title: In vivo and in vitro characterization of a novel neuroprotective strategy for stroke: ischemic postconditioning.
abstract: As clinical trials of pharmacological neuroprotective strategies in stroke have been disappointing, attention has turned to the brain's own endogenous strategies for neuroprotection. Recently, a hypothesis has been offered that modified reperfusion subsequent to a prolonged ischemic episode may also confer ischemic neuroprotection, a phenomenon termed 'postconditioning'. Here we characterize both in vivo and in vitro models of postconditioning in the brain and offer data suggesting a biological mechanism for protection. Postconditioning treatment reduced infarct volume by up to 50% in vivo and by approximately 30% in vitro. A duration of 10 mins of postconditioning ischemia after 10 mins of reperfusion produced the most effective postconditioning condition both in vivo and in vitro. The degree of neuroprotection after postconditioning was equivalent to that observed in models of ischemic preconditioning. However, subjecting the brain to both preconditioning as well as postconditioning did not cause greater protection than each treatment alone. The prosurvival protein kinases extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and Akt show prolonged phosphorylation in the cortex of postconditioned rats. Neuroprotection after postconditioning was inhibited only in the presence of LY294002, which blocks Akt activation, but not U0126 or SB203580, which block ERK and P38 MAP kinase activity. In contrast, preconditioning-induced protection was blocked by LY294002, U0126, and SB203580. Our data suggest that postconditioning may represent a novel neuroprotective approach for focal ischemia/reperfusion, and one that is mediated, at least in part, by the activation of the protein kinase Akt.
authors: Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA.
authors: Giuseppe
authors: G
authors: Pignataro
authors: Robert
authors: R
authors: Meller
authors: Koichi
authors: K
authors: Inoue
authors: Andrea N
authors: AN
authors: Ordonez
authors: Michelle D
authors: MD
authors: Ashley
authors: Zhigang
authors: Z
authors: Xiong
authors: Rosaria
authors: R
authors: Gala
authors: Roger P
authors: RP
authors: Simon
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000628:therapy*; D016923:Cell Death; D002560:Cerebrovascular Circulation / Q000502:physiology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D020521:Stroke / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases