Open AccessMEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia
Author(s) -
Alessandro Alessandrini,
Shobu Namura,
Michael A. Moskowitz,
Joseph V. Bonventre
Publication year - 1999
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.96.22.12866
Subject(s) - mapk/erk pathway , ischemia , neuroprotection , kinase , medicine , mitogen activated protein kinase , protein kinase a , antagonist , extracellular , pharmacology , microbiology and biotechnology , endocrinology , chemistry , biology , receptor
The MEK1 (M AP kinase/E RKk inase)/ERK (e xtracellular-signal-r esponsivek inase) 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.