A wide network of intracellular signaling pathways are activated in response to mild stresses such as sublethal ischemia or hypothermia to reduce metabolic demand, maintain basic cellular function, and increase survival in the event of a period of severe oxygen and glucose starvation such as stroke [8
]. These endogenous neuroprotective events confer what is termed ischemic tolerance or preconditioning. Strategies to identify and harness the cellular and molecular mechanisms of this protection hold tremendous potential for therapeutic benefit.
Preconditioning has been observed in multiple tissues, including the heart and brain, suggesting that conserved signaling pathways may mediate ischemic insult [8
]. In response to a number of preconditioning-stimuli, changes in gene expression and protein activation initiate common signaling pathways including upregulation of free radical scavengers, opening of KATP
channels, and activation of protein kinases including protein kinase C (PKC) [2
]. Protein kinase C is a widely-expressed family of serine/ threonine kinases. The role of εPKC has been well established in cardiac preconditioning [27
], and is a point of signaling convergence following multiple types of cardiac preconditioning stimuli including transient sublethal ischemia, ethanol and adenosine [26
]. More recently, a role for εPKC in cerebral tolerance has been suggested using various in vitro
models. These studies have demonstrated that εPKC is activated following a preconditioning stimulus such as application of adenosine or NMDA, and is required for preconditioning- induced protection [26
]. However, whether this protection correlates with the in vivo
activity of εPKC, in which the role of the vasculature, inflammation and other extra-parenchymal mediators are important, has not been addressed.
Here we determined the role of εPKC in cerebral ischemia in vivo
, using ψεRACK, an εPKC-specific activator peptide. Multiple reports have demonstrated that PKCs play an important role in mediating vascular tone [6
]. We therefore also examined the effects of εPKC activation on cerebrovascular function. A clear understanding of the mechanisms which govern preconditioning holds great promise for therapies against diseases such as stroke, as well as conditions associated with reduced blood flow to the brain, such as during cardiac bypass surgery. Here we demonstrate that εPKC may be an important target for acute neuroprotective therapies.