TY  - JOUR
AU  - Aranđelović, Jovana
AU  - Santrač, Anja
AU  - Batinić, Bojan
AU  - Todorović, Lidija
AU  - Stevanović, Vladimir
AU  - Tiruveedhula, Veera Venkata Naga Phani Babu
AU  - Sharmin, Dishary
AU  - Rashid, Farjana
AU  - Stanojević, Boban
AU  - Cook, James M.
AU  - Savić, Miroslav M.
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10360
AB  - Aims GABAergic modulation involved in cognitive processing appears to be substantially changed in Alzheimer's disease (AD). In a widely used 5xFAD model of AD, we aimed to assess if negative and positive allosteric modulators of α5 GABAA receptors (NAM and PAM, respectively) would affect social interaction, social, object and spatial memory, and neuroinflammation. Methods After 10-day treatment with PAM, NAM, or solvent, 6-month-old transgenic and non-transgenic 5xFAD mice underwent testing in a behavioral battery. Gene expressions of IL-1β, IL-6, TNF-α, GFAP, and IBA-1 were determined in hippocampus and prefrontal cortex by qPCR. Results PAM treatment impaired spatial learning in transgenic females compared to solvent-treated transgenic females, and social recognition in transgenic and non-transgenic males. NAM treatment declined social interaction in transgenic and non-transgenic males, while had beneficial effect on cognitive flexibility in non-transgenic males compared to solvent-treated non-transgenic males. Transgenic animals have not fully displayed cognitive symptoms, but neuroinflammation was confirmed. NAM reduced proinflammatory gene expressions in transgenic females and astrogliosis in transgenic males compared to pathological controls. Conclusion PAM and NAM failed to exert favorable behavioral effects in transgenic animals. Suppression of neuroinflammation obtained with NAM calls for more studies with GABAergic ligands in amyloid beta- and/or tau-dependent models with prominent neuroinflammation.
T2  - CNS Neuroscience & Therapeutics
T2  - CNS Neuroscience & Therapeutics
T1  - Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease
VL  - 28
IS  - 11
SP  - 1767
EP  - 1778
DO  - 10.1111/cns.13914
ER  - 

@article{
author = "Aranđelović, Jovana and Santrač, Anja and Batinić, Bojan and Todorović, Lidija and Stevanović, Vladimir and Tiruveedhula, Veera Venkata Naga Phani Babu and Sharmin, Dishary and Rashid, Farjana and Stanojević, Boban and Cook, James M. and Savić, Miroslav M.",
year = "2022",
abstract = "Aims GABAergic modulation involved in cognitive processing appears to be substantially changed in Alzheimer's disease (AD). In a widely used 5xFAD model of AD, we aimed to assess if negative and positive allosteric modulators of α5 GABAA receptors (NAM and PAM, respectively) would affect social interaction, social, object and spatial memory, and neuroinflammation. Methods After 10-day treatment with PAM, NAM, or solvent, 6-month-old transgenic and non-transgenic 5xFAD mice underwent testing in a behavioral battery. Gene expressions of IL-1β, IL-6, TNF-α, GFAP, and IBA-1 were determined in hippocampus and prefrontal cortex by qPCR. Results PAM treatment impaired spatial learning in transgenic females compared to solvent-treated transgenic females, and social recognition in transgenic and non-transgenic males. NAM treatment declined social interaction in transgenic and non-transgenic males, while had beneficial effect on cognitive flexibility in non-transgenic males compared to solvent-treated non-transgenic males. Transgenic animals have not fully displayed cognitive symptoms, but neuroinflammation was confirmed. NAM reduced proinflammatory gene expressions in transgenic females and astrogliosis in transgenic males compared to pathological controls. Conclusion PAM and NAM failed to exert favorable behavioral effects in transgenic animals. Suppression of neuroinflammation obtained with NAM calls for more studies with GABAergic ligands in amyloid beta- and/or tau-dependent models with prominent neuroinflammation.",
journal = "CNS Neuroscience & Therapeutics, CNS Neuroscience & Therapeutics",
title = "Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease",
volume = "28",
number = "11",
pages = "1767-1778",
doi = "10.1111/cns.13914"
}

Aranđelović, J., Santrač, A., Batinić, B., Todorović, L., Stevanović, V., Tiruveedhula, V. V. N. P. B., Sharmin, D., Rashid, F., Stanojević, B., Cook, J. M.,& Savić, M. M.. (2022). Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease. in CNS Neuroscience & Therapeutics, 28(11), 1767-1778.
https://doi.org/10.1111/cns.13914

Aranđelović J, Santrač A, Batinić B, Todorović L, Stevanović V, Tiruveedhula VVNPB, Sharmin D, Rashid F, Stanojević B, Cook JM, Savić MM. Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease. in CNS Neuroscience & Therapeutics. 2022;28(11):1767-1778.
doi:10.1111/cns.13914 .

