# Investigating Oatp-Mediated Delivery of Statins to the Brain in Males and Females: Relevance to Neuroprotective Treatment for Ischemic Stroke > **NIH NIH F31** · UNIVERSITY OF ARIZONA · 2023 · $47,694 ## Abstract PROJECT SUMMARY Stroke is the fifth leading cause of death in the United States. Approved stroke therapies are limited by narrow treatment windows, the risk of hemorrhagic transformation, and reperfusion injury. Therefore, there is a critical need for neuroprotective drugs that can improve post-stroke neurological performance. Currently, 3-hydroxy-3- methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (i.e., statins) are given to stroke patients due to their proven utility in improving cognitive and motor outcomes. Studies in our laboratory have uncovered a specific biological mechanism that enables statins to be effective drugs for stroke treatment: transport across the blood- brain barrier (BBB) via the endogenous uptake transporter organic anion transporting polypeptide 1a4 (Oatp1a4). We have shown, for the first time, that Oatp-mediated transport is required for atorvastatin to reduce cerebral infarction volume and improve sensorimotor performance at 24 h following transient middle cerebral artery occlusion (tMCAO). We also observed increased atorvastatin uptake in female rats subjected to tMCAO as compared with their age-matched male counterparts; however, it is unknown if these differences in Oatp- mediated transport at the BBB cause variations in atorvastatin’s ability to prevent stroke progression and/or worsening of neurocognitive deficits in the acute/subacute period. Our goals are to assess the role of sex as a biological variable on statin transport in the ischemic brain and to determine how these differences affect statin efficacy as stroke therapeutics. The central hypotheses of this F31 application are i) that functional expression of Oatp1a4 at the BBB is different in males as compared to females following tMCAO; and ii) that statin neuroprotective properties and/or their effects on post-stroke neurological outcomes are influenced by sex-dependent differences in BBB Oatp1a4 activity. Two aims will test these hypotheses: Aim 1: Investigate sex-dependent differences in Oatp1a4-mediated transport of statins at the BBB in stroke. We will perform our studies in male and female SD rats using the tMCAO model. Oatp1a4 localization and protein expression will be assessed using confocal microscopy and western blotting, respectively. Blood-to- brain transport of statins will be measured using in situ brain perfusion, a state-of-the-art methodology to study drug transport at the BBB. Aim 2: Evaluate sex-dependent differences in statin-associated neuroprotection and functional neurological recovery in stroke. In tMCAO operated male and female SD rats, we will use confocal microscopy and western blot analysis to examine molecular biomarkers associated with neuroprotection. We will also assess motor and cognitive performance in tMCAO-animals using robust behavioral tests (i.e., rotarod analysis, Morris Water Maze, Novel Object Recognition test). Overall, this project will provide critical mechanistic data on efficacy of statins as neuroprot... ## Key facts - **NIH application ID:** 10682409 - **Project number:** 5F31NS125917-02 - **Recipient organization:** UNIVERSITY OF ARIZONA - **Principal Investigator:** Erica Iris Williams - **Activity code:** F31 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2023 - **Award amount:** $47,694 - **Award type:** 5 - **Project period:** 2022-08-22 → 2024-10-21 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10682409 ## Citation > US National Institutes of Health, RePORTER application 10682409, Investigating Oatp-Mediated Delivery of Statins to the Brain in Males and Females: Relevance to Neuroprotective Treatment for Ischemic Stroke (5F31NS125917-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10682409. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*