Abstract WP244: Localization And Expression Of Transporters For Cationic Drugs At The Blood-brain Barrier: Relevance To The Pharmacotherapy Of Ischemic Stroke

Abstract

Purpose: Cationic drugs have often been considered for stroke treatment but their utility is dependent upondelivery across the blood-brain barrier (BBB). This process can involve transporters for cationic substratessuch as organic cation transporters 1 and 2 (Oct1 and Oct2) as well as the multidrug and toxin extruder 1(Mate1). The goal of this study was to show that the Oct/Mate system at the BBB represents an endogenoustransporter mechanism that can be exploited for efficient brain delivery of cationic drugs relevant to stroketherapy. Methods: Male Sprague-Dawley rats (200-250 g) were subjected to middle cerebral artery occlusion (MCAO;90 minutes) followed by reperfusion. Sham-operated rats were used as controls. Memantine (5 mg/kg, i.v.), arepresentative cationic neuroprotective drug, was injected 2 h following intraluminal suture removal in thepresence and absence of cimetidine (15 mg/kg, i.v.), an inhibitor of cation transporters. Localization andprotein expression of Oct1, Oct2, and Mate1 were evaluated by confocal microscopy and western blottingrespectively. Progression of cerebral infarction volume was determined via TTC-stained brain slices.Neurological and motor outcomes during the acute (1 day) and subacute (3-7 days) recovery period post-stroke were assessed using functional neuroscores (i.e., based upon the modified Rankin Scale) and rotorodanalysis. Results: Localization and protein expression of Oct1, Oct2, and Mate1 were confirmed in cerebralmicrovessels isolated from Sprague-Dawley rats subjected to MCAO and in Sham controls. Memantinereduced progression of cerebral infarction, reduced neurological scores, and improved rotorod performanceduring the acute and subacute recovery periods following MCAO. Pharmacological effectiveness of memantinewas decreased in the presence of cimetidine. Conclusions: Our data show that memantine cannot exert beneficial effects during acute and subacute post-stroke recovery without functional expression of endogenous transporters for organic cations (i.e., Oct1, Oct2,and Mate1) at the BBB. This work is highly translational and emphasizes the critical need to evaluate BBBtransport mechanisms during preclinical development of drugs for ischemic stroke treatment.