@article {Wang172, author = {Xinkang Wang and Hugh Wang and Lin Xu and Dennis J. Rozanski and Taku Sugawara and Pak H. Chan and James M. Trzaskos and Giora Z. Feuerstein}, title = {Significant Neuroprotection against Ischemic Brain Injury by Inhibition of the MEK1 Protein Kinase in Mice: Exploration of Potential Mechanism Associated with Apoptosis}, volume = {304}, number = {1}, pages = {172--178}, year = {2003}, doi = {10.1124/jpet.102.040246}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {MEK1/2 is a serine/threonine protein kinase that phosphorylates and activates extracellular signal-responsive kinase (ERK)1/2. In the present study we explored the role of MEK1/2 in ischemic brain injury using a selective MEK1/2 inhibitor, SL327, in mice. C57BL/6 mice were subjected to a 30-min occlusion of the middle cerebral artery (MCAO) followed by reperfusion. Western blot analysis demonstrated the immediate activation of MEK/ERK after reperfusion (within the first 10 min) in the ischemic brain; this activation was dose dependently blocked by SL327 (10{\textendash}100 mg/kg, i.p.). A single dose of SL327 (100 mg/kg) administered 15 min before or 25 min after the onset of ischemia resulted in 63.6\% (n = 18, p\< 0.001) and 50.7\% (n = 18, p\< 0.01) reduction in infarct size, respectively, compared with vehicle-treated mice. Similarly, SL327 significantly reduced neurological deficits 1 to 3 days after reperfusion (n = 12, p \< 0.01). The salutary effect of SL327-induced neuroprotection was independent of mitochondrial cytochrome c release or caspase-8-mediated apoptosis; however, SL327 markedly suppressed the levels of active caspase-3 and DNA fragmentation (as a measure of apoptosis) after ischemia/reperfusion. Our data suggest that the inhibition of MEK1/2 results in neuroprotection from reperfusion injury and that this protection may be associated with the reduction in apoptosis. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/304/1/172}, eprint = {https://jpet.aspetjournals.org/content/304/1/172.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }