Published Online
on February 27, 2003

A more recent version of this article appeared on March 1, 2003

This Article Full Text (PDF) All Versions of this Article: 34/3/752    most recent 01.STR.0000057813.31798.1Fv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vartiainen, N. Articles by Koistinaho, J. Search for Related Content PubMed PubMed Citation Articles by Vartiainen, N. Articles by Koistinaho, J. Related Collections Apoptosis Acute Cerebral Infarction Neuroprotectors

Submitted on September 4, 2002
Accepted on September 25, 2002

Aspirin Inhibits p44/42 Mitogen-Activated Protein Kinase and Is Protective Against Hypoxia/Reoxygenation Neuronal Damage

Nina Vartiainen PhD; Gundars Goldsteins PhD; Velta Keksa-Goldsteine MSc; Pak H. Chan PhD; and Jari Koistinaho MD, PhD^*

From the A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland (N.V., G.G., V.K-G., J.K.); Department of Oncology, University Hospital, Kuopio, Finland (J.K.); and Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Palo Alto, Calif (N.V., P.H.C., J.K.).

^* To whom correspondence should be addressed. E-mail: Jari.Koistinaho{at}uku.fi.

Background and Purpose--Acetylsalicylic acid (ASA) is preventive against stroke and protects against focal brain ischemia in rats. We studied the mechanisms of the manner in which ASA provides neuroprotection against hypoxia/reoxygenation (H/R) injury.

Methods--Spinal cord cultures exposed to 20 hours of hypoxia followed by reoxygenation were treated with a vehicle, ASA or inhibitors of inducible nitric oxide synthase (iNOS), mitogen-activated protein kinases p38 MAPK and ERK1/2, or an N-methyl-D-aspartic acid (NMDA) receptor antagonist. Cell viability was assessed by LDH release measurement and cell counts. Prostaglandin production was measured by enzyme immunoassay, MAPK signaling by immunoblotting, and DNA binding of nuclear factor-B (NF-B) and activating protein-1 (AP-1) by electrophoretic mobility shift assay.

Results--One to 3 mmol/L ASA inhibited H/R-induced neuronal death when present during H/R but not when administered only for the reoxygenation period. Prostaglandin E₂ production was very low and was not altered by ASA. The AP-1 and NF-B DNA binding activities increased after H/R. ASA increased the H/R-induced AP-1 binding but had no effect on NF-B binding. H/R induced a sustained ERK1/2 activation followed by neuronal death, whereas no changes in p38 or c-Jun N-terminal kinase were detected. ASA strongly inhibited this ERK1/2 activation. PD98059, an ERK1/2 inhibitor, was also neuroprotective, prevented H/R-induced ERK1/2 activation, and had no effect on NF-B binding activity. Inhibition of NMDA receptors, iNOS, or p38 MAPK did not provide neuroprotection.

Conclusions--Inhibition of the sustained activation of ERK1/2 may partially contribute to neuroprotection achieved by ASA against H/R injury.

Key words: cell death • cyclooxygenase • reactive oxygen species • transcription factors

This article has been cited by other articles:

				T. Jover-Mengual, R. S. Zukin, and A. M. Etgen MAPK Signaling Is Critical to Estradiol Protection of CA1 Neurons in Global Ischemia Endocrinology, March 1, 2007; 148(3): 1131 - 1143. [Abstract] [Full Text] [PDF]

				R. Furst, S. B. Blumenthal, A. K. Kiemer, S. Zahler, and A. M. Vollmar Nuclear Factor-{kappa}B-Independent Anti-Inflammatory Action of Salicylate in Human Endothelial Cells: Induction of Heme Oxygenase-1 by the c-Jun N-Terminal Kinase/Activator Protein-1 Pathway J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 389 - 394. [Abstract] [Full Text] [PDF]

				A. di Palma, G. Matarese, V. Leone, T. Di Matola, F. Acquaviva, A. M. Acquaviva, and P. Ricchi Aspirin reduces the outcome of anticancer therapy in Meth A-bearing mice through activation of AKT-glycogen synthase kinase signaling Mol. Cancer Ther., May 1, 2006; 5(5): 1318 - 1324. [Abstract] [Full Text] [PDF]

				G. Zhan, P. Fenik, D. Pratico, and S. C. Veasey Inducible Nitric Oxide Synthase in Long-term Intermittent Hypoxia: Hypersomnolence and Brain Injury Am. J. Respir. Crit. Care Med., June 15, 2005; 171(12): 1414 - 1420. [Abstract] [Full Text] [PDF]

				M. E. Jung, M. B. Gatch, and J. W. Simpkins Estrogen Neuroprotection Against the Neurotoxic Effects of Ethanol Withdrawal: Potential Mechanisms Experimental Biology and Medicine, January 1, 2005; 230(1): 8 - 22. [Abstract] [Full Text] [PDF]

				S. Muerkoster, K. Wegehenkel, A. Arlt, M. Witt, B. Sipos, M.-L. Kruse, T. Sebens, G. Kloppel, H. Kalthoff, U. R. Folsch, et al. Tumor Stroma Interactions Induce Chemoresistance in Pancreatic Ductal Carcinoma Cells Involving Increased Secretion and Paracrine Effects of Nitric Oxide and Interleukin-1{beta} Cancer Res., February 15, 2004; 64(4): 1331 - 1337. [Abstract] [Full Text] [PDF]

				S.-R. Lee and E. H. Lo Interactions Between p38 Mitogen-Activated Protein Kinase and Caspase-3 in Cerebral Endothelial Cell Death After Hypoxia-Reoxygenation Stroke, November 1, 2003; 34(11): 2704 - 2709. [Abstract] [Full Text] [PDF]