TY  - THES
AU  - Vasović, Dina
PY  - 2019
UR  - http://eteze.bg.ac.rs/application/showtheses?thesesId=7283
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:21040/bdef:Content/download
UR  - http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=51891471
UR  - http://nardus.mpn.gov.rs/123456789/12098
UR  - https://smile.stomf.bg.ac.rs/handle/123456789/1043
AB  - 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, (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...
AB  - 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 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...
PB  - Univerzitet u Beogradu, Stomatološki fakultet
T1  - Selective modulation of alpha6 subunit containing GABAA receptors on trigeminal neuropathic pain model
T1  - Selektivna modulacija GABAA receptora koji sadrže alfa6 podjedinicu na eksperimentalnom modelu trigeminalnog neuropatskog bola
UR  - https://hdl.handle.net/21.15107/rcub_nardus_12098
ER  - 

@phdthesis{
author = "Vasović, Dina",
year = "2019",
abstract = "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, (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..., 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 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...",
publisher = "Univerzitet u Beogradu, Stomatološki fakultet",
title = "Selective modulation of alpha6 subunit containing GABAA receptors on trigeminal neuropathic pain model, Selektivna modulacija GABAA receptora koji sadrže alfa6 podjedinicu na eksperimentalnom modelu trigeminalnog neuropatskog bola",
url = "https://hdl.handle.net/21.15107/rcub_nardus_12098"
}

Vasović, D.. (2019). Selective modulation of alpha6 subunit containing GABAA receptors on trigeminal neuropathic pain model. 
Univerzitet u Beogradu, Stomatološki fakultet..
https://hdl.handle.net/21.15107/rcub_nardus_12098

Vasović D. Selective modulation of alpha6 subunit containing GABAA receptors on trigeminal neuropathic pain model. 2019;.
https://hdl.handle.net/21.15107/rcub_nardus_12098 .

Vasović, Dina, "Selective modulation of alpha6 subunit containing GABAA receptors on trigeminal neuropathic pain model" (2019),
https://hdl.handle.net/21.15107/rcub_nardus_12098 .

TY  - JOUR
AU  - Vasović, Dina
AU  - Divović, Branka
AU  - Treven, Marco
AU  - Knutson, Daniel
AU  - Steudle, Friederike
AU  - Scholze, Petra
AU  - Obradović, Aleksandar
AU  - Fabjan, Jure
AU  - Brković, Božidar
AU  - Sieghart, Werner
AU  - Ernst, Margot
AU  - Cook, James
AU  - Savić, Miroslav
PY  - 2019
UR  - https://smile.stomf.bg.ac.rs/handle/123456789/2384
AB  - gamma-Aminobutyric acid type A (GABA(A)) receptors containing the alpha 6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 mu M enhanced gamma-aminobutyric acid (GABA) currents at recombinant rat alpha 6 beta 3 gamma 2, alpha 6 beta 3 delta and alpha 6 beta 3 receptors, whereas it was inactive at most GABA(A) receptor subtypes containing other alpha subunits. DK-I-87-1 at concentrations below 1 mu M was inactive at alpha 6-containing receptors and only weakly modulated other GABA(A) receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK-I-56-1 that positively modulates alpha 6 GABA(A) receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain.
PB  - Wiley, Hoboken
T2  - European Journal of Pain
T1  - Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors
VL  - 23
IS  - 5
SP  - 973
EP  - 984
DO  - 10.1002/ejp.1365
ER  - 

@article{
author = "Vasović, Dina and Divović, Branka and Treven, Marco and Knutson, Daniel and Steudle, Friederike and Scholze, Petra and Obradović, Aleksandar and Fabjan, Jure and Brković, Božidar and Sieghart, Werner and Ernst, Margot and Cook, James and Savić, Miroslav",
year = "2019",
abstract = "gamma-Aminobutyric acid type A (GABA(A)) receptors containing the alpha 6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 mu M enhanced gamma-aminobutyric acid (GABA) currents at recombinant rat alpha 6 beta 3 gamma 2, alpha 6 beta 3 delta and alpha 6 beta 3 receptors, whereas it was inactive at most GABA(A) receptor subtypes containing other alpha subunits. DK-I-87-1 at concentrations below 1 mu M was inactive at alpha 6-containing receptors and only weakly modulated other GABA(A) receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK-I-56-1 that positively modulates alpha 6 GABA(A) receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain.",
publisher = "Wiley, Hoboken",
journal = "European Journal of Pain",
title = "Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors",
volume = "23",
number = "5",
pages = "973-984",
doi = "10.1002/ejp.1365"
}

Vasović, D., Divović, B., Treven, M., Knutson, D., Steudle, F., Scholze, P., Obradović, A., Fabjan, J., Brković, B., Sieghart, W., Ernst, M., Cook, J.,& Savić, M.. (2019). Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors. in European Journal of Pain
Wiley, Hoboken., 23(5), 973-984.
https://doi.org/10.1002/ejp.1365

Vasović D, Divović B, Treven M, Knutson D, Steudle F, Scholze P, Obradović A, Fabjan J, Brković B, Sieghart W, Ernst M, Cook J, Savić M. Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors. in European Journal of Pain. 2019;23(5):973-984.
doi:10.1002/ejp.1365 .

Vasović, Dina, Divović, Branka, Treven, Marco, Knutson, Daniel, Steudle, Friederike, Scholze, Petra, Obradović, Aleksandar, Fabjan, Jure, Brković, Božidar, Sieghart, Werner, Ernst, Margot, Cook, James, Savić, Miroslav, "Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors" in European Journal of Pain, 23, no. 5 (2019):973-984,
https://doi.org/10.1002/ejp.1365 . .