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Selective modulation of alpha6 subunit containing GABAA receptors on trigeminal neuropathic pain model

dc.contributor.advisorBrković, Božidar
dc.contributor.otherSavić, Miroslav M.
dc.contributor.otherŠćepan, Ivana
dc.contributor.otherBrajović, Gavrilo
dc.contributor.otherRoganović, Jelena
dc.creatorVasović, Dina
dc.date.accessioned2020-02-27T11:21:43Z
dc.date.available2020-02-27T11:21:43Z
dc.date.available2020-07-03T09:15:31Z
dc.date.issued2019-10-22
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=7283
dc.identifier.urihttps://nardus.mpn.gov.rs/handle/123456789/12098
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:21040/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=51891471
dc.description.abstractTrigeminalni neuropatski bol je hronično bolno stanje orofacijalne regije koje nastaje kao posledica povrede trigeminalnog živca. Ova vrsta bola loše ili uopšte ne reaguje na terapiju, te njegovo lečenje predstavlja veliki terapijski problem koji utiče kvalitet života pacijenta. U trigeminalnom ganglionu eksprimiran je veliki broj hemijskih medijatora, a GABA je najznačajniji inhibitorni neurotransmiter. Zbog velikog broja podjedinica i njihovih različitih kombinacija, postoji veliki broj efekata koji GABA ostvaruje. U trigeminalnom ganglionu postoje GABAA receptori koji sadrže α6 podjedinicu. Smanjenje ove podjedinice primenom male interferirajuće RNK pojačava bolni odgovor kod eksperimentalnh životinja na modelima miofacijalnog i inflamatornog bola temporomandibularnog zgloba. Trigeminalni ganglion je supstrat za razvoj većeg broja patoloških stanja koje se sreću u stomatologiji, kao što su trigeminalna neuralgija i trigerminalna neuropatija. Hipoteza ove doktorske disertacije je bila da pojačavanje aktivnosti GABAA receptora koji sadrže α6 podjedinicu utiče na smanjenje bolnog odgovora u modelu trigeminalnog neuropatskog bola. Lekovi koji potenciraju aktivnost ove grupe receptora nisu dostupni u kliničkoj praksi. U ovoj doktorskoj disertaciji korišćen je DK-I-56-1, novosintetisani selektivni modulator α6 podjedinice GABAA receptora, koji pripada grupi deuterisanih pirazolohinolinona. Sprovedena je detaljna farmakokinetička analiza ovog jedinjenja na animalnom eksperimentalnom modelu. Dobijeni rezultati pokazuju da je kinetika ovog jedinjenja u plazmi i mozgu relativno spora, sa poluvremenom eliminacije od 6 h odnosno 13 h, pri čemu je postignuta slobodna koncentracija u mozgu u rasponu 10-300 nM. Ovakav farmakokinetički profil je podesan za ispitivanje u protokolima ponavljane primene...sr
dc.description.abstractpoorly controlled by current treatments. It represents major therapeutic concern and reduces patients quality of life. Numerous chemical mediators are present in trigeminal ganglia, and GABA is most common inhbitory neurotransmitter. Due to different subunit combinations, GABA can show diversity of pharmacological effects. GABAA receptors containing α6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. One of the most common orofacial pain states like trigeminal neuralgia or trigeminal neuropathy begin in trigeminal ganglia. We thus hypothesized that enhancing GABAA receptors containing the α6 subunit activity may help in neuropathic syndromes originating from the trigeminal system. Selective modulators that activate this specific receptor population are not commercially available. In this doctoral dissertation we used recently developed deuterated pyrazoloquinolinone compound, (DK-I-56-1) that selectively activates α6 subunit of GABAA receptors. Here, we performed a detailed pharmacokinetic analysis of DK-I-56-1 on animal experimental model. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 h and 13 h, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-h period. We confirmed that chronic constriction injury of infraorbital nerve is considered a reliable experimental animal model for trigeminal neuropathic pain. Results were obtained on IoN-CCI protocol in hypersensitive rats dosed intraperitoneally with 10 mg/kg DK-I-56-1 or DK-I-87-1, structurally similar pyrazoloquinolinone compound that can not induce GABA currents on α6 containing receptors...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Стоматолошки факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/175021/RS//
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/175076/RS//
dc.rightsopenAccessen
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/
dc.sourceУниверзитет у Београдуsr
dc.subjecthronični bolsr
dc.subjectchronic painen
dc.subjecttrigeminal neuropathyen
dc.subjectα6 GABAA receptorsen
dc.subjectselective positive modulationen
dc.subjectbehavioren
dc.subjectvon Frey filamentsen
dc.subjecttrigeminalna neuropatijasr
dc.subjectα6 GABAA receptorisr
dc.subjectselektivna pozitivna modulacijasr
dc.subjectponašanjesr
dc.subjectvon Frey filamentisr
dc.titleSelektivna modulacija GABAA receptora koji sadrže alfa6 podjedinicu na eksperimentalnom modelu trigeminalnog neuropatskog bolasr
dc.title.alternativeSelective modulation of alpha6 subunit containing GABAA receptors on trigeminal neuropathic pain modelen
dc.typedoctoralThesisen
dc.rights.licenseBY-NC
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/16437/Disertacija.pdf
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/16438/IzvestajKomisije22199.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/16437/Disertacija.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/16438/IzvestajKomisije22199.pdf
dc.identifier.rcubhttps://hdl.handle.net/21.15107/rcub_nardus_12098


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