Oatp (Organic Anion Transporting Polypeptide)-Mediated Transport: A Mechanism for Atorvastatin Neuroprotection in Stroke. 2023

Erica I Williams, and Robert D Betterton, and Joshua A Stanton, and Valeria M Moreno-Rodriguez, and Jeffrey J Lochhead, and Thomas P Davis, and Patrick T Ronaldson
Department of Pharmacology, College of Medicine, University of Arizona, Tucson.

BACKGROUND Drug discovery for stroke is challenging as indicated by poor clinical translatability. In contrast, HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (ie, statins) improve poststroke neurological outcomes. This property requires transport across the blood-brain barrier via an endogenous uptake transporter (ie, Oatp1a4 [organic anion transporting polypeptide 1a4]). Our goal was to study Oatp1a4 as a drug delivery mechanism because the blood-brain barrier cannot be assumed to be completely open for all drugs in ischemic stroke. METHODS Male Sprague-Dawley rats (200-250 g) were subjected to middle cerebral artery occlusion (90 minutes) followed by reperfusion for up to 7 days. Atorvastatin (20 mg/kg, IV) was administered 2 hours following intraluminal suture removal. Involvement of Oatp-mediated transport was determined using fexofenadine (3.2 mg/kg, IV), a competitive Oatp inhibitor. Oatp1a4 transport activity was measured by in situ brain perfusion. Infarction volumes/brain edema ratios and neuronal nuclei expression were determined using 2,3,5-triphenyltetrazolium chloride-stained brain tissue slices and confocal microscopy, respectively. Poststroke functional outcomes were assessed via neurological deficit scores and rotarod analysis. RESULTS At 2-hour post-middle cerebral artery occlusion, [3H]atorvastatin uptake was increased in ischemic brain tissue. A single dose of atorvastatin significantly reduced post-middle cerebral artery occlusion infarction volume, decreased brain edema ratio, increased caudoputamen neuronal nuclei expression, and improved functional neurological outcomes. All middle cerebral artery occlusion positive effects of atorvastatin were attenuated by fexofenadine coadministration (ie, an Oatp transport inhibitor). CONCLUSIONS Our data demonstrate that neuroprotective effects of atorvastatin may require central nervous system delivery by Oatp-mediated transport at the blood-brain barrier, a mechanism that persists despite increased cerebrovascular permeability in ischemic stroke. These novel and translational findings support utility of blood-brain barrier transporters in drug delivery for neuroprotective agents.

