Stroke is the third most common cause of death and the most common cause of acquired physical disability in Ireland. The only available drug, recombinant tPA, is only used in ~5% of patients, because most patients do not satisty the many criteria that must be fulfilled to receive it. Thus, the need for an effective and easily administered treatment remains paramount. We and others have found that fingolimod, used in the management of relapsing-remitting multiple sclerosis, is effective in several rodent stroke models. Such findings and the fact that fingolimod is already licensed for another neurological indication suggest that fingolimod is one of the most compelling candidates ever characterized in stroke models. But hundreds of drugs effective in animals have failed to show efficacy in humans; this has greatly raised the bar to justify the considerable expenses and risks of a clinical trials. We therefore propose to implement recommendations issued by the Stroke Therapy Academic Industry Roundtable to decrease the gap between preclinical and clinical studies. The idea behind these guidelines is to better mimic the clinical features of stroke. We will do so by using a thromboembolic rather than a filament occlusion model and fully characterize the optimal administration protocol for fingolimod (Objective 1). We will also use older rodents, as well as rodents with comorbid conditions typically associated with stroke (diabetes, hypertension, hyperlipidemia) (Objective 2). We will then study whether the presence of drugs commonly given to stroke patients, failure to recanalize or the presence of haemorrhage affect the efficacy and/or safety of fingolimod (Objective 3). If successful, our project should rapidly lead to clinical trials with a vastly increased likelihood of success, since fingolimod acts by several mechanisms, has an extended treatment window, and is currently used for another neurological indication.
