Reversal of postischemic hypoperfusion by tempol: Endothelial signal transduction mechanism

Tomoaki Okada, Kohsuke Teranishi, Ye Chen, Toshiki Tomori, Alois Strasser, Frederick Lenz, Richard M. McCarron, Maria Spatz

Research output: Contribution to journalArticle

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 cerebromi-crovascular 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 H 2O2 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. H 2O2 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.

Original languageEnglish (US)
Pages (from-to)680-688
Number of pages9
JournalNeurochemical Research
Volume37
Issue number4
DOIs
StatePublished - Apr 2012

Fingerprint

Reactive Nitrogen Species
Signal transduction
Reactive Oxygen Species
Signal Transduction
Inositol 1,4,5-trisphosphate 3-kinase
Phosphotransferases
Brain Ischemia
Brain
Chemical activation
Endothelial cells
Endothelial Cells
rho-Associated Kinases
Gerbillinae
Phosphoproteins
Tissue
Actin Cytoskeleton
Hydrogen Peroxide
Phosphorylation
Reperfusion
Free Radicals

Keywords

  • Antioxidants
  • Brain ischemia
  • Cerebral blood flow
  • Endothelium
  • Free radicals

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Biochemistry

Cite this

Reversal of postischemic hypoperfusion by tempol : Endothelial signal transduction mechanism. / Okada, Tomoaki; Teranishi, Kohsuke; Chen, Ye; Tomori, Toshiki; Strasser, Alois; Lenz, Frederick; McCarron, Richard M.; Spatz, Maria.

In: Neurochemical Research, Vol. 37, No. 4, 04.2012, p. 680-688.

Research output: Contribution to journalArticle

Okada, T, Teranishi, K, Chen, Y, Tomori, T, Strasser, A, Lenz, F, McCarron, RM & Spatz, M 2012, 'Reversal of postischemic hypoperfusion by tempol: Endothelial signal transduction mechanism', Neurochemical Research, vol. 37, no. 4, pp. 680-688. https://doi.org/10.1007/s11064-011-0595-y
Okada, Tomoaki ; Teranishi, Kohsuke ; Chen, Ye ; Tomori, Toshiki ; Strasser, Alois ; Lenz, Frederick ; McCarron, Richard M. ; Spatz, Maria. / Reversal of postischemic hypoperfusion by tempol : Endothelial signal transduction mechanism. In: Neurochemical Research. 2012 ; Vol. 37, No. 4. pp. 680-688.
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AB - 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 cerebromi-crovascular 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 H 2O2 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. H 2O2 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.

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