type 2 B antagonist, blocked stimulus dependent epileptiform discharges and generation of SDs in slices from animals treated with albumin in-vivo. We suggest that BBB opening facilitates the induction of peri-infarct SDs through impaired homeostasis of K+.

KW - Albumins

KW - Animals

KW - Blood-Brain Barrier

KW - Brain Infarction

KW - Capillary Permeability

KW - Disease Models, Animal

KW - Epilepsy

KW - Homeostasis

KW - Immunohistochemistry

KW - Male

KW - Organ Culture Techniques

KW - Patch-Clamp Techniques

KW - Potassium

KW - Rats

KW - Rats, Wistar

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.nbd.2012.06.024

DO - 10.1016/j.nbd.2012.06.024

M3 - SCORING: Journal article

C2 - 22782081

VL - 48

SP - 495

EP - 506

JO - NEUROBIOL DIS

JF - NEUROBIOL DIS

SN - 0969-9961

IS - 3

ER -