UI MeSH Term Description Entries
D008297 Male Males
D001929 Brain Edema Increased intracellular or extracellular fluid in brain tissue. Cytotoxic brain edema (swelling due to increased intracellular fluid) is indicative of a disturbance in cell metabolism, and is commonly associated with hypoxic or ischemic injuries (see HYPOXIA, BRAIN). An increase in extracellular fluid may be caused by increased brain capillary permeability (vasogenic edema), an osmotic gradient, local blockages in interstitial fluid pathways, or by obstruction of CSF flow (e.g., obstructive HYDROCEPHALUS). (From Childs Nerv Syst 1992 Sep; 8(6):301-6) Brain Swelling,Cerebral Edema,Cytotoxic Brain Edema,Intracranial Edema,Vasogenic Cerebral Edema,Cerebral Edema, Cytotoxic,Cerebral Edema, Vasogenic,Cytotoxic Cerebral Edema,Vasogenic Brain Edema,Brain Edema, Cytotoxic,Brain Edema, Vasogenic,Brain Swellings,Cerebral Edemas, Vasogenic,Edema, Brain,Edema, Cerebral,Edema, Cytotoxic Brain,Edema, Cytotoxic Cerebral,Edema, Intracranial,Edema, Vasogenic Brain,Edema, Vasogenic Cerebral,Swelling, Brain
D000066829 Neuroprotection The physiological processes and techniques used by the body to prevent neuronal injury and degeneration in the central nervous system following acute disorders or as a result of chronic neurodegenerative diseases. Neural Protection,Neuron Protection,Neuronal Protection,Protection, Neural,Protection, Neuron,Protection, Neuronal
D000069059 Atorvastatin A pyrrole and heptanoic acid derivative, HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITOR (statin), and ANTICHOLESTEREMIC AGENT that is used to reduce serum levels of LDL-CHOLESTEROL; APOLIPOPROTEIN B; and TRIGLYCERIDES. It is used to increase serum levels of HDL-CHOLESTEROL in the treatment of HYPERLIPIDEMIAS, and for the prevention of CARDIOVASCULAR DISEASES in patients with multiple risk factors. (3R,5R)-7-(2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoic acid,Atorvastatin Calcium,Atorvastatin Calcium Anhydrous,Atorvastatin Calcium Hydrate,Atorvastatin Calcium Trihydrate,Atorvastatin, Calcium Salt,CI 981,CI-981,Lipitor,Liptonorm,CI981
D000083242 Ischemic Stroke Stroke due to BRAIN ISCHEMIA resulting in interruption or reduction of blood flow to a part of the brain. When obstruction is due to a BLOOD CLOT formed within in a cerebral blood vessel it is a thrombotic stroke. When obstruction is formed elsewhere and moved to block a cerebral blood vessel (see CEREBRAL EMBOLISM) it is referred to as embolic stroke. Wake-up stroke refers to ischemic stroke occurring during sleep while cryptogenic stroke refers to ischemic stroke of unknown origin. Acute Ischemic Stroke,Cryptogenic Embolism Stroke,Cryptogenic Ischemic Stroke,Cryptogenic Stroke,Ischaemic Stroke,Wake-up Stroke,Acute Ischemic Strokes,Cryptogenic Embolism Strokes,Cryptogenic Ischemic Strokes,Cryptogenic Strokes,Embolism Stroke, Cryptogenic,Ischaemic Strokes,Ischemic Stroke, Acute,Ischemic Stroke, Cryptogenic,Ischemic Strokes,Stroke, Acute Ischemic,Stroke, Cryptogenic,Stroke, Cryptogenic Embolism,Stroke, Cryptogenic Ischemic,Stroke, Ischaemic,Stroke, Ischemic,Stroke, Wake-up,Wake up Stroke,Wake-up Strokes
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D017207 Rats, Sprague-Dawley A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company. Holtzman Rat,Rats, Holtzman,Sprague-Dawley Rat,Rats, Sprague Dawley,Holtzman Rats,Rat, Holtzman,Rat, Sprague-Dawley,Sprague Dawley Rat,Sprague Dawley Rats,Sprague-Dawley Rats
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D018696 Neuroprotective Agents Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids. Neuroprotectant,Neuroprotective Agent,Neuroprotective Drug,Neuroprotectants,Neuroprotective Drugs,Neuroprotective Effect,Neuroprotective Effects,Agent, Neuroprotective,Agents, Neuroprotective,Drug, Neuroprotective,Drugs, Neuroprotective,Effect, Neuroprotective,Effects, Neuroprotective
D020244 Infarction, Middle Cerebral Artery NECROSIS occurring in the MIDDLE CEREBRAL ARTERY distribution system which brings blood to the entire lateral aspects of each CEREBRAL HEMISPHERE. Clinical signs include impaired cognition; APHASIA; AGRAPHIA; weak and numbness in the face and arms, contralaterally or bilaterally depending on the infarction. Cerebral Infarction, Middle Cerebral Artery,Embolic Infarction, Middle Cerebral Artery,MCA Infarct,Middle Cerebral Artery Embolus,Middle Cerebral Artery Infarction,Stroke, Middle Cerebral Artery,Thrombotic Infarction, Middle Cerebral Artery,Embolus, Middle Cerebral Artery,Left Middle Cerebral Artery Infarction,MCA Infarction,Middle Cerebral Artery Circulation Infarction,Middle Cerebral Artery Embolic Infarction,Middle Cerebral Artery Occlusion,Middle Cerebral Artery Stroke,Middle Cerebral Artery Syndrome,Middle Cerebral Artery Thrombosis,Middle Cerebral Artery Thrombotic Infarction,Occlusion, Middle Cerebral Artery,Right Middle Cerebral Artery Infarction,Thrombosis, Middle Cerebral Artery,Infarct, MCA,Infarcts, MCA,MCA Infarcts

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