We have shown that while many neuroprotectants interact additively, demonstrating a true multiplicative synergistic effect is quite difficult. We have considerable experience combining glutamate antagonist with GABA agonists. To date we have been able to extend the therapeutic window out to 4 hours following onset of ischemia using combinations. Future studies will explore further delays in therapy time as well as fundamental investigations of the mechanism of multiplicative versus additive synergism. There is a renewed interest in understanding the blood brain barrier, and its response to injury, with the advent of thrombolytic therapy for stroke.
Brain hemorrhage is the limiting side effect of thrombolytic therapy.
We have been exploring in particular the role of matrix metalloproteinases in mediating such injury. Using small molecule inhibitors of MMPs we have shown a reduction in blood brain barrier breakdown and hemorrhage following ischemic injury. We are pursuing studies of the effect of such injuries as chronic hypertension and aging on blood brain barrier integrity. We are also studying the interaction of changing physiologic variables such as blood pressure during ischemia and the effect of this change on blood brain barrier function. Our approach to this has been to study the effect of cytoprotectants of blood brain barrier integrity after ischemic injury.