Abstract
Hyperglycemia aggravates ischemic brain injury, possibly due to the activation of signaling pathways involving reactive oxygen species, Src and mitogen-activated protein kinases. The aim of this study was to investigate the effects of the spin trap agent α-phenyl-N-tert-butyl nitrone (PBN), the Src family kinase inhibitor PP2 and the MEK1-inhibitor U0126 on focal hyperglycemic ischemic brain injury. Temporary middle cerebral artery occlusion (90 min) was induced in four groups of rats (PBN, PP2, and U0126 vs. control). Neurological testing and tetrazolium red staining were performed after 1 day. PBN decreased the infarct volume by 70% compared with the control (P<0.05) and a tendency towards reduced infarcts was seen in the PP2 or U0126 groups. Furthermore, neurological testing was consistent with the volumetric analysis. In conclusion, PBN appears to be a potential neuroprotective agent in hyperglycemic, focal ischemic brain injury, while the efficacy of PP2 and U0126 could not be confirmed by the present data.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alessandrini A, Namura S, Moskowitz MA, Bonventre JV (1999) MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci USA 96:12866–12869
Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H (1986) Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17:472–476
Clausen F, Lundqvist H, Ekmark S, Lewen A, Ebendal T, Hillered L (2004) Oxygen free radical-dependent activation of extracellular signal-regulated kinase mediates apoptosis-like cell death after traumatic brain injury. J Neurotrauma 21:1168–1182
Farrokhnia N, Roos MW, Terent A, Lennmyr F (2005) Differential early mitogen-activated protein kinase activation in hyperglycemic ischemic brain injury in the rat. Eur J Clin Invest 35(7):457–463
Floyd RA (1999) Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 222:236–245
Folbergrova J, Zhao Q, Katsura K, Siesjo BK (1995) N-tert-butyl-alpha-phenylnitrone improves recovery of brain energy state in rats following transient focal ischemia. Proc Natl Acad Sci USA 92:5057–5061
Ginsberg MD, Prado R, Dietrich WD, Busto R, Watson BD (1987) Hyperglycemia reduces the extent of cerebral infarction in rats. Stroke 18:570–574
Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ, Pollok BA, Connelly PA (1996) Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J Biol Chem 271:695–701
Irving EA, Barone FC, Reith AD, Hadingham SJ, Parsons AA (2000) Differential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat. Brain Res Mol Brain Res 77:65–75
Jope RS, Zhang L, Song L (2000) Peroxynitrite modulates the activation of p38 and extracellular regulated kinases in PC12 cells. Arch Biochem Biophys 376:365–370
Kelicen P, Cantuti-Castelvetri I, Pekiner C, Paulson KE (2002) The spin trap** agent PBN stimulates H2O2 -induced Erk and Src kinase activity in human neuroblastoma cells. Neuroreport 13:1057–1061
Lee YJ, Cho HN, Soh JW, Jhon GJ, Cho CK, Chung HY, Bae S, Lee SJ, Lee YS (2003) Oxidative stress-induced apoptosis is mediated by ERK1/2 phosphorylation. Exp Cell Res 291:251–266
Lennmyr F, Ericsson A, Gerwins P, Akterin S, Ahlstrom H, Terent A (2004) Src family kinase-inhibitor PP2 reduces focal ischemic brain injury. Acta Neurol Scand 110: 175–179
Lennmyr F, Karlsson S, Gerwins P, Ata KA, Terent A (2002) Activation of mitogen-activated protein kinases in experimental cerebral ischemia. Acta Neurol Scand 106: 333–340
Li PA, He QP, Yi-Bing O, Hu BR, Siesjo BK (2001) Phosphorylation of extracellular signal-regulated kinase after transient cerebral ischemia in hyperglycemic rats. Neurobiol Dis 8:127–135
Li PA, Liu GJ, He QP, Floyd RA, Siesjo BK (1999) Production of hydroxyl free radical by brain tissues in hyperglycemic rats subjected to transient forebrain ischemia. Free Radic Biol Med 27:1033–1040
Li PA, Shamloo M, Smith ML, Katsura K, Siesjo BK (1994) The influence of plasma glucose concentrations on ischemic brain damage is a threshold function. Neurosci Lett 177:63–65
Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91
Namura S, Iihara K, Takami S, Nagata I, Kikuchi H, Matsushita K, Moskowitz MA, Bonventre JV, Alessandrini A (2001) Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia. Proc Natl Acad Sci USA 98:11569–11574
Park CK, Mendelow AD, Graham DI, McCulloch J, Teasdale GM (1988) Correlation of triphenyltetrazolium chloride perfusion staining with conventional neurohistology in the detection of early brain ischaemia. Neuropathol Appl Neurobiol 14:289–298
Paul R, Zhang ZG, Eliceiri BP, Jiang Q, Boccia AD, Zhang RL, Chopp M, Cheresh DA (2001) Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Nat Med 7:222–227
Roos MW, Ericsson A, Berg M, Sperber GO, Sjoquist M, Meyerson BJ (2003) Functional evaluation of cerebral microembolization in the rat. Brain Res 961:15–21
Thomas SM, Brugge JS (1997) Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 13:513–609
Wu DC, Ye W, Che XM, Yang GY (2000) Activation of mitogen-activated protein kinases after permanent cerebral artery occlusion in mouse brain. J Cereb Blood Flow Metab 20:1320–1330
Yip PK, He YY, Hsu CY, Garg N, Marangos P, Hogan EL (1991) Effect of plasma glucose on infarct size in focal cerebral ischemia-reperfusion. Neurology 41:899–905
Zausinger S, Hungerhuber E, Baethmann A, Reulen H, Schmid-Elsaesser R (2000) Neurological impairment in rats after transient middle cerebral artery occlusion: a comparative study under various treatment paradigms. Brain Res 863:94–105
Acknowledgements
This study was supported by grants from Erik, Karin and Gösta Selander’s Foundation, the Laerdal Foundation for Acute Medicine and Stroke Riksförbundet. The authors wish to thank Ulla Svensson for technical assistance.
Author information
Authors and Affiliations
Corresponding author
Additional information
This study was approved by the Uppsala Ethical Committee of Animal Research (C133/2).
Rights and permissions
About this article
Cite this article
Farrokhnia, N., Roos, M.W., Terént, A. et al. Experimental treatment for focal hyperglycemic ischemic brain injury in the rat. Exp Brain Res 167, 310–314 (2005). https://doi.org/10.1007/s00221-005-0157-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-005-0157-0