MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia.
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.
Alessandrini
A
A
Medical Services, Massachusetts General Hospital, Charlestown, MA 02129, USA. alessand@helix.mgh.harvard.edu
Namura
S
S
Moskowitz
M A
MA
Bonventre
J V
JV
D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002319:Cardiovascular System / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D048369:MAP Kinase Kinase 1; D008297:Male; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines / Q000494:pharmacology; D012119:Respiration / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D018696:Neuroprotective Agents; D011725:Pyridines; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one