Aranđelović, Jovana, Santrač, Anja, Batinić, Bojan, Todorović, Lidija, Stevanović, Vladimir, Tiruveedhula, Veera Venkata Naga Phani Babu, Sharmin, Dishary, Rashid, Farjana, Stanojević, Boban, Cook, James M., Savić, Miroslav M., "Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease" in CNS Neuroscience & Therapeutics, 28, no. 11 (2022):1767-1778,
https://doi.org/10.1111/cns.13914 . .

TY  - JOUR
AU  - Divović Matović, Branka
AU  - Knutson, Dan
AU  - Mitrović, Jelena
AU  - Stevanović, Vladimir
AU  - Stanojević, Boban
AU  - Savić, Snežana
AU  - Cook, James M.
AU  - Savić, Miroslav M.
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10454
AB  - Several pyrazoloquinolinone (PQ) ligands were recently discovered as functionally selective positive modulators at the PQ site of α6-containing GABAA receptors. PQs are also neutral modulators at the benzodiazepine site. We assessed the influence of PQ compounds from three structural groups (PZ-II-029 and related deuterated analogues DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related analogues DK-I-58-1 and DK-II-58-1; and DK-I-87-1), alone and in combination with diazepam, on the behaviour of male Sprague–Dawley rats. An excellent behavioural safety profile of all tested PQs was demonstrated in the spontaneous locomotor activity, rotarod, loss of righting reflex and pentylenetetrazol tests. In interaction studies, only PZ-II-029 and its analogues prevented the ataxic effects of the benzodiazepine, as assessed in the rotarod test and during monitoring of rat locomotor activity after awakening from the loss of righting reflex. Published electrophysiological profiles of PQ ligands imply that positive modulation elicited at α6-GABAA receptors that contain the γ2 and δ subunit, rather than their neutral modulatory action at the benzodiazepine site, may prevent the ataxic action of diazepam. Thus, PZ-II-029 and its deuterated analogues are not prone to untoward interactions with benzodiazepines and may indeed completely abolish their ataxic action, seen at therapeutic, and especially toxic concentrations.
T2  - Basic & Clinical Pharmacology & Toxicology
T1  - Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature
VL  - 131
IS  - 6
SP  - 514
EP  - 524
DO  - 10.1111/bcpt.13801
ER  - 

@article{
author = "Divović Matović, Branka and Knutson, Dan and Mitrović, Jelena and Stevanović, Vladimir and Stanojević, Boban and Savić, Snežana and Cook, James M. and Savić, Miroslav M.",
year = "2022",
abstract = "Several pyrazoloquinolinone (PQ) ligands were recently discovered as functionally selective positive modulators at the PQ site of α6-containing GABAA receptors. PQs are also neutral modulators at the benzodiazepine site. We assessed the influence of PQ compounds from three structural groups (PZ-II-029 and related deuterated analogues DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related analogues DK-I-58-1 and DK-II-58-1; and DK-I-87-1), alone and in combination with diazepam, on the behaviour of male Sprague–Dawley rats. An excellent behavioural safety profile of all tested PQs was demonstrated in the spontaneous locomotor activity, rotarod, loss of righting reflex and pentylenetetrazol tests. In interaction studies, only PZ-II-029 and its analogues prevented the ataxic effects of the benzodiazepine, as assessed in the rotarod test and during monitoring of rat locomotor activity after awakening from the loss of righting reflex. Published electrophysiological profiles of PQ ligands imply that positive modulation elicited at α6-GABAA receptors that contain the γ2 and δ subunit, rather than their neutral modulatory action at the benzodiazepine site, may prevent the ataxic action of diazepam. Thus, PZ-II-029 and its deuterated analogues are not prone to untoward interactions with benzodiazepines and may indeed completely abolish their ataxic action, seen at therapeutic, and especially toxic concentrations.",
journal = "Basic & Clinical Pharmacology & Toxicology",
title = "Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature",
volume = "131",
number = "6",
pages = "514-524",
doi = "10.1111/bcpt.13801"
}

Divović Matović, B., Knutson, D., Mitrović, J., Stevanović, V., Stanojević, B., Savić, S., Cook, J. M.,& Savić, M. M.. (2022). Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature. in Basic & Clinical Pharmacology & Toxicology, 131(6), 514-524.
https://doi.org/10.1111/bcpt.13801

Divović Matović B, Knutson D, Mitrović J, Stevanović V, Stanojević B, Savić S, Cook JM, Savić MM. Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature. in Basic & Clinical Pharmacology & Toxicology. 2022;131(6):514-524.
doi:10.1111/bcpt.13801 .

Divović Matović, Branka, Knutson, Dan, Mitrović, Jelena, Stevanović, Vladimir, Stanojević, Boban, Savić, Snežana, Cook, James M., Savić, Miroslav M., "Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature" in Basic & Clinical Pharmacology & Toxicology, 131, no. 6 (2022):514-524,
https://doi.org/10.1111/bcpt.13801 . .