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MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia
A Alessandrini1, S Namura, M A Moskowitz
1Medical Services, Massachusetts General Hospital, Charlestown, MA 02129, USA. alessand@helix.mgh.harvard.edu
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.
Insights
The MEK1/ERK pathway is activated during stroke and contributes to brain damage. Inhibiting this pathway with PD98059 significantly reduced infarct volume and protected the brain from injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- The MEK1 (MAP kinase/ERK kinase)/ERK (extracellular-signal-responsive kinase) pathway is crucial for cell growth and differentiation.
- This pathway has been observed to be activated during focal cerebral ischemia.
Purpose of the Study:
- To investigate the role of the MEK/ERK pathway in focal cerebral ischemia-induced brain damage.
- To evaluate the neuroprotective potential of the MEK1-specific inhibitor PD98059.
Main Methods:
- Mice were treated with the MEK1 inhibitor PD98059 30 minutes before inducing transient middle cerebral artery occlusion.
- Infarct volume was measured at 22 and 72 hours post-ischemia.
- Immunohistochemical staining for phospho-ERK1/2 was performed.
Main Results:
- PD98059 treatment reduced focal infarct volume by 55% at 22 hours and 36% at 72 hours post-ischemia.
- Inhibition of MEK1 led to a reduction in phospho-ERK1/2 staining, indicating pathway inhibition.
- PD98059 demonstrated significant neuroprotective effects.
Conclusions:
- The MEK1/ERK pathway plays a significant role in brain injury following focal cerebral ischemia.
- The MEK1-specific inhibitor PD98059 is a potent neuroprotective agent against ischemic stroke damage.