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Protective mechanism of arylpiperazine dopaminergic D2ligands on nitric oxide and 6-hydroxydopamine induced SH-SY5Y human neuroblastoma cell death

dc.contributor.advisorAnđus, Pavle
dc.contributor.otherZogović, Nevena
dc.contributor.otherTrajković, Vladimir
dc.contributor.otherTomić, Mirko
dc.creatorTovilović, Gordana I.
dc.date.accessioned2016-01-05T11:46:41Z
dc.date.available2016-01-05T11:46:41Z
dc.date.available2020-07-03T08:10:27Z
dc.date.issued2012-12-28
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=167
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/2081
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:5401/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1024560050
dc.description.abstractU ovom radu je ispitivan uticaj 20 novosintetisanih arilpiperazinskih dopaminergičkih liganada na vijabilnost humanih SH-SY5Y neuroblastomskih ćelija tretiranih donorom azot monoksida (engl. nitric oxide, NO) natrijum nitroprusidom (engl. sodium nitroprusside, SNP) i uzročnikom oksidativnog stresa dopaminergičkim neurotoksinom 6-hidroksidopaminom (6-OHDA). Supstanca koje je pružala najjaču zaštitu od donora NO je bio N-{4-[2-(4-fenil-piperazin-1-il)-etil]-fenil}-pikolinamid (arilpiperazin 6a), dok je N-{3-[2-(4-fenil-piperazin-1-il)-etil]-fenil}-pikolinamid (arilpiperazin 6b) najefikasnije štitio humanu neuroblastomsku ćelijsku liniju SH-SY5Y od 6-OHDA. Arilpiperazin 6a je delimično sprečavao povećanje sadržaja superoksid anjon radikala, smanjenje potencijala membrane mitohondrija i unutarćelijskog sadržaja adenozin-trifosfata (ATP), aktivaciju kaspaza i sledstvenu fragmentaciju DNK koje je izazivao NO. Uočeno smanjenje unutarćelijske koncentracije superoksida nije bilo posledica direktne interakcije ispitivanog arilpiperazina sa O2 -∙, niti je supstanca 6a uticala na akumulaciju NO unutar ćelije. Arilpiperazin 6a je sprečavao inhibiciju protektivnog Akt, kao i aktivaciju proapoptotskih ERK, JNK i AMPK signalnih puteva izazvane SNP-om, ukazujući na bitnu ulogu ovih molekula u njegovom zaštitnom delovanju. Potencijalni značaj arilpiperazina 6a u sprečavanju neurodegenerativnih/neurozapaljenskih procesa posebno naglašava činjenica da je štitio neuronima slične SH-SY5Y ćelije i od citotoksičnog efekta NO-a poreklom od stimulisanih makrofaga. Slično, arilpiperazin 6b je sprečavao povećanje unutarćelijskog sadržaja superoksid anjon radikala (O2 -∙), smanjenje potencijala membrane mitohondrija posledične apoptotske događaje – aktivaciju kaspaza i fragmentaciju DNK – koje je izazivao 6-OHDA. Stabilizacija potencijala mitohondrijalne membrane pod dejstvom arilpiperazina 6b se vremenski poklapala sa smanjenjem unutarćelijskog sadržaja O2 -∙,što ukazuje da je supstanca 6b inhibirala oslobađanje superoksida iz oštećenih mitohondrija stabilizacijom potencijala njihove membrane...sr
dc.description.abstractWe investigated the protective ability of 20 novel arylpiperazine-based dopaminergic ligands against nitric oxide (NO) and dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA)-mediated neurotoxicity. The most potent neuroprotective compound against NO-induced toxicity was N-{4-[2-(4-phenylpiperazin- 1-yl)-ethyl]-phenyl}-picolinamide (arylpiperazine 6a), while N-{3-[2-(4- phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide (arylpiperazine 6b) most effectively protected SH-SY5Y human neuron-like cells from 6-OHDA-generated oxidative injury. Arylpiperazine 6a diminished the proapoptotic action of NO donor sodium nitroprusside (SNP) by decreasing superoxide anion content, mitochondrial membrane depolarization, decline in intracellular adenozine-triphosphate (ATP) content, caspase activation and subsequent phosphatydilserine externalization/DNA fragmentation. The observed decrease of intracellular superoxide concentration was not mediated by direct O2 -∙ scavenging. Arylpiperazine 6a did not interfere with NO accumulation within the cell. The protective effect of arylpiperazine 6a in NO-induced stress was associated with activation of anti-apoptotic (Akt) and the inhibition of proapoptotic (JNK, ERK, AMPK) signaling pathways. A potential therapeutic value of the arylpiperazine 6a in neurodegenerative/neuroinflammatory diseases prevention was additionally supported by the ability of this arylpiperazine to protect SH-SY5Y neuronlike cells from macrophage-derived NO. Similarly, arylpiperazine 6b prevented 6-OHDA-induced increase in superoxide anion content, mitochondrial membrane depolarization and following apoptotic related events – caspase activation and DNA fragmentation. The stabilization of 6-OHDA-disrupted mitochondrial membrane potential by arylpiperazine 6b correlated with the decrease in intracellular superoxide anion (O2 -∙) content, suggesting that decline in O2 -∙ concentration resulted from mitohondrial membrane stabilizationen
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173053/RS//
dc.relationinfo:eu-repo/grantAgreement/MESTD/Integrated and Interdisciplinary Research (IIR or III)/41030/RS//
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectarilpiperazinisr
dc.subjectarylpiperazinesen
dc.subjectneuroprotekcijasr
dc.subjectazot monoksidsr
dc.subjectoksidativni stressr
dc.subject6-hidroksidopaminsr
dc.subjectapoptozasr
dc.subjectautofagijasr
dc.subjectdopaminski D2 receptorisr
dc.subjectneuroprotectionen
dc.subjectnitric oxideen
dc.subjectoxidative stressen
dc.subject6-hydroxydopamineen
dc.subjectapoptosisen
dc.subjectautophagyen
dc.subjectdopamine D2 receptorsen
dc.titleMehanizam zaštitnog dejstva arilpiperazinskih liganada za dopaminske D2 receptore u azot monoksidom i 6-hidroksidopaminom izazvanoj smrti SH-SY5Y ćelija humanog neuroblastomasr
dc.titleProtective mechanism of arylpiperazine dopaminergic D2ligands on nitric oxide and 6-hydroxydopamine induced SH-SY5Y human neuroblastoma cell deathen
dc.typedoctoralThesis
dc.rights.licenseBY-NC-ND
dcterms.abstractAнђус, Павле; Зоговић, Невена; Томић, Мирко; Трајковић, Владимир; Товиловић, Гордана И.;
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/2309/Disertacija.pdf


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