Activin A Reduces Brain Injury After Stroke

The World Heath Organization estimates that 15 million people worldwide have a stroke annually with many of these individuals suffering from an ischemic attack that will lead to their permanent disability or death. One approach for developing targeted stroke therapies is to identify endogenous responses to cerebral ischemia and determine whether their addition promotes tissue survival. The studies in this thesis focus on the effects of activin A in cerebral ischemia. In this study, experimental cerebral ischemia and reperfusion resulted in the rise of activin βA mRNA in the ischemic hemisphere and increased phosphorylated smad2/3 signals in neurons adjacent to the site of injury. In a defined cell culture model that uses hydrogen peroxide (H2O2)-free radical stress, activin A addition protected cortical neurons against oxidative challenge. H2O2 treatment increased neuronal activin βA mRNA expression and inhibition with neutralizing antibodies to activin A resulted in robust neuronal death. These studies indicate that cells respond to cerebral ischemia with increased activin βA expression and activin A addition promotes the survival of cortical neurons. Studies investigating the effects of added activin A after cerebral ischemia and reperfusion in vivo revealed a robust tissue protective effect. Intraventricular administration of activin A prior to stroke onset protected against ischemia-induced tissue death and provides evidence that activin A promotes tissue survival in ischemic stroke. Analysis of activin A treatment 6 hours after ischemia and reperfusion revealed that despite delayed administration, activin A effectively reduced tissue death at 24 and 72 hours and improved neurobehavior. Moreover, activin A treatment spared neurons within the ischemic hemisphere and led to a concomitant reduction in microglial activation. Activin A resulted in reduced phosphorylation of the stress-responsive signals, p38 and c-jun N-terminal kinase (JNK), members of the mitogen activated protein kinase (MAPK) family, both of which are implicated in neuronal apoptosis. Taken together, these novel data demonstrate that activin A is an endogenous response to cerebral ischemia and reperfusion injury and its addition promotes tissue survival after ischemic stroke.