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Selektivna modulacija GABAA receptora koji sadrže alfa6 podjedinicu na eksperimentalnom modelu trigeminalnog neuropatskog bola

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

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Author
Vasović, Dina
Mentor
Brković, Božidar
Committee members
Savić, Miroslav M.
Šćepan, Ivana
Brajović, Gavrilo
Roganović, Jelena
Metadata
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Abstract
Trigeminalni 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 bil...a 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...

poorly 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, (D...K-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...

Faculty:
Универзитет у Београду, Стоматолошки факултет
Date:
22-10-2019
Projects:
  • Pain Control and Molecular Mechanisms as Factors for Tissue Regeneration in Dentistry in Healthy and Diabetic Patients (RS-175021)
  • Behavioral ?ffects following repeated administration of newly synthesized ligands selective for distinct subtypes of GABAA receptor benzodiazepine binding site: comparison with standard psychopharmacologic drugs (RS-175076)
Keywords:
hronični bol / chronic pain / trigeminal neuropathy / α6 GABAA receptors / selective positive modulation / behavior / von Frey filaments / trigeminalna neuropatija / α6 GABAA receptori / selektivna pozitivna modulacija / ponašanje / von Frey filamenti
[ Google Scholar ]
Handle
https://hdl.handle.net/21.15107/rcub_nardus_12098
URI
http://eteze.bg.ac.rs/application/showtheses?thesesId=7283
https://nardus.mpn.gov.rs/handle/123456789/12098
https://fedorabg.bg.ac.rs/fedora/get/o:21040/bdef:Content/download
http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=51891471

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