MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia
A Alessandrini, S Namura… - Proceedings of the …, 1999 - National Acad Sciences
A Alessandrini, S Namura, MA Moskowitz, JV Bonventre
Proceedings of the National Academy of Sciences, 1999•National Acad SciencesThe MEK1 (M AP kinase/E RK k inase)/ERK (e xtracellular-signal-r esponsive k inase)
pathway has been implicated in cell growth and differentiation [Seger, R. & Krebs, EG (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, DR, Cuenda, A., Cohen, P.,
Dudley, DT & Saltiel, AR (1995) J. Biol. Chem. 270, 27489–27494] reduces focal infarct …
pathway has been implicated in cell growth and differentiation [Seger, R. & Krebs, EG (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, DR, Cuenda, A., Cohen, P.,
Dudley, DT & Saltiel, AR (1995) J. Biol. Chem. 270, 27489–27494] reduces focal infarct …
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.
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