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.
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 epilepticrats 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 epilepticrat 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 epileptichuman and rat neocortex challenges previous speculations that the resistance of the human brain against SD is markedly higher than that of the rodent brain.
Authors: David Y Chung; Homa Sadeghian; Tao Qin; Sevda Lule; Hang Lee; Fahri Karakaya; Stacy Goins; Fumiaki Oka; Mohammad A Yaseen; Thijs Houben; Else A Tolner; Arn M J M van den Maagdenberg; Michael J Whalen; Sava Sakadžic; Cenk Ayata Journal: Cereb Cortex Date: 2019-03-01 Impact factor: 5.357
Authors: Jens P Dreier; Thomas Isele; Clemens Reiffurth; Nikolas Offenhauser; Sergei A Kirov; Markus A Dahlem; Oscar Herreras Journal: Neuroscientist Date: 2012-07-24 Impact factor: 7.519
Authors: E G Lapilover; K Lippmann; S Salar; A Maslarova; J P Dreier; U Heinemann; A Friedman Journal: Neurobiol Dis Date: 2012-07-07 Impact factor: 5.996
Authors: Péter Hertelendy; Ákos Menyhárt; Péter Makra; Zoltán Süle; Tamás Kiss; Gergely Tóth; Orsolya Ivánkovits-Kiss; Ferenc Bari; Eszter Farkas Journal: J Cereb Blood Flow Metab Date: 2016-01-01 Impact factor: 6.200
Authors: Jens P Dreier; Martin Fabricius; Cenk Ayata; Oliver W Sakowitz; C William Shuttleworth; Christian Dohmen; Rudolf Graf; Peter Vajkoczy; Raimund Helbok; Michiyasu Suzuki; Alois J Schiefecker; Sebastian Major; Maren Kl Winkler; Eun-Jeung Kang; Denny Milakara; Ana I Oliveira-Ferreira; Clemens Reiffurth; Gajanan S Revankar; Kazutaka Sugimoto; Nora F Dengler; Nils Hecht; Brandon Foreman; Bart Feyen; Daniel Kondziella; Christian K Friberg; Henning Piilgaard; Eric S Rosenthal; M Brandon Westover; Anna Maslarova; Edgar Santos; Daniel Hertle; Renán Sánchez-Porras; Sharon L Jewell; Baptiste Balança; Johannes Platz; Jason M Hinzman; Janos Lückl; Karl Schoknecht; Michael Schöll; Christoph Drenckhahn; Delphine Feuerstein; Nina Eriksen; Viktor Horst; Julia S Bretz; Paul Jahnke; Michael Scheel; Georg Bohner; Egill Rostrup; Bente Pakkenberg; Uwe Heinemann; Jan Claassen; Andrew P Carlson; Christina M Kowoll; Svetlana Lublinsky; Yoash Chassidim; Ilan Shelef; Alon Friedman; Gerrit Brinker; Michael Reiner; Sergei A Kirov; R David Andrew; Eszter Farkas; Erdem Güresir; Hartmut Vatter; Lee S Chung; K C Brennan; Thomas Lieutaud; Stephane Marinesco; Andrew Ir Maas; Juan Sahuquillo; Markus A Dahlem; Frank Richter; Oscar Herreras; Martyn G Boutelle; David O Okonkwo; M Ross Bullock; Otto W Witte; Peter Martus; Arn Mjm van den Maagdenberg; Michel D Ferrari; Rick M Dijkhuizen; Lori A Shutter; Norberto Andaluz; André P Schulte; Brian MacVicar; Tomas Watanabe; Johannes Woitzik; Martin Lauritzen; Anthony J Strong; Jed A Hartings Journal: J Cereb Blood Flow Metab Date: 2016-01-01 Impact factor: 6.200