Ischemic tolerance (IT) is induced by a variety of insults to the brain (e.g., nonfatal ischemia, heat and hypoxia) and it provides a strong neuroprotective effect. Although the mechanisms are still not fully elucidated, Ca2+ is regarded as a key mediator of IT. Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of ca(2+) from intracellular stores. In brain, neuronal RyRs are thought to play a role in various neuropathological conditions, including ischemia. The purpose of the present study was to investigate the involvement of RyRs in IT. Pretreatment with a RyR antagonist, dantrolene (25 mg/kg, i.p), blocked IT in a gerbil global ischemia model, while a RyR agonist, caffeine (100 mg/kg, i.p), stimulated the production of IT. In vitro, using rat hippocampal cells, short-term oxygen/glucose deprivation induced preconditioning and RyR antagonists, dantrolene (50 and 100 mu M) and ryanodine (100 and 200 mu M) prevented it. RyR protein and mRNA levels were transiently decreased after induction of IT. These results suggest that RyRs are involved in the induction of ischemic tolerance. (C) 2016 Elsevier Inc. All rights reserved.