A study of the neurotoxicity of MPTP and analogs in human neuroblastoma SH-SY5Y cells

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dc.contributor.authorSong, Xiaoouen
dc.contributor.committeechairEhrich, Marion F.en
dc.contributor.committeememberBloomquist, Jeffrey R.en
dc.contributor.committeememberEng, Ludemanen
dc.contributor.committeememberHolladay, Steven D.en
dc.contributor.committeememberJortner, Bernard S.en
dc.contributor.departmentVeterinary Medical Sciencesen
dc.date.accessioned2014-03-14T21:17:29Zen
dc.date.adate2007-08-08en
dc.date.available2014-03-14T21:17:29Zen
dc.date.issued1996en
dc.date.rdate2007-08-08en
dc.date.sdate2007-08-08en
dc.description.abstractNeuronal alterations resulting from exposure to Parkinsonian-inducing 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP) in an in vitro model SH-SYSY human neuroblastoma cells were explored using cytotoxic effects, neurochemical changes and pathological injury as endpoints. The results suggested that: MPTP entered the SH-SYS5Y human neuroblastoma cells through a non-dopamine transport mechanism, and was metabolized to 1-methyl-4-phenyl-2,3-dihydropyridium (MPDP⁺) and 1-methyl-4-phenylpyridium (MPP⁺) by monoamine oxidase (MAO). MPP⁺, the neurotoxic analog of MPTP, was taken up into cells through a dopamine (DA) uptake mechanism. MPTP, via its metabolite MPP⁺, inhibited NADH dehydrogenase activity. The MPTP-induced alterations of morphology included formation of blebs, attenuated neutrites, abnormal mitochondria with electron-density of matrix and disorganization of cristae, and abnormal aggregation of filamentous material of the cytoskeleton. MPTP was neurotoxic to the dopaminergic system, inhibiting monoamine oxidase (MAO) activity, and decreasing levels of dopamine (DA) and other catecholamines. In addition, MPTP enhanced ³H-DA release from cells, and its metabolite MPP⁺ inhibited ³H-DA uptake. MPTP was found to directly act on the cholinergic system in SH-SY5Y cells, causing dose-related decreases in the binding at muscarinic and nicotinic receptors. MPTP also inhibited acetylcholinesterase (AChE) activity and increased choline levels. The MPTP-induced increase in DA release and the decreases in catecholamines in SH-SYSY cells were blocked by pretreatment with acetylcholine receptor antagonists atropine and d-tubocurarine. MPTP caused increases in tau proteins, and also caused an increased expression of the reverse transcriptase polymerase chain reaction (RT-PCR) product after treatment for 2 to 5 days at 10⁻³ to 10⁻⁴ M. The results, for the first time, demonstrated that MPTP affected cytoskeletal associated tau protein and altered its mRNA. These results demonstrated that the human neuroblastoma cell line, SH-SYSY, can be used as an in vitro model for the study of the neurotoxicity of MPTP, including the mechanisms associated with exposure to this neurotoxicitant.en
dc.description.degreePh. D.en
dc.format.extentxxii, 258 leavesen
dc.format.mediumBTDen
dc.format.mimetypeapplication/pdfen
dc.identifier.otheretd-08082007-120224en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-08082007-120224/en
dc.identifier.urihttp://hdl.handle.net/10919/39095en
dc.language.isoenen
dc.publisherVirginia Techen
dc.relation.haspartLD5655.V856_1996.S697.pdfen
dc.relation.isformatofOCLC# 35286248en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subject1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineen
dc.subjecthuman neuroblastomaen
dc.subjectin vitroen
dc.subjectdopaminergic systemen
dc.subjectcholinergic systemen
dc.subjecttau proteinen
dc.subject.lccLD5655.V856 1996.S697en
dc.titleA study of the neurotoxicity of MPTP and analogs in human neuroblastoma SH-SY5Y cellsen
dc.typeDissertationen
dc.type.dcmitypeTexten
thesis.degree.disciplineVeterinary Medical Sciencesen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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