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

Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12866-9. doi: 10.1073/pnas.96.22.12866.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Body Temperature Regulation / drug effects
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / enzymology
  • Brain Ischemia / pathology
  • Cardiovascular System / drug effects
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Flavonoids / pharmacology
  • Flavonoids / 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
  • Neuroprotective Agents / therapeutic use
  • Phosphorylation
  • Protein Serine-Threonine Kinases*
  • Pyridines / pharmacology
  • Respiration / drug effects
  • p38 Mitogen-Activated Protein Kinases

Substances

  • 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