Intravenous administration of MEK inhibitor U0126 affords brain protectionagainst forebrain ischemia and focal cerebral ischemia

Brain subjected to acute ischemic attack caused by an arterial blockage nee ds immediate arterial recanalization. However, restoration of cerebral bloo d flow can cause tissue injury, which is termed reperfusion injury. It is i mportant to inhibit reperfusion injury to achieve greater brain protection. Because oxidative stress has been shown to activate mitogen-activated prot ein kinases (MAPKs), and because oxidative stress contributes to reperfusio n injury, MAPK may be a potential target to inhibit reperfusion injury afte r brain ischemia. Here, we demonstrate that reperfusion after forebrain isc hemia dramatically increases phosphorylation level of extracellular signal- regulated kinase 2 (ERK2) in the gerbil hippocampus. In addition, i.v. admi nistration of U0126 (100-200 mg/kg), a specific inhibitor of MEK (MAPK/ERK kinase), protects the hippocampus against forebrain ischemia. Moreover, tre atment with U0126 at 3 h after ischemia significantly reduces infarct volum e after transient (3 h) focal cerebral ischemia in mice. This protection is accompanied by reduced phosphorylation level of ERK2, substrates for MEK, in the damaged brain areas. Furthermore, U0126 protects mouse primary cultu red cortical neurons against oxygen deprivation for 9 h as well as nitric o xide toxicity. These results provide further evidence for the role of MEK/E RK activation in brain injury resulting from ischemia/reperfusion, and indi cate that MEK inhibition may increase the resistance of tissue to ischemic injury.