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 M.
AU  - Savić, Miroslav
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3315
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 M. 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. M.,& 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 JM, 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 M., 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 . .

TY  - JOUR
AU  - Batinić, Bojan
AU  - Stanković, Tamara
AU  - Stephen, Michael
AU  - Kodali, Revathi
AU  - Tiruveedhula, Veera V.
AU  - Li, Guanguan
AU  - Scholze, Petra
AU  - Marković, Bojan
AU  - Obradović, Aleksandar
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3070
AB  - It is unclear whether GABA(A) receptors (GABA(A)Rs) that contain the alpha 3-subunit are substantially involved in the anxiolytic effects of benzodiazepines (BDZs). In the present study, we tested YT-III-31, a newer BDZ ligand with functional preference for alpha 3 ss gamma 2 GABA(A) Rs, in two paradigms of unconditioned anxiety, the open field and elevated plus maze in rats. The effective dose of YT-III-31 (2 mg/kg) displayed a clear anxiolytic-like profile, unhampered by sedative action, in both tests. At a higher dose (10 mg/kg), YT-III-31 induced ataxia in the rotarod and sedation in spontaneous locomotor activity test. The latter effect was preventable by flumazenil and ss CCt, the non-selective and alpha 1 ss gamma 2 GABA(A)R affinity-selective antagonist, respectively, demonstrating that sedative properties of YT-III-31, when attained, are mediated by the alpha 1 gamma 2 site. To elucidate the receptor substrate of subtle behavioral differences between YT-III-31 and diazepam, we approximated in vivo receptor potentiation for both ligands, based on estimated unbound concentrations in rat brains. Far different from diazepam, YT-III-31 has significantly lower affinity for the alpha 1 gamma 2 over other BDZ-sensitive sites, and at lower doses (1-2 mg/kg) was devoid of potentiation at alpha 1 ss gamma 2 GABA(A)Rs. The approximation approach revealed a modest selectivity of YT-III-31 for alpha 3 gamma 2- in comparison to alpha 2 gamma 2 and alpha 5 gamma 2 binding sites, suggesting that its anxiolytic-like activity may not necessarily or predominantly reflect potentiation at alpha 3 ss gamma 2 GABA(A)Rs. Nonetheless, as the anxiolytic effects are achievable at a dose devoid of any sedative potential, and having favorable safety (cytotoxicity) and metabolic stability profile, YT-III-31 represents a valuable candidate for further translational research.
PB  - Elsevier Science BV, Amsterdam
T2  - European Neuropsychopharmacology
T1  - Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!
VL  - 28
IS  - 8
SP  - 903
EP  - 914
DO  - 10.1016/j.euroneuro.2018.05.014
ER  - 

@article{
author = "Batinić, Bojan and Stanković, Tamara and Stephen, Michael and Kodali, Revathi and Tiruveedhula, Veera V. and Li, Guanguan and Scholze, Petra and Marković, Bojan and Obradović, Aleksandar and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2018",
abstract = "It is unclear whether GABA(A) receptors (GABA(A)Rs) that contain the alpha 3-subunit are substantially involved in the anxiolytic effects of benzodiazepines (BDZs). In the present study, we tested YT-III-31, a newer BDZ ligand with functional preference for alpha 3 ss gamma 2 GABA(A) Rs, in two paradigms of unconditioned anxiety, the open field and elevated plus maze in rats. The effective dose of YT-III-31 (2 mg/kg) displayed a clear anxiolytic-like profile, unhampered by sedative action, in both tests. At a higher dose (10 mg/kg), YT-III-31 induced ataxia in the rotarod and sedation in spontaneous locomotor activity test. The latter effect was preventable by flumazenil and ss CCt, the non-selective and alpha 1 ss gamma 2 GABA(A)R affinity-selective antagonist, respectively, demonstrating that sedative properties of YT-III-31, when attained, are mediated by the alpha 1 gamma 2 site. To elucidate the receptor substrate of subtle behavioral differences between YT-III-31 and diazepam, we approximated in vivo receptor potentiation for both ligands, based on estimated unbound concentrations in rat brains. Far different from diazepam, YT-III-31 has significantly lower affinity for the alpha 1 gamma 2 over other BDZ-sensitive sites, and at lower doses (1-2 mg/kg) was devoid of potentiation at alpha 1 ss gamma 2 GABA(A)Rs. The approximation approach revealed a modest selectivity of YT-III-31 for alpha 3 gamma 2- in comparison to alpha 2 gamma 2 and alpha 5 gamma 2 binding sites, suggesting that its anxiolytic-like activity may not necessarily or predominantly reflect potentiation at alpha 3 ss gamma 2 GABA(A)Rs. Nonetheless, as the anxiolytic effects are achievable at a dose devoid of any sedative potential, and having favorable safety (cytotoxicity) and metabolic stability profile, YT-III-31 represents a valuable candidate for further translational research.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!",
volume = "28",
number = "8",
pages = "903-914",
doi = "10.1016/j.euroneuro.2018.05.014"
}

