Functional Expression of Organic Cation Transporters at the Blood-Brain Barrier: Relevance to the Treatment of Ischemic Stroke
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PublisherThe University of Arizona.
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AbstractIt is currently unclear how cationic solutes are transported across the Blood-Brain Barrier (BBB). This is especially critical for drugs, which must be able to effectively permeate the BBB in order to achieve effective concentrations in the brain. Memantine (MEM) is a cationic drug that has previously shown beneficial effects in preclinical trials for neurological diseases including ischemic stroke; however, the specific mechanism that enables MEM transport from the systemic circulation into brain tissue is unknown. This is especially true in disease conditions (i.e., ischemic stroke) where transport processes and CNS drug delivery can be dramatically modulated. The objective of this project is to study Organic Cation Transporter 1 (Oct1) and Organic Cation Transporter 2 (Oct2) at the BBB in the setting of ischemic stroke to understand how cationic substances are transported at the luminal (i.e., blood) side of the BBB in the setting . Male Sprague-Dawley rats (aged 3-4 months) were subjected to middle cerebral artery occlusion (MCAO), an established in vivo model of experimental ischemic stroke. These rats were then used to perform western blot analysis, in situ brain perfusion, and various behavioral tests. We found that both Oct1 and Oct2 did not see any significant change in expression in the setting of ischemic stroke and verified that Oct-mediated transport is required for MEM transport across the BBB. Of translational importance, transport by Oct1/Oct2 was shown to be required for MEM to exert beneifical effects in the setting of ischemic stroke including improved neurocognitive performance, reduced infarction progression, and decreased edema formation.