Stroke is the third most common cause of death in the United States, but there is no generally accepted specific therapy for most types of strokes. The search for pharmacological treatments that will minimize or prevent ischemic cerebral damage has been hindered by the lack of adequate animal models that simulate the clinical problem and are sufficiently sensitive and reproducible to allow adequate assessment of therapeutic efficacy. We have developed a series of coordinated models of embolic stroke that are specifically designed to allow us to determine, with considerable sensitivity, whether various pharmacological agents can improve neurological function. These methods will also allow us to estimate the frequency of complications that are likely to be encountered. In preliminary studies we found that tissue plasminogen activator (tPA), a thrombolytic agent, appears to substantially reduce neurological damage when given shortly after blood clots enter the cerebral circulation. Drug induced hemorrhagic complications were not observed. We propose to extend these studies to determine the most effective way of using tPA for treatment of acute embolic stroke. Since it is anticipated that tPA will be used in conjunction with heparin, we also propose to study the independent effects of heparin in these carefully controlled animal models and to determine whether any interactions can be anticipated in the combined use of these two agents. Finally, in most previous studies of stroke therapy, reversible ischemia models have been used. However, reversible ischemia represents only a portion of the clinical problem. The embolic stroke models we have developed allow us to study irreversible ischemia in a graded fashion. We propose to study drugs that have been shown to be effective for treatment of reversible ischemia in irreversible embolic stroke. If we can identify therapies that are effective in both types of models, there is an increased probability that these agents will produce beneficial results in clinical trials.
Showing the most recent 10 out of 41 publications