Batinić, B., Stanković, T., Stephen, M., Kodali, R., Tiruveedhula, V. V., Li, G., Scholze, P., Marković, B., Obradović, A., Ernst, M., Cook, J. M.,& Savić, M.. (2018). Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 28(8), 903-914.
https://doi.org/10.1016/j.euroneuro.2018.05.014

Batinić B, Stanković T, Stephen M, Kodali R, Tiruveedhula VV, Li G, Scholze P, Marković B, Obradović A, Ernst M, Cook JM, Savić M. Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!. in European Neuropsychopharmacology. 2018;28(8):903-914.
doi:10.1016/j.euroneuro.2018.05.014 .

Batinić, Bojan, Stanković, Tamara, Stephen, Michael, Kodali, Revathi, Tiruveedhula, Veera V., Li, Guanguan, Scholze, Petra, Marković, Bojan, Obradović, Aleksandar, Ernst, Margot, Cook, James M., Savić, Miroslav, "Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!" in European Neuropsychopharmacology, 28, no. 8 (2018):903-914,
https://doi.org/10.1016/j.euroneuro.2018.05.014 . .

TY  - JOUR
AU  - Obradović, Aleksandar
AU  - Savić, Miroslav
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2976
AB  - Antidepressants are one of the most widely used and criticized drug classes. Long-term effects leading to clinical efficacy of antidepressants in indications such as depression or anxiety disorders are poorly understood. The analysis of clinical trials suggests that, to a substantial degree, listening to antidepressants means hearing placebo. The precipitation of suicidal ideation is a possibility that needs to be considered when introducing antidepressants, especially in young patients. The discontinuation symptoms following cessation of treatment emerge frequently, and essentially are manifestations of withdrawal. Many, if not most, patients require multiple modifications in treatment in order to reach remission and avoid relapse or recurrence. However, these drugs are needed in clinical practice, and it is of paramount importance to precisely tailor treatment with antidepressants and adjunctive drugs to achieve optimal efficacy with minimal adverse effects. There are also hopes that novel drugs with rapid ketamine-like antidepressant actions may be introduced in the near future, thus solving the issue of acute management of severe depressions.
AB  - Antidepresivi spadaju u lekove koji su u isto vreme najviše korišćeni i kritikovani. Dugotrajni efekti antidepresiva koji obezbeđuju kliničku efikasnost u indikacijama kao što su depresija ili anksiozni poremećaji slabo su razjašnjeni. Analiza rezultata kliničkih ispitivanja sugeriše da antidepresivnom dejstvu ovih lekova, u znatnom obimu, doprinosi placebo efekat. Precipitacija misli o suicidu predstavlja mogućnost koja se mora temeljno razmotriti prilikom uvođenja antidepresiva, posebno kod mladih pacijenata. Simptomi diskontinuacije nakon prekida terapije javljaju se često, i suštinski predstavljaju manifestacije obustave. Višestruke modifikacije tretmana, a u cilju postizanja remisije i izbegavanja relapsa ili recidiva, zahtevaju brojni pacijenti, ako ne i većina njih. Uprkos svemu, ovi lekovi jesu neophodni u kliničkoj praksi, i precizno prilagođavanje tretmana antidepresivima i adjuvantnim lekovima od neprocenjivog je značaja u cilju postizanja optimalne efikasnosti sa minimumom neželjenih efekata. Dodatno, postoje očekivanja da bi novi lekovi sa brzim antidepresivnim dejstvom sličnim ketaminu mogli da budu uvedeni u skorijoj budućnosti, čime bi se prevazišao problem akutnog zbrinjavanja teških depresija.
PB  - Savez farmaceutskih udruženja Srbije, Beograd
T2  - Arhiv za farmaciju
T1  - Antidepressants: Myths, facts and perspectives
T1  - Antidepresivi - mitovi, činjenice i perspektive
VL  - 67
IS  - 5
SP  - 291
EP  - 301
DO  - 10.5937/arhfarm1705291O
ER  - 

