A cost-effective rabbit embolic stroke bioassay: insight into the development of acute ischemic stroke therapy.

Abstract

Preface: 30 Years a ModelThis article was written to acknowledge the scientificachievement of Dr. Justin A. Zivin, the originator ofthe rabbit embolic stroke model and investigator respon-sible for the “translational stroke research” that led tothe NINDS rt-PA trial and eventual approval of tissueplasminogen activator (tPA) for the treatment of acuteischemic stroke 20 years ago. In 1984–1985, the term“translational stroke research” did not exist, nor did thisjournal bearing the name Translational Stroke Research.Nevertheless, over the years, the rabbit embolic strokemodel has been integral in the development and testingof novel therapies, and the model remains important fortranslational stroke therapy development. TranslationalStroke Research has become an important means of dis-seminating advances in basic and translational strokeresearch and will be integral in future stroke therapydiscovery.tPA, a Cost-Effective TreatmenttPA has been described as a cost-effective treatment forstroke [1]whenadministered3to4.5hafterastroke.The specific conclusion is derived using a disease-baseddecision analytic model, which included probabilisticsensitivity analyses, indicating that “improvement inlong-term patient outcomes in most patient subgroups(except for diabetes and atrial fibrillation) and is a goodeconomic value versus no treatment” [1]. This has beenconfirmed in two recent reports using extensive patientdatabases [2, 3].In 1996, the Food and Drug Administration (FDA)approved the thrombolytic tPA for the treatment ofacute ischemic stroke resulting from blockage of a ves-sel due to an embolus or blood clot. tPA, a thrombolyticthat promotes clot lysis, is also known as a clot busterthat increases blood flow to the formerly clot-affectedcore and possibly salvageable penumbra [4–13]; thisresults in clinical and/or behavioral improvement onthe National Institutes of Health Stroke Scale (NIHSS)andmodifiedRankinScale(mRS).Almost20yearshave passed without the approval of another stroketreatment despite the tremendous financial investmentsand achievements of many investigators worldwide!A Rigorous Model and Bioassay for Therapy Testingand DevelopmentThe approval of tPA was based upon a randomized andblinded clinical trial comparing tPA to tPA-placebo; thetrial was initiated based upon preclinical data by Zivinandcolleagues,whichwaspublished30yearsagoinalandmark science paper [14] and eventually detailed in avolume dedicated to the history of tPA [15]aswellasother comprehensive books on thrombolytics and trans-lational stroke research [16–19]. In retrospect, the au-thors simply showed that tPA could effectively improvebehavioral function when tested in a noninvasive rabbitembolic stroke model, now known as the rabbit small