Despite the significant advances that have been made in understanding the pathophysiology of cerebral ischemia on the cellular and molecular level, only one drug, the thrombolytic tissue plasminogen activator (rt-PA), is approved by the FDA for use in patients with acute ischemic stroke. Therefore, there is a critical need for additional safe and effective treatments for stroke. In order to identify novel compounds that might be effective, we have developed a cell culture-based assay with death being an endpoint as a screening tool. We have performed an initial screening for potential neuroprotective drugs among a group of flavonoids by using the mouse hippocampal cell line, HT22, in combination with chemical ischemia. Further screens were provided by biochemical assays for ATP and glutathione, the major intracellular antioxidant, as well as for long-term induction of antioxidant proteins. Based upon the results of these screens, we tested the best flavonoid, fisetin, in the small clot embolism model of cerebral ischemia in rabbits. Fisetin significantly reduced the behavioral deficits following a stroke, providing proof of principle for this novel approach to identifying new compounds for the treatment of stroke.

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Background and Purpose-Transcranial near-infrared laser therapy (TLT) is currently under investigation in a pivotal clinical trial that excludes thrombolytic therapy. To determine if combining tissue plasminogen activator (tPA; Alteplase) and TLT is safe, this study assessed the safety profile of TLT administered alone and in combination with Alteplase. The purpose for this study is to determine if the combination of TLT and thrombolysis should be investigated further in a human clinical trial. Methods-We determined whether postembolization treatment with TLT in the absence or presence of tPA would affect measures of hemorrhage or survival after large clot embolism-induced strokes in New Zealand white rabbits. Results-TLT did not significantly alter hemorrhage incidence after embolization, but there was a trend for a modest reduction of hemorrhage volume (by 65%) in the TLT-treated group compared with controls. Intravenous administration of tPA, using an optimized dosing regimen, significantly increased hemorrhage incidence by 160%. The tPA-induced increase in hemorrhage incidence was not significantly affected by TLT, although there was a 30% decrease in hemorrhage incidence in combination-treated rabbits. There was no effect of TLT on hemorrhage volume measured in tPA-treated rabbits and no effect of any treatment on 24-hour survival rate. Conclusion-In the embolism model, TLT administration did not affect the tPA-induced increase in hemorrhage incidence.TLT may be administered safely either alone or in combination with tPA because neither treatment affected hemorrhage incidence or volume. Our results support the study of TLT in combination with Alteplase in patients with stroke.

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