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Background  Cerebral ischemia induces transcriptional upregulation of inflammatory genes in the brain parenchyma and in cerebral arteries, thereby contributing to the infarct development. The present study was designed to evaluate the involvement of calcium-calmodulin-dependent protein kinase (CaMKII) II and extracellular signal-regulated kinase1/2 (ERK1/2) on inflammatory mediators in rat cerebral arteries using organ culture as a method for inducing ischemic-like vascular wall changes.    Methods  Rat basilar arteries were cultured in serum-free medium for 0, 3, 6 or 24 hours in the presence or absence of the CaMKII inhibitor KN93 or the MEK1/2 inhibitor U0126. Protein expression of activated CaMKII, ERK1/2, and inflammatory-associated protein kinases and mediators were examined with western blot and immunohistochemistry. Caspase-3 mRNA levels in basilar arteries were studied with real-time PCR.    Results  Western blot evaluation showed that organ culture induced a significant increase in phosphorylated ERK1/2 at 3, 6 and 24 hours, while CaMKII was found to be already activated in fresh non-incubated arteries and to decrease with incubation time. The addition of U0126 or KN93 decreased levels of phosphorylated c-Jun N-terminal kinase and p-p38, as evaluated by immunohistochemistry. KN93 affected the increase in caspase-3 mRNA expression only when given at the start of incubation, while U0126 had an inhibitory effect when given up to six hours later. Tumor necrosis factor receptor 1 was elevated after organ culture. This inflammatory marker was reduced by both of the two different protein kinase inhibitors.    Conclusions  The novel findings of the present study are that the cross-talk between the two protein kinases and the inhibition of CaMKII or MEK1/2 in a time-dependent manner attenuates inflammatory-associated protein kinases and mediators, suggesting that they play a role in cerebrovascular inflammation.

CaMKII and MEK1/2 inhibition time-dependently modify inflammatory signaling in rat cerebral arteries during organ culture