Therapeutic use of bryostatin-1 to extend tPA time window following MCAO

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There is a tremendous clinical need for improved treatment of acute ischemic stroke. Currently, recombinant tissue plasminogen activator (tPA) is the only FDA approved drug for treatment of acute ischemic stroke. However, less than 5% of people suffering an ischemic stroke receive tPA due to increased risk of secondary cerebral hemorrhage and edema formation. Thus, an unmet need exists to develop novel therapeutics that work in combination with tPA to improve stroke outcome, reduce secondary complications, and extend the time window for administering tPA. Bryostatin-1, an ultrapotent PKC modulator, may provide substantial benefit for treatment of acute ischemic stroke. The long-term goal of our research is to identify and develop therapeutics that markedly improve the safety profile of tPA so that more victims of ischemic stroke are eligible for thrombolysis. The objective of this proposal is to determine if tPA time window can be extended in aged rats co- administered bryostatin-1 with tPA. The central hypothesis is that PKCϵ activation by administration of bryostatin-1 during the acute phase of ischemic cerebral infarction attenuates cerebral endothelium dysfunction; thus, decreasing the degree of injury & increasing the window, in which reperfusion can be safely accomplished. Rationale is that using two separate models of neurological injury (MCAO & mild traumatic brain injury), administration of bryostatin-1 reduced hemispheric swelling & BBB permeability with improved survival & functional recovery. Using our clinically relevant ischemic stroke model, we will use biochemical, neuropathological, and behavioral measures, to test our central hypothesis and accomplish the objective of this proposal, as described in these two specific aims: (1) Identify optimal dose of bryostatin-1 & validate PKCϵ as a therapeutic target & (2) identify therapeutic target of bryostatin-1 that improves cerebrovascular function post- MCAO. Specific aim 1 tests the working hypothesis that co-administration of bryostatin-1 with tPA at 6 h after MCAO will selectively activate PKCe in neurons & cerebral microvessels & it will be lower doses of bryostatin-1 (10-30 mcg/m2) that produce the most efficacious stroke outcome. Specific aim 2 test the working hyothesis that co-administration of bryostatin-1 with tPA at 6 h after MCAO reduces cerebral swelling, mitigates hemorrhagic transformation & improves stroke outcome by selective PKCε activation in cerebral endothelial cells attenuating BBB dysfunction in the infarcted hemisphere. Due to the prevalence & debilitating effects of ischemic stroke, the need for better therapeutic strategies cannot be overstated. Unfortunately, the ability to translate promising preclinical findings into effective drugs that clinically mitigate post-stroke brain damage has, to date, failed. This proposal will determine if co-administration of bryostatin-1 with tPA improves stroke outcome & extends the tPA time window following acute ischemic stroke. Results from this proposal have the translational potential to vastly improve the way ischemic stroke is treated.