title: Reversal of postischemic hypoperfusion by tempol: endothelial signal transduction mechanism.
abstract: This report entails in vivo and in vitro studies concerned with free radical species involved in brain ischemia. The participation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the early manifestation of cerebral ischemia/reperfusion was investigated in gerbils exposed to transient global ischemia using 4-OH-2,2,6,6-tetramethylpiperidine-1-oxyl (TPL), a well-known antioxidant. TPL treatment reversed cerebral postischemic hypoperfusion and tissue edema in these animals. The findings are consistent with ROS/RNS participation in tissue injury and the reduction of cerebromicrovascular blood flow (CBF) during postischemic recirculation. The activation/deactivation of signal transduction pathway by oxidation/antioxidation [i.e., using hydrogen peroxide (H₂O₂)/TPL] was evaluated in cultured human brain endothelial cells (HBEC) to assess the involvement of endothelial-dependent mechanisms. The data showed that H₂O₂ activates various "stress" kinases and vasodilalator-stimulated phosphoprotein (VASP); activation of this pathway was reduced by inhibitors of Rho- or IP-3 kinases, as well as TPL. H₂O₂ also induced cytoskeleton (actin) rearrangements in HBEC; this effect was prevented by inhibitors of Rho/IP3 kinase or TPL. The observed activation/deactivation of H₂O₂-induced "stress" kinase is in agreement with the reported capacity of ROS/RNS to stimulate the oxidative signal transduction pathway. The noted TPL reduction of H₂O₂-induced phosphorylation of kinase strongly suggests that the beneficial effect of TPL implicates the stress signal transduction pathway. This may represent a mechanism for the cerebral postischemic manifestations observed by in vivo experiments.
authors.affiliation: Neuro Trauma Department, Operational and Undersea Medicine, Naval Medical Research Center, 503 Robert Grant Ave., Silver Spring, MD 20910-7500, USA.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Okada
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Teranishi
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.forename: Toshiki
authors.initials: T
authors.lastname: Tomori
authors.forename: Alois
authors.initials: A
authors.lastname: Strasser
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Lenz
authors.forename: Richard M
authors.initials: RM
authors.lastname: McCarron
authors.forename: Maria
authors.initials: M
authors.lastname: Spatz
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology* / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005849:Gerbillinae; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013113:Spin Labels
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; C001803:tempol