@article{
author = "Obradović, Aleksandar and Savić, Miroslav",
year = "2017",
abstract = "Antidepressants are one of the most widely used and criticized drug classes. Long-term effects leading to clinical efficacy of antidepressants in indications such as depression or anxiety disorders are poorly understood. The analysis of clinical trials suggests that, to a substantial degree, listening to antidepressants means hearing placebo. The precipitation of suicidal ideation is a possibility that needs to be considered when introducing antidepressants, especially in young patients. The discontinuation symptoms following cessation of treatment emerge frequently, and essentially are manifestations of withdrawal. Many, if not most, patients require multiple modifications in treatment in order to reach remission and avoid relapse or recurrence. However, these drugs are needed in clinical practice, and it is of paramount importance to precisely tailor treatment with antidepressants and adjunctive drugs to achieve optimal efficacy with minimal adverse effects. There are also hopes that novel drugs with rapid ketamine-like antidepressant actions may be introduced in the near future, thus solving the issue of acute management of severe depressions., Antidepresivi spadaju u lekove koji su u isto vreme najviše korišćeni i kritikovani. Dugotrajni efekti antidepresiva koji obezbeđuju kliničku efikasnost u indikacijama kao što su depresija ili anksiozni poremećaji slabo su razjašnjeni. Analiza rezultata kliničkih ispitivanja sugeriše da antidepresivnom dejstvu ovih lekova, u znatnom obimu, doprinosi placebo efekat. Precipitacija misli o suicidu predstavlja mogućnost koja se mora temeljno razmotriti prilikom uvođenja antidepresiva, posebno kod mladih pacijenata. Simptomi diskontinuacije nakon prekida terapije javljaju se često, i suštinski predstavljaju manifestacije obustave. Višestruke modifikacije tretmana, a u cilju postizanja remisije i izbegavanja relapsa ili recidiva, zahtevaju brojni pacijenti, ako ne i većina njih. Uprkos svemu, ovi lekovi jesu neophodni u kliničkoj praksi, i precizno prilagođavanje tretmana antidepresivima i adjuvantnim lekovima od neprocenjivog je značaja u cilju postizanja optimalne efikasnosti sa minimumom neželjenih efekata. Dodatno, postoje očekivanja da bi novi lekovi sa brzim antidepresivnim dejstvom sličnim ketaminu mogli da budu uvedeni u skorijoj budućnosti, čime bi se prevazišao problem akutnog zbrinjavanja teških depresija.",
publisher = "Savez farmaceutskih udruženja Srbije, Beograd",
journal = "Arhiv za farmaciju",
title = "Antidepressants: Myths, facts and perspectives, Antidepresivi - mitovi, činjenice i perspektive",
volume = "67",
number = "5",
pages = "291-301",
doi = "10.5937/arhfarm1705291O"
}

Obradović, A.,& Savić, M.. (2017). Antidepressants: Myths, facts and perspectives. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije, Beograd., 67(5), 291-301.
https://doi.org/10.5937/arhfarm1705291O

Obradović A, Savić M. Antidepressants: Myths, facts and perspectives. in Arhiv za farmaciju. 2017;67(5):291-301.
doi:10.5937/arhfarm1705291O .

Obradović, Aleksandar, Savić, Miroslav, "Antidepressants: Myths, facts and perspectives" in Arhiv za farmaciju, 67, no. 5 (2017):291-301,
https://doi.org/10.5937/arhfarm1705291O . .

