Astrocyte-mediated ischemic tolerance.
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.
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Department of Liaison Academy, Faculty of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
Yuri
Y
Hirayama
Department of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
Yuri
Y
Ikeda-Matsuo
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Shoji
S
Notomi
Department of Ophthalmology, Faculty of Medicine, Saga University, Saga, 849-0937, Japan.
Hiroshi
H
Enaida
Department of Neurosurgery, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan, and.
Hiroyuki
H
Kinouchi
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo 102-0076, Japan skoizumi@yamanashi.ac.jp.
Schuichi
http://orcid.org/0000-0001-6184-3106
S
Koizumi
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000473:pathology; D019194:Ischemic Preconditioning; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology; D058486:Receptors, Purinergic P2X7 / Q000096:biosynthesis / Q000235:genetics
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D058486:Receptors, Purinergic P2X7; D004921:Erythropoietin
HIF-1α; P2X7 receptor; astrocytes; ischemic tolerance; neuroprotection; preconditioning