Date of Graduation
Effective interventions and therapeutic strategies for stroke victims are few. Investigative focus on the discovery of neuroprotective drugs has drawn attention from gaining a deeper understanding of stroke pathophysiology and mechanisms underlying ultimate neuronal and functional loss. In this study we have described a method for improving the precision and accuracy of clot placement within the middle cerebral artery (MCA) of rats, creating thromboembolic method of occlusion relevant to the majority of strokes seen clinically and included the use of aged animals. We evaluated the pathologic and physiologic differences of stroke in young, adult and elderly female rats, demonstrating an association between animal age and the degree of resultant neuronal damage and functional deficit. The response of supporting cells and structures to ischemia, upon which neuronal survival is critically dependent, is essential in our attempt to reduce severity of acute brain damage. We have examined the role of blood-brain barrier function in stroke progression, demonstrating that aged rats suffer larger infarcts with increased BBB disruption, greater neuronal damage, and reduced functional recovery. Moreover, BBB disruption in the absence of significant neuronal damage suggests a potential mechanism by which alteration in BBB integrity, during stroke, contributes to a greater degree of subsequent neuronal injury. Finally we have examined signaling pathways implicated in cellular response to ischemic injury in young and aged animals. Activation of the janus kinase (JAK) and signal transduction and activator of transcription pathway is rapid following stroke, and the reponse was attenuated in the aged brain. Our data demonstrate early activation of the JAK/STAT signal during stroke in all animals. The phosphorylation of STAT3 in young animals persists, while it is absent in aged animals by 72h post-occlusion. As STAT3 phosphrylation/activation has been demonstrated to promote survival mechanisms, this could unlerlie the inability of aged animals to compensate for neuronal insult. These data emphasize the need for inclusion of aged animals in preclinical evaluation of potential stroke therapies. An accurate MCAO model, which mimics the stroke population and allows for effective, reliable reperfusion, is imperative for the successful translation of therapeutic strategies and improved stroke outcomes in elderly patients.
DiNapoli, Vincent A., "Alterations in JAK/STAT signaling pathway and blood-brain barrier function: Mechanisms underlying worsened outcome following stroke in the aged rat." (2008). Graduate Theses, Dissertations, and Problem Reports. 8760.