TY  - JOUR
AU  - Batinić, Bojan
AU  - Santrač, Anja
AU  - Divović, Branka
AU  - Timić, Tamara
AU  - Stanković, Tamara
AU  - Obradović, Aleksandar
AU  - Joksimović, Srđan
AU  - Savić, Miroslav
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2558
AB  - Numerous basic and epidemiological studies have connected prenatal maternal immune activation with the occurrence of schizophrenia and/or autism. Depending on subtle differences in protocols of the used animal model, a variety of behavioral abnormalities has been reported. This study investigated behavioral differences in Wistar rat offspring of both genders, exposed to the 100 mu g/kg per day dose of lipopolysaccharide (LPS) in late embryogenesis (embryonic days 15 and 16), while tested at their adolescent and young adult age (postnatal days 40 and 60, respectively). Immune activation was confirmed by detecting high levels of TNF-alpha and IL-6 in dam blood withdrawn 2 h after the first dose of LPS. The animals were assessed in three consecutive trials of locomotor activity (novelty exploration, response to i.p. saline injection and challenge with 0.5 mg/kg amphetamine), Morris water maze and social interaction tests. Overt behavioral dysfunction was perceived in adult rats only, and these changes were gender-distinctive. When compared with control rats, LPS females displayed baseline hypolocomotion and a decreased reactivity to amphetamine, while LPS males exhibited spatial learning (acquisition trials) and memory (probe trial) impairments. Prenatal treatment did not affect the time spent in social interaction. As maternal exposure to LPS in late gestation resulted in behavioral changes in offspring in early adulthood, it may model schizophrenia-like, but not autism-like endophenotypes. However, lack of a potentiated response to amphetamine testified that this model could not mimic positive symptoms, but rather certain traits of cognitive dysfunction and deficit symptoms, in males and females, respectively.
PB  - Elsevier Science BV, Amsterdam
T2  - Behavioural Brain Research
T1  - Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring
VL  - 299
SP  - 72
EP  - 80
DO  - 10.1016/j.bbr.2015.11.025
ER  - 

@article{
author = "Batinić, Bojan and Santrač, Anja and Divović, Branka and Timić, Tamara and Stanković, Tamara and Obradović, Aleksandar and Joksimović, Srđan and Savić, Miroslav",
year = "2016",
abstract = "Numerous basic and epidemiological studies have connected prenatal maternal immune activation with the occurrence of schizophrenia and/or autism. Depending on subtle differences in protocols of the used animal model, a variety of behavioral abnormalities has been reported. This study investigated behavioral differences in Wistar rat offspring of both genders, exposed to the 100 mu g/kg per day dose of lipopolysaccharide (LPS) in late embryogenesis (embryonic days 15 and 16), while tested at their adolescent and young adult age (postnatal days 40 and 60, respectively). Immune activation was confirmed by detecting high levels of TNF-alpha and IL-6 in dam blood withdrawn 2 h after the first dose of LPS. The animals were assessed in three consecutive trials of locomotor activity (novelty exploration, response to i.p. saline injection and challenge with 0.5 mg/kg amphetamine), Morris water maze and social interaction tests. Overt behavioral dysfunction was perceived in adult rats only, and these changes were gender-distinctive. When compared with control rats, LPS females displayed baseline hypolocomotion and a decreased reactivity to amphetamine, while LPS males exhibited spatial learning (acquisition trials) and memory (probe trial) impairments. Prenatal treatment did not affect the time spent in social interaction. As maternal exposure to LPS in late gestation resulted in behavioral changes in offspring in early adulthood, it may model schizophrenia-like, but not autism-like endophenotypes. However, lack of a potentiated response to amphetamine testified that this model could not mimic positive symptoms, but rather certain traits of cognitive dysfunction and deficit symptoms, in males and females, respectively.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Behavioural Brain Research",
title = "Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring",
volume = "299",
pages = "72-80",
doi = "10.1016/j.bbr.2015.11.025"
}

Batinić, B., Santrač, A., Divović, B., Timić, T., Stanković, T., Obradović, A., Joksimović, S.,& Savić, M.. (2016). Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring. in Behavioural Brain Research
Elsevier Science BV, Amsterdam., 299, 72-80.
https://doi.org/10.1016/j.bbr.2015.11.025

Batinić B, Santrač A, Divović B, Timić T, Stanković T, Obradović A, Joksimović S, Savić M. Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring. in Behavioural Brain Research. 2016;299:72-80.
doi:10.1016/j.bbr.2015.11.025 .

