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PMID: 10536014 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 22 ·1999-10-26 ·Pages 12866-9

Alessandrini A, Namura S, Moskowitz MA, Bonventre JV

Abstract

The MEK1 (MAP kinase/ERK kinase)/ERK (extracellular-signal-responsive kinase) pathway has been implicated in cell growth and differentiation [Seger, R. & Krebs, E. G. (1995) FASEB J. 9, 726-735]. Here we show that the MEK/ERK pathway is activated during focal cerebral ischemia and may play a role in inducing damage. Treatment of mice 30 min before ischemia with the MEK1-specific inhibitor PD98059 [Alessi, D. R., Cuenda, A., Cohen, P. , Dudley, D. T. & Saltiel, A. R. (1995) J. Biol. Chem. 270, 27489-27494] reduces focal infarct volume at 22 hr after ischemia by 55% after transient occlusion of the middle cerebral artery. This is accompanied by a reduction in phospho-ERK1/2 immunohistochemical staining. MEK1 inhibition also results in reduced brain damage 72 hr after ischemia, with focal infarct volume reduced by 36%. This study indicates that the MEK1/ERK pathway contributes to brain injury during focal cerebral ischemia and that PD98059, a MEK1-specific antagonist, is a potent neuroprotective agent.

MeSH Terms
Animals Body Temperature Regulation/drug effects Brain Ischemia/drug therapy,enzymology,pathology Cardiovascular System/drug effects Enzyme Inhibitors/pharmacology,therapeutic use Flavonoids/pharmacology,therapeutic use Imidazoles/pharmacology Immunohistochemistry MAP Kinase Kinase 1 Male Mice Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors Mitogen-Activated Protein Kinases/metabolism Neuroprotective Agents/pharmacology,therapeutic use Phosphorylation Protein Serine-Threonine Kinases Pyridines/pharmacology Respiration/drug effects p38 Mitogen-Activated Protein Kinases
Chemicals
Enzyme Inhibitors Flavonoids Imidazoles Neuroprotective Agents Pyridines Protein Serine-Threonine Kinases Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases MAP Kinase Kinase 1 Map2k1 protein, mouse Mitogen-Activated Protein Kinase Kinases SB 203580 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Alessandrini A
Medical Services, Massachusetts General Hospital, Charlestown, MA 02129, USA. alessand@helix.mgh.harvard.edu
Namura S
Moskowitz M A
Bonventre J V
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.22.12866
Email
alessand@helix.mgh.harvard.edu
Published
1999-10-26
Pages
12866-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC23136
Subset
IM
Grants
NINDS NIH HHS · P50 NS010828 · United States
NINDS NIH HHS · 2P50NS10828 · United States
NIDDK NIH HHS · R37-DK39773 · United States
External Links
PubMed source DOI: 10.1073/pnas.96.22.12866 PMC Full Text View journal details
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