Chronically Epileptic Human and Rat Neocortex Display a Similar Resistance Against Spreading Depolarization In Vitro

Abstract

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 (23.6Ϯ2.4 mmol/L versus 22.3Ϯ2.8 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. (Stroke. 2011;42:2917-2922.)

The Stroke-Migraine Depolarization Continuum

“…By contrast, both repeated IEEs and SDs seem to have inhibiting or ''anti-kindling'' effects on SD; supporting evidence includes the following: (1) in various models, the susceptibility to SD decreased during epileptogenesis (Kö hling et al, 2003;Maslarova et al, 2011;Tomkins et al, 2007), (2) SDs do not invade penicillin-induced epileptic foci but typically circulate around them (Koroleva and Bures, 1979), (3) single daily SDs induced for 1 or 2 weeks in mice decreased the susceptibility to SD (Sukhotinsky et al, 2011), and (4) even within the same cluster of SDs, subsequent SDs typically propagate through a smaller region than the first SD (James et al, 1999). In the light of these observations, it appears that there are strikingly different types of pathologic hyperexcitability states in the brain which can be associated with either increased or decreased susceptibility to SD.…”

“…The potassium threshold for SD in neocortical slices is between $12 mM in young and $16 mM in older animals (Maslarova et al, 2011). The threshold seems to be in a similar range in neocortex in vivo (Petzold et al, 2005b), but due to glial buffering, the potassium gradient between artificial cerebrospinal fluid (ACSF) and cortex is steep when potassium is applied topically to the brain.…”

Spreading Depolarization, A Pathophysiological Mechanism of Stroke and Migraine Aura

“…Among the differences is an anti-thetic susceptibility to spreading depolarization. It was thus demonstrated recently that the potassium threshold for spreading depolarization was not lowered but markedly elevated in neocortex slices from chronically epileptic rats compared with agematched controls, and this threshold of chronically epileptic rodent tissue was in fact similarly high as that of neocortex slices from patients with intractable epilepsy [103]. In a similar fashion, Köhling and colleagues reported that the GABA A receptor antagonist bicuculline readily induced spreading depolarizations in neocortex slices from healthy rats whereas, in chronically epileptic neocortex slices from rats or patients, bicuculline failed [102].…”

Advancing age and ischemia elevate the electric threshold to elicit spreading depolarization in the cerebral cortex of young adult rats

“…13 On the other hand, the aging nervous tissue proves to be increasingly resistant to experimental SD elicitation, requiring rising concentration of K þ to trigger SD. 14,15 Similarly, the likelihood of spontaneous SD occurrence in the ischemic rat cortex decreases with age. 16 It is, however, uncertain at what age the threshold of SD elicitation starts to rise, especially in ischemic tissue.…”