Batinić, Bojan, Santrač, Anja, Divović, Branka, Timić, Tamara, Stanković, Tamara, Obradović, Aleksandar, Joksimović, Srđan, Savić, Miroslav, "Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring" in Behavioural Brain Research, 299 (2016):72-80,
https://doi.org/10.1016/j.bbr.2015.11.025 . .

TY  - JOUR
AU  - Obradović, Aleksandar
AU  - Joksimović, Srđan
AU  - Poe, Michael M.
AU  - Ramerstorfer, Joachim
AU  - Varagić, Zdravko
AU  - Namjoshi, Ojas A.
AU  - Batinić, Bojan
AU  - Radulović, Tamara
AU  - Marković, Bojan
AU  - Roth, Brian L.
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2200
AB  - Enormous progress in understanding the role of four populations of benzodiazepine-sensitive GABA(A) receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently nonselective modulators. We report on SH-I-048A, a newly synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2 mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10 mg/kg dose of the novel ligand and 2 mg/kg diazepam; however, SH-I-048A was relatively more active at and as-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24 h after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at al-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the as subunit. The current results encourage further innovative approaches aimed at linking in vitro an in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands.
PB  - Elsevier Science BV, Amsterdam
T2  - Brain Research
T1  - Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects
VL  - 1554
SP  - 36
EP  - 48
DO  - 10.1016/j.brainres.2014.01.036
ER  - 

@article{
author = "Obradović, Aleksandar and Joksimović, Srđan and Poe, Michael M. and Ramerstorfer, Joachim and Varagić, Zdravko and Namjoshi, Ojas A. and Batinić, Bojan and Radulović, Tamara and Marković, Bojan and Roth, Brian L. and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2014",
abstract = "Enormous progress in understanding the role of four populations of benzodiazepine-sensitive GABA(A) receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently nonselective modulators. We report on SH-I-048A, a newly synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2 mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10 mg/kg dose of the novel ligand and 2 mg/kg diazepam; however, SH-I-048A was relatively more active at and as-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24 h after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at al-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the as subunit. The current results encourage further innovative approaches aimed at linking in vitro an in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Brain Research",
title = "Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects",
volume = "1554",
pages = "36-48",
doi = "10.1016/j.brainres.2014.01.036"
}

Obradović, A., Joksimović, S., Poe, M. M., Ramerstorfer, J., Varagić, Z., Namjoshi, O. A., Batinić, B., Radulović, T., Marković, B., Roth, B. L., Sieghart, W., Cook, J. M.,& Savić, M.. (2014). Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects. in Brain Research
Elsevier Science BV, Amsterdam., 1554, 36-48.
https://doi.org/10.1016/j.brainres.2014.01.036

Obradović A, Joksimović S, Poe MM, Ramerstorfer J, Varagić Z, Namjoshi OA, Batinić B, Radulović T, Marković B, Roth BL, Sieghart W, Cook JM, Savić M. Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects. in Brain Research. 2014;1554:36-48.
doi:10.1016/j.brainres.2014.01.036 .

Obradović, Aleksandar, Joksimović, Srđan, Poe, Michael M., Ramerstorfer, Joachim, Varagić, Zdravko, Namjoshi, Ojas A., Batinić, Bojan, Radulović, Tamara, Marković, Bojan, Roth, Brian L., Sieghart, Werner, Cook, James M., Savić, Miroslav, "Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects" in Brain Research, 1554 (2014):36-48,
https://doi.org/10.1016/j.brainres.2014.01.036 . .

