Abstract TP205: Organic Anion Transporting Polypeptides: Endogenous Blood-brain Barrier Transporters That Are Required For Statins To Exert Neuroprotective Effects In Ischemic Stroke

Abstract

Clinical development of new drugs for ischemic stroke has been challenging. In contrast, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (i.e., statins) are routinely administered to stroke patients because they improve neurological outcomes. This property of statins requires delivery across the blood-brain barrier (BBB). We have uncovered a BBB uptake transporter for statins: organic anion transporting polypeptide 1a4 (Oatp1a4). Our goal was to determine whether Oatp-mediated transport at the BBB is a required mechanism for a commonly prescribed statin (i.e., atorvastatin; ATV) to exert neuroprotective effects following ischemic stroke. Methods: Male Sprague-Dawley rats (200-250 g) were subjected to middle cerebral artery occlusion (MCAO; 90 min) followed by reperfusion. ATV (20 mg/kg, i.v.) was administered 2 h following intraluminal suture removal. Involvement of Oatp-mediated transport was determined using fexofenadine (FEX; 3.2 mg/kg, i.v.), a competitive Oatp inhibitor. Oatp1a4 transport activity was measured by in situ brain perfusion. Following MCAO/reperfusion, infarction volumes and brain edema ratios were calculated from TTC-stained brain tissue slices. Hippocampal neuronal cell numbers were assessed by immunofluorescence imaging of neuronal nuclei (NeuN) staining. Post-stroke functional outcomes were assessed via neurological deficit scores and rotarod analysis. At 2 h post-MCAO, ATV uptake was increased in ischemic brain tissue. FEX blocked blood-to-brain uptake of ATV, which confirmed involvement of an Oatp-mediated transport mechanism. ATV reduced post-MCAO infarction volume and brain edema ratio, increased hippocampal NeuN staining, and improved neurological outcomes. All positive effects of ATV were attenuated by co-administration of FEX. Conclusions: Our data demonstrate ATV requires functional expression of an endogenous BBB transporter (i.e., Oatp1a4) to exert neuroprotective effects and promote post-stroke recovery. These novel and translational findings provide mechanistic evidence on the critical role of BBB transporters in delivery of stroke drugs to the ischemic brain, information that can facilitate therapeutic advancement in clinical trials.