Hypoxia/Reoxygenation Stress Modulates Atorvastatin Transport at the Blood-Brain Barrier: A Role for Organic Anion Transporting Polypeptide

Persistent Link:
http://hdl.handle.net/10150/337292
Title:
Hypoxia/Reoxygenation Stress Modulates Atorvastatin Transport at the Blood-Brain Barrier: A Role for Organic Anion Transporting Polypeptide
Author:
Thompson, Brandon
Issue Date:
2014
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Cerebral ischemia occurs when blood flow to the brain is insufficient to meet metabolic demand. This can result from cerebral artery occlusion that interrupts blood flow, limits CNS supply of oxygen and glucose, and causes an infarction/ischemic stroke. Ischemia initiates a cascade of molecular events in neurons and cerebrovascular endothelial cells including energy depletion, dissipation of ion gradients, calcium overload, excitotoxicity, oxidative stress, and accumulation of ions and fluid. Blood-brain barrier (BBB) disruption is associated with cerebral ischemia and leads to vasogenic edema, a primary cause of stroke-associated mortality. To date, only a single drug has received US Food and Drug Administration (FDA) approval for treatment of acute ischemia/reperfusion injury, recombinant tissue plasminogen activator (rt-PA). While rt-PA therapy restores perfusion to ischemic brain, considerable tissue damage occurs when cerebral blood flow is re-established. Therefore, there is a critical need for novel therapeutic approaches that can "rescue" salvageable brain tissue and/or protect BBB integrity during cerebral hypoxia and subsequent reoxygenation stress (H/R). One approach that may enable neural tissue rescue following H/R is CNS delivery of drugs with brain protective effects such as HMG-CoA reductase inhibitors (i.e., statins). Our present in vivo data demonstrates that atorvastatin, a commonly prescribed statin, attenuates poly (ADP-ribose) polymerase (PARP) cleavage in the brain following H/R, suggesting neuroprotective efficacy. However, atorvastatin use as a CNS therapeutic is limited by poor blood-brain barrier (BBB) penetration. Therefore, we examined regulation and functional expression of the known statin transporter Oatp1a4 at the BBB under H/R conditions. In rat brain microvessels H/R (6% O₂, 60 min followed by 21% O₂, 10 min) increased Oatp1a4 expression. Brain uptake of taurocholate (i.e., Oap1a4 probe substrate) and atorvastatin were reduced by Oatp inhibitors (i.e., estrone-3-sulfate, fexofenadine), suggesting involvement of Oatp1a4 in brain drug delivery. Pharmacological inhibition of TGF-β/ALK5 signaling with the selective inhibitor SB431542 increased Oatp1a4 functional expression, suggesting a role for TGF-β/ALK5 signaling in Oatp1a4 regulation. Taken together, our novel data show that targeting an endogenous BBB drug uptake transporter (i.e., Oatp1a4) may be a viable approach for optimizing CNS drug delivery for treatment of diseases with an H/R component.
Type:
text; Electronic Dissertation
Keywords:
Blood-Brain Barrier; Hypoxia; Organic Anion Transporting Polypeptide; Physiological Sciences; Atorvastatin
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Physiological Sciences
Degree Grantor:
University of Arizona
Advisor:
Vanderah, Todd W.
Committee Chair:
Vanderah, Todd W.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleHypoxia/Reoxygenation Stress Modulates Atorvastatin Transport at the Blood-Brain Barrier: A Role for Organic Anion Transporting Polypeptideen_US
dc.creatorThompson, Brandonen_US
dc.contributor.authorThompson, Brandonen_US
dc.date.issued2014-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractCerebral ischemia occurs when blood flow to the brain is insufficient to meet metabolic demand. This can result from cerebral artery occlusion that interrupts blood flow, limits CNS supply of oxygen and glucose, and causes an infarction/ischemic stroke. Ischemia initiates a cascade of molecular events in neurons and cerebrovascular endothelial cells including energy depletion, dissipation of ion gradients, calcium overload, excitotoxicity, oxidative stress, and accumulation of ions and fluid. Blood-brain barrier (BBB) disruption is associated with cerebral ischemia and leads to vasogenic edema, a primary cause of stroke-associated mortality. To date, only a single drug has received US Food and Drug Administration (FDA) approval for treatment of acute ischemia/reperfusion injury, recombinant tissue plasminogen activator (rt-PA). While rt-PA therapy restores perfusion to ischemic brain, considerable tissue damage occurs when cerebral blood flow is re-established. Therefore, there is a critical need for novel therapeutic approaches that can "rescue" salvageable brain tissue and/or protect BBB integrity during cerebral hypoxia and subsequent reoxygenation stress (H/R). One approach that may enable neural tissue rescue following H/R is CNS delivery of drugs with brain protective effects such as HMG-CoA reductase inhibitors (i.e., statins). Our present in vivo data demonstrates that atorvastatin, a commonly prescribed statin, attenuates poly (ADP-ribose) polymerase (PARP) cleavage in the brain following H/R, suggesting neuroprotective efficacy. However, atorvastatin use as a CNS therapeutic is limited by poor blood-brain barrier (BBB) penetration. Therefore, we examined regulation and functional expression of the known statin transporter Oatp1a4 at the BBB under H/R conditions. In rat brain microvessels H/R (6% O₂, 60 min followed by 21% O₂, 10 min) increased Oatp1a4 expression. Brain uptake of taurocholate (i.e., Oap1a4 probe substrate) and atorvastatin were reduced by Oatp inhibitors (i.e., estrone-3-sulfate, fexofenadine), suggesting involvement of Oatp1a4 in brain drug delivery. Pharmacological inhibition of TGF-β/ALK5 signaling with the selective inhibitor SB431542 increased Oatp1a4 functional expression, suggesting a role for TGF-β/ALK5 signaling in Oatp1a4 regulation. Taken together, our novel data show that targeting an endogenous BBB drug uptake transporter (i.e., Oatp1a4) may be a viable approach for optimizing CNS drug delivery for treatment of diseases with an H/R component.en_US
dc.typetexten
dc.typeElectronic Dissertationen
dc.subjectBlood-Brain Barrieren_US
dc.subjectHypoxiaen_US
dc.subjectOrganic Anion Transporting Polypeptideen_US
dc.subjectPhysiological Sciencesen_US
dc.subjectAtorvastatinen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePhysiological Sciencesen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorVanderah, Todd W.en_US
dc.contributor.chairVanderah, Todd W.en_US
dc.contributor.committeememberVanderah, Todd W.en_US
dc.contributor.committeememberBrooks, Heddwen L.en_US
dc.contributor.committeememberLynch, Ronald M.en_US
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