TY  - JOUR
AU  - Obradović, Aleksandar
AU  - Joksimović, Srđan
AU  - Michael, Poe M.
AU  - Timić, Tamara
AU  - James, Cook M.
AU  - Savić, Miroslav
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2284
AB  - The complex clinical picture of mono-neuropathy following injury of peripheral nerve is often accompanied by changes in the patients' affective states. It has been shown that positive allosteric modulators of GABAA receptors can decrease nociceptive transmission in animal pain models. However, recent findings suggest a possibility that at least some of the antinociceptive effects of benzodiazepines, related to neuropathic painful stimuli, may to a significant degree be a consequence of their anxiolytic action. In this study we evaluated the possible delayed effects of SH-I-048A, a newly- synthesized high-efficacy nonselective positive modulator of GABAA receptors, on anxiety-like behavior and locomotor activity in Wistar rats with a previously induced peripheral nerve injury. Assessment of behavioral parameters, using spontaneous locomotor activity and elevated plus maze tests, was performed 48h after completion of single-day three i.p. injections treatment consisting of zero, one, two or three doses of SH-I-048A (10 mg/kg). In general, rats' behavior observed 72 h after a moderate peripheral nerve injury did not indicate the persistence of sequelae of mono-neuropathic pain. The rats treated with three doses of SH-I-048A displayed an enhanced immobility time in the locomotor activity test, without concomitant decrease of the total distance traveled. On the other hand, in the group treated with two doses of SH-I-048A, a decrease in the emotional reactivity in the elevated plus maze test was observed. Subtle changes in the regimen of dosing of SH-I-048A affect locomotor activity and anxiety-related behavior in animals with peripheral nerve injury.
AB  - Kompleksna klinička slika neuropatije nakon povrede perifernog nerva često je praćena i promenama afektivnog stanja pacijenata. U animalnim modelima bola pokazano je da pozitivni alosterni modulatori GABAA receptora mogu da smanje nociceptivnu transmisiju. Međutim, skorašnji nalazi ukazuju i na mogućnost da je prividni antinociceptivni efekat benzodiazepina nakon delovanja akutnog bolnog stimulusa u značajnoj meri posledica anksiolitičnog efekta. U ovoj studiji ispitani su mogući odloženi efekti novosintetisanog, neselektivnog liganda GABAA receptora (SH-I-048A) na lokomotornu aktivnost i ponašanje u vezi sa anksioznošću kod pacova soja Wistar prethodno podvrgnutih povredi perifernog nerva. Procena bihejvioralnih parametara sprovedena je testovima spontane lokomotorne aktivnosti i uzdignutog plus lavirinta 48 sati nakon što su životinje u periodu od 24 sata primile rastvarač, jednu, dve ili tri doze SH-I-048A (10 mg/kg). Generalno, ponašanje pacova praćeno 72 sata nakon umerene povrede perifernog nerva nije ukazivalo na prisustvo perzistentnih posledica neuropatskog bola. Pacovi prethodno tretirani sa tri doze SH-I-048A ispoljili su povećano vreme imobilnosti u testu lokomotorne aktivnosti, bez značajnog smanjenja ukupnog pređenog puta. S druge strane, u grupi koja je tretirana sa dve doze SH-I-048A zapažena je smanjena emocionalna reaktivnost u uzdignutom plus lavirintu. Kod životinja sa povredom perifernog nerva, suptilne razlike u režimu doziranja pozitivnog modulatora GABAA, mogu značajno da utiču na ponašanje vezano za lomotornu aktivnost i nivo anksioznosti.
PB  - Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd
T2  - Acta veterinaria
T1  - Delayed behavioral effects of SH-I-048A, a novel nonselective positive modulator of GABAA receptors, after peripheral nerve injury in rats
T1  - Odloženi bihejvioralni efekti SH-I-048A, novog neselektivnog pozitivnog modulatora GABAA receptora, nakon povrede perifernog nerva pacova
VL  - 64
IS  - 2
SP  - 189
EP  - 199
DO  - 10.2478/acve-2014-0018
ER  - 

