Chronically epileptic human and rat neocortex display a similar resistance against spreading depolarization in vitro

TY - JOUR

T1 - Chronically epileptic human and rat neocortex display a similar resistance against spreading depolarization in vitro

AU - Maslarova, Anna

AU - Alam, Mesbah

AU - Reiffurth, Clemens

AU - Lapilover, Ezequiel

AU - Gorji, Ali

AU - Dreier, Jens P

PY - 2011/10

Y1 - 2011/10

N2 - BACKGROUND AND PURPOSE: Experimental and clinical evidence suggests that prolonged spreading depolarizations (SDs) are a promising target for therapeutic intervention in stroke because they recruit tissue at risk into necrosis by protracted intracellular calcium surge and massive glutamate release. Unfortunately, unlike SDs in healthy tissue, they are resistant to drugs such as N-methyl-d-aspartate-receptor antagonists. This drug resistance of SD in low perfusion areas may be due to the gradual rise of extracellular potassium before SD onset. Brain slices from patients undergoing surgery for intractable epilepsy allow for screening of drugs, targeting pharmacoresistant SDs under elevated potassium in human tissue. However, network changes associated with epilepsy may interfere with tissue susceptibility to SD. This could distort the results of pharmacological tests.METHODS: We investigated the threshold for SD, induced by a gradual rise of potassium, in neocortex slices of patients with intractable epilepsy and of chronically epileptic rats as well as age-matched and younger control rats using combined extracellular potassium/field recordings and intrinsic optical imaging.RESULTS: Both age and epilepsy significantly increased the potassium threshold, which was similarly high in epileptic rat and human slices (23.6±2.4 mmol/L versus 22.3±2.8 mmol/L).CONCLUSIONS: Our results suggest that chronic epilepsy confers resistance against SD. This should be considered when human tissue is used for screening of neuroprotective drugs. The finding of similar potassium thresholds for SD in epileptic human and rat neocortex challenges previous speculations that the resistance of the human brain against SD is markedly higher than that of the rodent brain.

AB - BACKGROUND AND PURPOSE: Experimental and clinical evidence suggests that prolonged spreading depolarizations (SDs) are a promising target for therapeutic intervention in stroke because they recruit tissue at risk into necrosis by protracted intracellular calcium surge and massive glutamate release. Unfortunately, unlike SDs in healthy tissue, they are resistant to drugs such as N-methyl-d-aspartate-receptor antagonists. This drug resistance of SD in low perfusion areas may be due to the gradual rise of extracellular potassium before SD onset. Brain slices from patients undergoing surgery for intractable epilepsy allow for screening of drugs, targeting pharmacoresistant SDs under elevated potassium in human tissue. However, network changes associated with epilepsy may interfere with tissue susceptibility to SD. This could distort the results of pharmacological tests.METHODS: We investigated the threshold for SD, induced by a gradual rise of potassium, in neocortex slices of patients with intractable epilepsy and of chronically epileptic rats as well as age-matched and younger control rats using combined extracellular potassium/field recordings and intrinsic optical imaging.RESULTS: Both age and epilepsy significantly increased the potassium threshold, which was similarly high in epileptic rat and human slices (23.6±2.4 mmol/L versus 22.3±2.8 mmol/L).CONCLUSIONS: Our results suggest that chronic epilepsy confers resistance against SD. This should be considered when human tissue is used for screening of neuroprotective drugs. The finding of similar potassium thresholds for SD in epileptic human and rat neocortex challenges previous speculations that the resistance of the human brain against SD is markedly higher than that of the rodent brain.

KW - Animals

KW - Cortical Spreading Depression

KW - Epilepsy

KW - Humans

KW - Male

KW - Neocortex

KW - Pilocarpine

KW - Rats

KW - Rats, Wistar

KW - Journal Article

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

U2 - 10.1161/STROKEAHA.111.621581

DO - 10.1161/STROKEAHA.111.621581

M3 - SCORING: Journal article

C2 - 21836085

VL - 42

SP - 2917

EP - 2922

JO - STROKE

JF - STROKE

SN - 0039-2499

IS - 10

ER -