Effects of Dantrolene on Extracellular Glutamate Concentration and Neuronal Death in the Rat Hippocampal CA1 Region Subjected to Transient Ischemia

Abstract

Intracerebroventricular dantrolene prevents delayed neuronal loss in the rat hippocampal CA1 region subjected to transient ischemia; however, this neuroprotection cannot be accounted for only by the reduced concentrations of extracellular glutamate during ischemia.

Ischemia Enhances Activation by Ca2+and Redox Modification of Ryanodine Receptor Channels from Rat Brain Cortex

“…The importance of our results resides in the fact that, at the concentrations of Mg 2ϩ and ATP present in the cytoplasm, only high activity channels, such as those that preferentially emerged during ischemia, are sufficiently activated by Ca 2ϩ to sustain CICR (Bull et al, 2007). Previous experiments, showing that RyR inhibition with dantrolene reduces the sustained [Ca 2ϩ ] increase and the subsequent neuronal death in animal models of ischemia, support the hypothesis that RyR channels mediate CICR during ischemia (Frandsen and Schousboe, 1991;Zhang et al, 1993;Wei and Perry, 1996;Yano et al, 2001;Clodfelter et al, 2002;Nakayama et al, 2002;Li et al, 2005). We propose that local production of reactive species caused by ischemia initially increases markedly the high activity response of RyR channels by S-glutathionylation of RyR2 and thus facilitates RyR-mediated CICR in brain cortex and steadily amplifies the cytoplasmic [Ca 2ϩ ] increase produced by ischemia-enhanced Ca 2ϩ entry.…”

Endoplasmic Reticulum Ca2+Handling in Excitable Cells in Health and Disease

“…Ischemia-reperfusion damage to the heart (myocardial infarction) and brain (stroke) is a common cause of morbidity and mortality. The ischemic damage involves cellular Ca 2ϩ overload, and dantrolene treatment can reduce cellular damage and cell death and can improve functional outcome in animal models of myocardial infarction, stroke, and ischemia (Wei and Perry, 1996;Nakayama et al, 2002;Muehlschlegel and Sims, 2009;Boys et al, 2010). Preclinical studies also showed that dantrolene can protect neurons against damage caused by amyloid ␤-peptide in an experimental in vitro model relevant to Alzheimer disease (Guo et al, 1997).…”

Na+ and Ca2+ homeostasis pathways, cell death and protection after oxygen–glucose-deprivation in organotypic hippocampal slice cultures

“…Different SERCA inhibitors have been described to trigger toxicity in neuronal cultures through an apoptotic pathway (Nguyen et al, 2002). By contrast, blockade of endoplasmic reticulum Ca 2ϩ release via the ryanodine-sensitive receptors reduced the [Ca 2ϩ ] i rise induced by oxygen-glucose-deprivation (OGD) in hippocampal slices and the neuronal vulnerability in in vivo ischemic models (Nakayama et al, 2002;Zhang et al, 1993).…”