Role of Na+-H+ and Na+-Ca2+ exchange in hypoxia-related acute astrocyte death

✍ Scribed by Alexander Bondarenko; Nataliya Svichar; Mitchell Chesler

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 246 KB
• Volume: 49
• Category: Article
• ISSN: 0894-1491
• DOI: 10.1002/glia.20107

✦ Synopsis

Abstract

Cultured astrocytes do not succumb to hypoxia/zero glucose for up to 24 h, yet astrocyte death following injury can occur within 1 h. It was previously demonstrated that astrocyte loss can occur quickly when the gaseous and interstitial ionic changes of transient brain ischemia are simulated: After a 20–40‐min exposure to hypoxic, acidic, ion‐shifted Ringer (HAIR), most cells died within 30 min after return to normal saline (i.e., “reperfusion”). Astrocyte death required external Ca^2+^ and was blocked by KB‐R7943, an inhibitor of reversed Na^+^‐Ca^2+^ exchange, suggesting that injury was triggered by a rise in [Ca^2+^]~i~. In the present study, we confirmed the elevation of [Ca^2+^]~i~ during reperfusion and studied the role of Na^+^‐Ca^2+^ and Na^+^‐H^+^ exchange in this process. Upon reperfusion, elevation of [Ca^2+^]~i~ was detectable by Fura‐2 and was blocked by KB‐R7943. The low‐affinity Ca^2+^ indicator Fura‐FF indicated a mean [Ca^2+^]~i~ rise to 4.8 ± 0.4 μM. Loading astrocytes with Fura‐2 provided significant protection from injury, presumably due to the high affinity of the dye for Ca^2+^. Injury was prevented by the Na^+^‐H^+^ exchange inhibitors ethyl isopropyl amiloride or HOE‐694, and the rise of [Ca^2+^]~i~ at the onset of reperfusion was blocked by HOE‐694. Acidic reperfusion media was also protective. These data are consistent with Na^+^ loading via Na^+^‐H^+^ exchange, fostering reversal of Na^+^‐Ca^2+^ exchange and cytotoxic elevation of [Ca^2+^]~i~. The results indicate that mechanisms involved in pH regulation may play a role in the fate of astrocytes following acute CNS injuries. © 2004 Wiley‐Liss, Inc.