RRC ID 32807
Author Hirayama Y, Ikeda-Matsuo Y, Notomi S, Enaida H, Kinouchi H, Koizumi S.
Title Astrocyte-mediated ischemic tolerance.
Journal J Neurosci
Abstract Preconditioning (PC) using a preceding sublethal ischemic insult is an attractive strategy for protecting neurons by inducing ischemic tolerance in the brain. Although the underlying molecular mechanisms have been extensively studied, almost all studies have focused on neurons. Here, using a middle cerebral artery occlusion model in mice, we show that astrocytes play an essential role in the induction of brain ischemic tolerance. PC caused activation of glial cells without producing any noticeable brain damage. The spatiotemporal pattern of astrocytic, but not microglial, activation correlated well with that of ischemic tolerance. Interestingly, such activation in astrocytes lasted at least 8 weeks. Importantly, inhibiting astrocytes with fluorocitrate abolished the induction of ischemic tolerance. To investigate the underlying mechanisms, we focused on the P2X7 receptor as a key molecule in astrocyte-mediated ischemic tolerance. P2X7 receptors were dramatically upregulated in activated astrocytes. PC-induced ischemic tolerance was abolished in P2X7 receptor knock-out mice. Moreover, our results suggest that hypoxia-inducible factor-1α, a well known mediator of ischemic tolerance, is involved in P2X7 receptor-mediated ischemic tolerance. Unlike previous reports focusing on neuron-based mechanisms, our results show that astrocytes play indispensable roles in inducing ischemic tolerance, and that upregulation of P2X7 receptors in astrocytes is essential.
Volume 35(9)
Pages 3794-805
Published 2015-3-4
DOI 10.1523/JNEUROSCI.4218-14.2015
PII 35/9/3794
PMID 25740510
PMC PMC6605570
MeSH Animals Astrocytes / metabolism Astrocytes / pathology* Brain Ischemia / pathology* Erythropoietin / biosynthesis Erythropoietin / genetics Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis Hypoxia-Inducible Factor 1, alpha Subunit / genetics Infarction, Middle Cerebral Artery / pathology Ischemic Attack, Transient / pathology Ischemic Preconditioning Mice Mice, Inbred C57BL Mice, Knockout Microglia / physiology Receptors, Purinergic P2X7 / biosynthesis Receptors, Purinergic P2X7 / genetics
IF 5.674
Times Cited 55