A clinically relevant rabbit embolic stroke model for acute ischemic stroke therapy development: Mechanisms and targets

Abstract

Alteplase (tissue plasminogen activator, tPA) is currently the only FDA-approved treatment that can be given to acute ischemic stroke (AIS) patients, if patients present within 3 h of an ischemic stroke. Recent clinical trial evidence now suggests that the therapeutic treatment window for tPA can be expanded 4.5 h, but this is not formally approved by the FDA. Even though there remains a significant risk of intracerebral hemorrhage (ICH) associated with alteplase administration, there is an increased chance of favorable outcome with tPA treatment. Over the last 30 years, significant progress in the understanding of mechanisms involved in stroke damage have resulted from the sue of a series of in vivo stroke models. The use of preclinical models has also assisted with the identification of new treatments strategies, but the new strategies have not been easily translated from the laboratory animal into the stroke patient. Current research trends emphasize the development of new and potentially useful thrombolytics, neuroprotective agents and devices, which are also being tested for efficacy in preclinical and clinical trials. We have used the rabbit small clot embolic stroke model (RSCEM) to optimize treatment strategies prior to the development of clinical trials. Originally, the RSCEM was used to develop tPA for efficacy, and it remains the only preclinical model used to gain FDA approval of a therapeutic agent for stroke. This chapter will focus on recent studies of new therapeutic approaches developed using the RSCEM. Analysis from existing preclinical and clinical trials indicates that the RSCEM can be used as an effective translational tool to gauge the clinical potential of new treatments.