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Propofol-induced changes in neurotrophic signaling in 14-day-old rat forebrain

dc.contributor.advisorKanazir, Selma
dc.contributor.otherNedeljković, Nadežda
dc.contributor.otherPešić, Vesna
dc.contributor.otherRuždijić, Sabera
dc.creatorPopić, Jelena
dc.date.accessioned2016-01-05T11:45:29Z
dc.date.available2016-01-05T11:45:29Z
dc.date.available2020-07-03T08:11:25Z
dc.date.issued2012-07-06
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=38
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/2034
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:2344/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=41535247
dc.description.abstractNeurotrofini čine familiju signalnih molekula sa brojnim uticajima na rast, preživljavanje, diferencijaciju i sinaptičku plastičnost postmitotskih neurona, kako u adultnom mozgu, tako i u mozgu tokom razvića. Neurotrofini (BDNF, NGF) se sa određenim afinitetom vezuju za Trk receptore, iniciraju njihovu dimerizaciju i autofosforilaciju i na taj način se pokreće aktivacija signalnih puteva kao što su PI3K/Akt i MAPK/ERK. Akt i ERK kinaze imaju ključne regulatorne uloge u mozgu u procesima kao što su neuronalna proliferacija, diferencijacija, razviće, migracija, preživljavanje i dugotrajna sinaptička plastičnost. Aktivan (fosforilisan) Akt štiti ćeliju od apoptoze tako što stimuliše ekspresiju proteina koji favorizuju preživljavanje ćelija i sa druge strane inhibira egzekutorske kaspaze. Aktivacija ERK1/2 kinaze pomoviše preživljavanje, međutim u određenim uslovima ERK1/2 može imati i pro-apoptotske odlike. S obzirom da je uloga neurotrofina u neurotoksičnosti koja je indukovana anestezijom tokom ranog postnatalnog razvića pokazana u nekoliko studija, cilj ove doktorske disertacije je bio da se na molekulskom nivou ispitaju promene u signalnom putu neurotrofina koje nastaju u kori i talamusu postnatalnih pacova nakon primene anestetske doze propofola, kao i da se utvrdi potencijal tretmana da indukuje ćelijsku smrt i/ili promene u sinaptičkoj plastičnosti. Nakon jednokratne primene propofola (25 mg/kg i.p.) ispitana je vremenska i prostorna ekspresija neurotrofina BDNF i NGF, njihovih aktiviranih receptora TrkB, TrkA i p75 receptora, kao i nishodnih kinaza Akt i ERK kod 14 dana starih (PND14) pacova. Ispitan je i potencijal propofolskog tretman da indukuje ćelijsku smrt, praćenjem ekspresije TNF-α, TNFR1, aktivnog fragmenta kaspaze-3, njegovog inhibitora XIAP proteina, kao i transkripcionog faktora NFκB. Finalno je ispitivan potencijal propofolskog tretmana da indukuje promene u ekspresiji markera sinaptičke plastičnosti (MAP-2, drebrina, GAP-43, sinaptofizina, sinukleina-1 i N-kadherina). Promene su praćene u kori i talamusu kao primarnim ciljevima dejstva anestetskog delovanja. Primenom sledećih metoda Western blot analize, RT- i PCR-a u realnom vremenu ispitivane su promene u ekspresiji ciljnih proteina i iRNK, a primenom Fluoro-žad B histološkog bojenja analizirana je pojava neurona u degeneraciji...sr
dc.description.abstractThe neurotrophins are a family of secreted proteins that mediate numerous functions in both the developing and mature nervous system, including growth, survival, differentiation and synaptic plasticity of postmitotic neurons. The binding of neurotrophins (BDNF, NGF) to Trk receptors induces their dimerization which is followed by autophosphorylation of tyrosine residues within the intracellular kinase domain, that leads to the activation of signaling pathways such as the PI3K/Akt and MAPK/ERK pathways. Akt and ERK kinases play a crucial role in regulating various processes in the brain, including neuronal proliferation, differentiation, development, migration, survival and long-term synaptic plasticity. Phosphorylated Akt can protect cells from apoptosis via stimulation of the expression of proteins that favor cell survival and by inhibiting executor caspases. Activation of ERK1/2 generally promotes cell survival, although under certain conditions, ERK1/2 can possess proapoptotic properties. Since several studies have revealed a role for neurotrophins in anesthesia-induced neurotoxicity in the developing brain, the goal of this study was to explore the potential of anesthetic dose of propofol to influence neurotrophic signaling pathway in the cortex and thalamus of 14-day-old (PND14) rats, and also to investigate whether same treatment is able to induce neurodegeneration and/or changes in synaptic plasticity. In this study we monitored the spatial and temporal expression of neurotrophic signaling molecules (BDNF, NGF, TrkA, TrkB, p75, Akt and ERK) in the brain of PND14 Wistar rats after the application of a single propofol dose (25 mg/kg i.p). The potential of propofol treatment to induce cell death was also examined, following the expression of TNF-α, TNFR1, cleaved caspase-3 fragment, XIAP and NFκB. Finally, we investigated the changes in the markers of synaptic plasticity (MAP-2, drebrin, GAP-43, synaptophysin, synuclein-1 and N-cadherin) after the propofol treatment. The structures of interest were the cortex and thalamus as the primary areas of anesthetic actions. Changes of the levels of mRNA and proteins of interest were assessed by RT- or Real Time PCR and Western immunoblot analysis at different time points during the first 24 h after the treatment. Fluoro-Jade B staining was used to follow the appearance of degenerating neurons...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173056/RS//
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173056/RS//
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectPropofolsr
dc.subjectPropofolen
dc.subjectkorasr
dc.subjecttalamussr
dc.subjectrano postnatalno razvićesr
dc.subjectsignalni put neurotrofinasr
dc.subjectneuroapoptozasr
dc.subjectsinaptička plastičnostsr
dc.subjectcortexen
dc.subjectthalamusen
dc.subjectpostnatal developmenten
dc.subjectneurotrophic signaling pathwayen
dc.subjectneuroapoptosisen
dc.subjectsynaptic plasticityen
dc.titleUticaj propofola na signalni put neurotrofina u prednjem mozgu pacova starih 14 danasr
dc.titlePropofol-induced changes in neurotrophic signaling in 14-day-old rat forebrainen
dc.typedoctoralThesis
dc.rights.licenseBY-NC-ND
dcterms.abstractКаназир, Селма; Руждијић, Сабера; Недељковић, Надежда; Пешић, Весна; Попић, Јелена; Утицај пропофола на сигнални пут неуротрофина у предњем мозгу пацова старих 14 дана; Утицај пропофола на сигнални пут неуротрофина у предњем мозгу пацова старих 14 дана;
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/2513/Disertacija.pdf


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