@article{
author = "Obradović, Aleksandar and Joksimović, Srđan and Michael, Poe M. and Timić, Tamara and James, Cook M. and Savić, Miroslav",
year = "2014",
abstract = "The complex clinical picture of mono-neuropathy following injury of peripheral nerve is often accompanied by changes in the patients' affective states. It has been shown that positive allosteric modulators of GABAA receptors can decrease nociceptive transmission in animal pain models. However, recent findings suggest a possibility that at least some of the antinociceptive effects of benzodiazepines, related to neuropathic painful stimuli, may to a significant degree be a consequence of their anxiolytic action. In this study we evaluated the possible delayed effects of SH-I-048A, a newly- synthesized high-efficacy nonselective positive modulator of GABAA receptors, on anxiety-like behavior and locomotor activity in Wistar rats with a previously induced peripheral nerve injury. Assessment of behavioral parameters, using spontaneous locomotor activity and elevated plus maze tests, was performed 48h after completion of single-day three i.p. injections treatment consisting of zero, one, two or three doses of SH-I-048A (10 mg/kg). In general, rats' behavior observed 72 h after a moderate peripheral nerve injury did not indicate the persistence of sequelae of mono-neuropathic pain. The rats treated with three doses of SH-I-048A displayed an enhanced immobility time in the locomotor activity test, without concomitant decrease of the total distance traveled. On the other hand, in the group treated with two doses of SH-I-048A, a decrease in the emotional reactivity in the elevated plus maze test was observed. Subtle changes in the regimen of dosing of SH-I-048A affect locomotor activity and anxiety-related behavior in animals with peripheral nerve injury., Kompleksna klinička slika neuropatije nakon povrede perifernog nerva često je praćena i promenama afektivnog stanja pacijenata. U animalnim modelima bola pokazano je da pozitivni alosterni modulatori GABAA receptora mogu da smanje nociceptivnu transmisiju. Međutim, skorašnji nalazi ukazuju i na mogućnost da je prividni antinociceptivni efekat benzodiazepina nakon delovanja akutnog bolnog stimulusa u značajnoj meri posledica anksiolitičnog efekta. U ovoj studiji ispitani su mogući odloženi efekti novosintetisanog, neselektivnog liganda GABAA receptora (SH-I-048A) na lokomotornu aktivnost i ponašanje u vezi sa anksioznošću kod pacova soja Wistar prethodno podvrgnutih povredi perifernog nerva. Procena bihejvioralnih parametara sprovedena je testovima spontane lokomotorne aktivnosti i uzdignutog plus lavirinta 48 sati nakon što su životinje u periodu od 24 sata primile rastvarač, jednu, dve ili tri doze SH-I-048A (10 mg/kg). Generalno, ponašanje pacova praćeno 72 sata nakon umerene povrede perifernog nerva nije ukazivalo na prisustvo perzistentnih posledica neuropatskog bola. Pacovi prethodno tretirani sa tri doze SH-I-048A ispoljili su povećano vreme imobilnosti u testu lokomotorne aktivnosti, bez značajnog smanjenja ukupnog pređenog puta. S druge strane, u grupi koja je tretirana sa dve doze SH-I-048A zapažena je smanjena emocionalna reaktivnost u uzdignutom plus lavirintu. Kod životinja sa povredom perifernog nerva, suptilne razlike u režimu doziranja pozitivnog modulatora GABAA, mogu značajno da utiču na ponašanje vezano za lomotornu aktivnost i nivo anksioznosti.",
publisher = "Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd",
journal = "Acta veterinaria",
title = "Delayed behavioral effects of SH-I-048A, a novel nonselective positive modulator of GABAA receptors, after peripheral nerve injury in rats, Odloženi bihejvioralni efekti SH-I-048A, novog neselektivnog pozitivnog modulatora GABAA receptora, nakon povrede perifernog nerva pacova",
volume = "64",
number = "2",
pages = "189-199",
doi = "10.2478/acve-2014-0018"
}

Obradović, A., Joksimović, S., Michael, P. M., Timić, T., James, C. M.,& Savić, M.. (2014). Delayed behavioral effects of SH-I-048A, a novel nonselective positive modulator of GABAA receptors, after peripheral nerve injury in rats. in Acta veterinaria
Univerzitet u Beogradu - Fakultet veterinarske medicine, Beograd., 64(2), 189-199.
https://doi.org/10.2478/acve-2014-0018

Obradović A, Joksimović S, Michael PM, Timić T, James CM, Savić M. Delayed behavioral effects of SH-I-048A, a novel nonselective positive modulator of GABAA receptors, after peripheral nerve injury in rats. in Acta veterinaria. 2014;64(2):189-199.
doi:10.2478/acve-2014-0018 .

Obradović, Aleksandar, Joksimović, Srđan, Michael, Poe M., Timić, Tamara, James, Cook M., Savić, Miroslav, "Delayed behavioral effects of SH-I-048A, a novel nonselective positive modulator of GABAA receptors, after peripheral nerve injury in rats" in Acta veterinaria, 64, no. 2 (2014):189-199,
https://doi.org/10.2478/acve-2014-0018 . .

