Activation of the extracellular-signal-responsive kinase (ERK 1/2) by MAP kinase/ERK kinase (MEK1/2) following ischemia/reperfusion in the brain has been associated with cell death since inhibition of MEK1/2 provides neuroprotection in cerebral ischemia injury. Since inflammation has been implicated in ischemic brain injury, the present study investigated whether MEK1/2 modifies expression of two key inflammatory cytokines, IL-1 beta and TNF alpha, that have been shown to exacerbate ischemic brain injury. A mouse model of transient cerebral ischemia was deployed to test the effect of selective MEK1/2 inhibitor (SL327) on infarct size and cytokine expression. SL327 (100 mg/kg, i.p.) administered 15 min prior to ischemia resulted in 64% reduction in infarct size over controls (n=S, P<0.01). Under the same condition, SL327 significantly reduced peak expression of IL-1 mRNA (59% reduction compared to vehicle, P<0.01, n=4) but not TNF- mRNA. A parallel reduction in IL-1 beta protein (67%, P<0.059 n=6) was also observed using ELISA analysis. These data suggest that the neuroprotective effect of MEK1/2 inhibition may be mediated by suppression of IL-1. The study also demonstrates for the first time that these two cytokines are differentially regulated by kinase mediated signaling pathways.