Role of the ryanodine receptor in ischemic brain damage - Localized reduction of ryanodine receptor binding during ischemia in hippocampus CA1

1. The ryanodine receptor has recently been shown to play a pivotal role in the regulation of intracellular Ca2+ concentration via Call-induced Ca2+ r elease (CICR). Effects of ischemia on CICR in the brain tissue, however, re main largely unknown since only a few reports have been published on this s ubject. In this paper we report on work in this area by our group and revie w related progress in this field. 2. We examined alterations of ryanodine receptor binding and local cerebral blood how (LCBF) at 15 min, 30 min, and 2 hr after occlusion of the right common carotid artery in the gerbil brain. A quantitative autoradiographic method permitted simultaneous measurement of these parameters in the same b rain. The LCBF was significantly reduced in most of the cerebral regions on the occluded side during each time period of ischemia. In contrast, only i n the hippocampus CA 1 on the occluded side was a significant reduction in ryanodine binding found at 15 min, 30 min and 2 hr after the occlusion. 3. These findings suggest that suppression of ryanodine binding in the hipp ocampus CA1 may be attributable to a regionally specific perturbation of CI CR and that this perturbation may be closely associated with the pathophysi ological mechanism that leads to the selective ischemic vulnerability of th is region. 4. Other recent studies have also reported an important role for ryanodine receptors in neuronal injury such as the delayed neuronal death in the hjpp ocampus CA1. These data suggest that derangement of CICR is likely to be in volved in acute neuronal necrosis as well as in delayed neuronal death in i schemia. 5. Further studies on clarifying the role of CICR in ischemic brain damage are needed in order to develop new therapeutic strategies for stroke patien ts.