TY  - CONF
AU  - Joksimović, Srđan
AU  - Obradović, Aleksandar
AU  - Timić, Tamara
AU  - Radulović, Tamara
AU  - Biawat, Poonam
AU  - Kovacević, Jovana
AU  - Milić, Marija
AU  - Batinić, Bojan
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1888
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia
VL  - 23
IS  - Supplement 2
SP  - S260
EP  - S260
DO  - 10.1016/S0924-977X(13)70406-1
ER  - 

@conference{
author = "Joksimović, Srđan and Obradović, Aleksandar and Timić, Tamara and Radulović, Tamara and Biawat, Poonam and Kovacević, Jovana and Milić, Marija and Batinić, Bojan and Cook, James M. and Savić, Miroslav",
year = "2013",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia",
volume = "23",
number = "Supplement 2",
pages = "S260-S260",
doi = "10.1016/S0924-977X(13)70406-1"
}

Joksimović, S., Obradović, A., Timić, T., Radulović, T., Biawat, P., Kovacević, J., Milić, M., Batinić, B., Cook, J. M.,& Savić, M.. (2013). PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 23(Supplement 2), S260-S260.
https://doi.org/10.1016/S0924-977X(13)70406-1

Joksimović S, Obradović A, Timić T, Radulović T, Biawat P, Kovacević J, Milić M, Batinić B, Cook JM, Savić M. PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia. in European Neuropsychopharmacology. 2013;23(Supplement 2):S260-S260.
doi:10.1016/S0924-977X(13)70406-1 .

Joksimović, Srđan, Obradović, Aleksandar, Timić, Tamara, Radulović, Tamara, Biawat, Poonam, Kovacević, Jovana, Milić, Marija, Batinić, Bojan, Cook, James M., Savić, Miroslav, "PWZ-029 alleviates MK-801-induced memory deficits in the rat: implications for the treatment of cognitive impairment in schizophrenia" in European Neuropsychopharmacology, 23, no. Supplement 2 (2013):S260-S260,
https://doi.org/10.1016/S0924-977X(13)70406-1 . .

TY  - CONF
AU  - Timić, Tamara
AU  - Joksimović, Srđan
AU  - Obradović, Aleksandar
AU  - Poe, Michael M.
AU  - Biawat, Poonam
AU  - Ramerstorfer, Joachim
AU  - Roth, Brian L.
AU  - Sieghart, Werner
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1887
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors
VL  - 23
IS  - Supplement 2
SP  - S259
EP  - S260
DO  - 10.1016/S0924-977X(13)70405-X
ER  - 

@conference{
author = "Timić, Tamara and Joksimović, Srđan and Obradović, Aleksandar and Poe, Michael M. and Biawat, Poonam and Ramerstorfer, Joachim and Roth, Brian L. and Sieghart, Werner and Cook, James M. and Savić, Miroslav",
year = "2013",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors",
volume = "23",
number = "Supplement 2",
pages = "S259-S260",
doi = "10.1016/S0924-977X(13)70405-X"
}

Timić, T., Joksimović, S., Obradović, A., Poe, M. M., Biawat, P., Ramerstorfer, J., Roth, B. L., Sieghart, W., Cook, J. M.,& Savić, M.. (2013). MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 23(Supplement 2), S259-S260.
https://doi.org/10.1016/S0924-977X(13)70405-X

Timić T, Joksimović S, Obradović A, Poe MM, Biawat P, Ramerstorfer J, Roth BL, Sieghart W, Cook JM, Savić M. MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors. in European Neuropsychopharmacology. 2013;23(Supplement 2):S259-S260.
doi:10.1016/S0924-977X(13)70405-X .

Timić, Tamara, Joksimović, Srđan, Obradović, Aleksandar, Poe, Michael M., Biawat, Poonam, Ramerstorfer, Joachim, Roth, Brian L., Sieghart, Werner, Cook, James M., Savić, Miroslav, "MK-801-induced hyperlocomotion in rats is affected by modulation of alpha(5)-containing GABA(A) receptors" in European Neuropsychopharmacology, 23, no. Supplement 2 (2013):S259-S260,
https://doi.org/10.1016/S0924-977X(13)70405-X . .