Regulation of permeability of human brain microvessel endothelial cells by polyunsaturated fatty acids

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dc.contributor.authorDalvi, Siddhartha
dc.contributor.examiningcommitteeMcNicol, Archibald (Oral Biology) Miller, Donald (Pharmacology and Therapeutics) Smyth, Donald (Pharmacology and Therapeutics)en_US
dc.contributor.supervisorHatch, Grant (Pharmacology and Therapeutics)en_US
dc.date.accessioned2013-07-04T19:54:32Z
dc.date.available2013-07-04T19:54:32Z
dc.date.issued2013-07-04
dc.degree.disciplinePharmacology and Therapeuticsen_US
dc.degree.levelMaster of Science (M.Sc.)en_US
dc.description.abstractThe blood-brain barrier, formed by brain microvessel endothelial cells, is the restrictive barrier between the brain parenchyma and the circulating blood. It was previously demonstrated in our laboratory that knock down of fatty acid transport proteins FATP-1 and CD36 attenuated apical to basolateral monounsaturated fatty acid transport across human brain microvessel endothelial cells (HBMEC). Arachidonic acid (AA; 5,8,11,14 - cis-eicosatetraenoic acid) is a conditionally essential, polyunsaturated fatty acid [20:4(n-6)] and a major constituent of brain lipids. We examined transport of AA across confluent monolayers of HBMEC. Control cells or HBMEC with knock down of FATP-1 or CD36 were cultured on Transwell® plates and incubated apically with [3H]AA and incorporation of [3H]AA into the basolateral medium was determined temporally. [3H]AA was rapidly incorporated into the basolateral medium with time in control cells. Surprisingly, knock down of FATP-1 or CD36 did not alter [3H]AA movement into the basolateral medium. The increased permeability mediated by AA was likely caused by a metabolite of AA produced de novo and was confirmed by an increased movement of fluorescent dextran from apical to basolateral medium. HBMECs expressed PGE2 synthase, cyclooxygenase-1 and -2, PGE2 receptors, tight junction proteins and prostaglandin transporters. The AA-mediated increase in membrane permeability was not attenuated by cyclooxygenase inhibitor drugs (NSAIDs). Incubation of the HBMEC monolayers with exogenous PGE2 resulted in attenuation of the AA-mediated permeability increases. The results indicate that AA increases the permeability of the HBMEC monolayer likely via increased production of metabolites or by-products of the lipoxygenase or epoxygenase pathways. These observations may explain the rapid influx of AA into the brain previously observed upon plasma infusion with AA.en_US
dc.description.noteOctober 2013en_US
dc.identifier.urihttp://hdl.handle.net/1993/21704
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectBlood brain barrieren_US
dc.subjectHuman brain microvessel endothelial cellsen_US
dc.subjectArachidonic aciden_US
dc.subjectPolyunsaturated fatty acidsen_US
dc.subjectProstaglandin E2en_US
dc.subjectGene expression analysisen_US
dc.titleRegulation of permeability of human brain microvessel endothelial cells by polyunsaturated fatty acidsen_US
dc.typemaster thesisen_US
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