Neuroprotective effect of WIN 55,212-2 pretreatment against focal cerebral ischemia through activation of extracellular signal-regulated kinases in rats

It is well documented that cannabinoid receptor agonist WIN 55,212-2 had protective effect against cerebral ischemic injury. Our previous study indicated that WIN 55,212-2 pretreatment induced ischemic tolerance to focal cerebral ischemia in a dose-dependent manner. The aim of the present study was to investigate the time–effect relationship of the WIN 55,212-2 pretreatment and explore the role of phosphorylated extracellular signal-regulated kinase 1/2. Rats were pretreated with 1 mg/kg WIN 55,212-2 once a day for 1, 3 and 5 days. Twenty four hours after the end of pretreatment, focal cerebral ischemia was induced by the middle cerebral artery occlusion. Brain ischemic injury was evaluated by neurological function scores and infarction volumes. The effect of U0126, a potent and specific inhibitor of mitogen-activated protein kinase kinase, on WIN 55,212-2 pretreatment was also studied. Moreover, the expression of phosphorylated extracellular signal-regulated kinase 1/2 in the penumbra of ischemic side 4 h after reperfusion was investigated by immunohistochemistry and Western blotting. The results showed that WIN 55,212-2 pretreatment can protect the rat brain against transient focal cerebral ischemia injury, and its protective effect was enhanced gradually with increasing numbers of pretreatment, and was partially reversed by U0126. We further found that WIN 55,212-2 pretreatment up-regulated the levels of phosphorylated extracellular signal-regulated kinase 1/2. These findings suggest that the neuroprotective effect of WIN 55,212-2 pretreatment against focal cerebral ischemia is through the activation of extracellular signal-regulated kinases in rats.