TY  - JOUR
AU  - Milosavljević, Filip
AU  - Brusini, Irene
AU  - Atanasov, Andrea
AU  - Manojlović, Marina
AU  - Vučić, Marija
AU  - Oreščanin-Dušić, Zorana
AU  - Brkljačić, Jelena
AU  - Miljević, Čedo
AU  - Nikolić-Kokić, Aleksandra
AU  - Blagojević, Duško
AU  - Wang, Chunliang
AU  - Damberg, Peter
AU  - Pešić, Vesna
AU  - Tyndale, Rachel F.
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin M.
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5758
AB  - Aims: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia.

Methods: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride.

Results: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice.

Conclusions: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.
PB  - Hoboken: Wiley
T2  - Neuropathology and Applied Neurobiology
T1  - The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
IS  - 1
VL  - 49
DO  - 10.1111/nan.12867
SP  - e12867
ER  - 

@article{
author = "Milosavljević, Filip and Brusini, Irene and Atanasov, Andrea and Manojlović, Marina and Vučić, Marija and Oreščanin-Dušić, Zorana and Brkljačić, Jelena and Miljević, Čedo and Nikolić-Kokić, Aleksandra and Blagojević, Duško and Wang, Chunliang and Damberg, Peter and Pešić, Vesna and Tyndale, Rachel F. and Ingelman-Sundberg, Magnus and Jukić, Marin M.",
year = "2023",
abstract = "Aims: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia.

Methods: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride.

Results: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice.

Conclusions: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.",
publisher = "Hoboken: Wiley",
journal = "Neuropathology and Applied Neurobiology",
title = "The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia",
number = "1",
volume = "49",
doi = "10.1111/nan.12867",
pages = "e12867"
}

Milosavljević, F., Brusini, I., Atanasov, A., Manojlović, M., Vučić, M., Oreščanin-Dušić, Z., Brkljačić, J., Miljević, Č., Nikolić-Kokić, A., Blagojević, D., Wang, C., Damberg, P., Pešić, V., Tyndale, R. F., Ingelman-Sundberg, M.,& Jukić, M. M.. (2023). The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia. in Neuropathology and Applied Neurobiology
Hoboken: Wiley., 49(1), e12867.
https://doi.org/10.1111/nan.12867

Milosavljević F, Brusini I, Atanasov A, Manojlović M, Vučić M, Oreščanin-Dušić Z, Brkljačić J, Miljević Č, Nikolić-Kokić A, Blagojević D, Wang C, Damberg P, Pešić V, Tyndale RF, Ingelman-Sundberg M, Jukić MM. The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia. in Neuropathology and Applied Neurobiology. 2023;49(1):e12867.
doi:10.1111/nan.12867 .

Milosavljević, Filip, Brusini, Irene, Atanasov, Andrea, Manojlović, Marina, Vučić, Marija, Oreščanin-Dušić, Zorana, Brkljačić, Jelena, Miljević, Čedo, Nikolić-Kokić, Aleksandra, Blagojević, Duško, Wang, Chunliang, Damberg, Peter, Pešić, Vesna, Tyndale, Rachel F., Ingelman-Sundberg, Magnus, Jukić, Marin M., "The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia" in Neuropathology and Applied Neurobiology, 49, no. 1 (2023):e12867,
https://doi.org/10.1111/nan.12867 . .

TY  - JOUR
AU  - Miljević, Čedo D.
AU  - Nikolić-Kokić, Aleksandra
AU  - Blagojević, Duško
AU  - Milovanović, Maja
AU  - Munjiza, Ana
AU  - Jukić, Marin M
AU  - Pešić, Vesna
AU  - Lečić-Toševski, Dušica
AU  - Spasić, Mihajlo
PY  - 2018
UR  - https://www.sciencedirect.com/science/article/pii/S0165178117323272?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3154
AB  - To determine the relationship between alterations in the activity of the enzymes participating in antioxidative defense system and neurological soft signs (NSS) in schizophrenic patients with the first episode psychosis (SFE, n = 19), patients in relapse (SR, n = 46), and healthy controls (HC, n = 20). NSS intensity and enzymatic plasma activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were compared between SFE, SR and HC subjects and a follow-up correlation analyses between the enzyme activities and NSS intensity was performed. NSS intensity was increased four times in schizophrenic patients compared with healthy controls. Activities of SOD and CAT were 40% decreased in SFE and these reductions were ameliorated by antipsychotic treatment. GPX activity was 20% decreased in both patient groups compared with controls. A negative correlation between NSS intensity and GPX activity was specifically found in the SFE patients. The data in this report argue that a reduction of GPX activity might be one of the causes for the emergence of NSS at the onset of schizophrenia, and provide the evidence that antipsychotic therapy can attenuate activity reductions of SOD and CAT, but not the activity reduction of GPX and the intensity of NSS.
T2  - Psychiatry research
T1  - Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients.
VL  - 269
DO  - 10.1016/j.psychres.2018.09.009
SP  - 746
EP  - 752
ER  - 

@article{
author = "Miljević, Čedo D. and Nikolić-Kokić, Aleksandra and Blagojević, Duško and Milovanović, Maja and Munjiza, Ana and Jukić, Marin M and Pešić, Vesna and Lečić-Toševski, Dušica and Spasić, Mihajlo",
year = "2018",
abstract = "To determine the relationship between alterations in the activity of the enzymes participating in antioxidative defense system and neurological soft signs (NSS) in schizophrenic patients with the first episode psychosis (SFE, n = 19), patients in relapse (SR, n = 46), and healthy controls (HC, n = 20). NSS intensity and enzymatic plasma activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were compared between SFE, SR and HC subjects and a follow-up correlation analyses between the enzyme activities and NSS intensity was performed. NSS intensity was increased four times in schizophrenic patients compared with healthy controls. Activities of SOD and CAT were 40% decreased in SFE and these reductions were ameliorated by antipsychotic treatment. GPX activity was 20% decreased in both patient groups compared with controls. A negative correlation between NSS intensity and GPX activity was specifically found in the SFE patients. The data in this report argue that a reduction of GPX activity might be one of the causes for the emergence of NSS at the onset of schizophrenia, and provide the evidence that antipsychotic therapy can attenuate activity reductions of SOD and CAT, but not the activity reduction of GPX and the intensity of NSS.",
journal = "Psychiatry research",
title = "Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients.",
volume = "269",
doi = "10.1016/j.psychres.2018.09.009",
pages = "746-752"
}

Miljević, Č. D., Nikolić-Kokić, A., Blagojević, D., Milovanović, M., Munjiza, A., Jukić, M. M., Pešić, V., Lečić-Toševski, D.,& Spasić, M.. (2018). Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients.. in Psychiatry research, 269, 746-752.
https://doi.org/10.1016/j.psychres.2018.09.009

Miljević ČD, Nikolić-Kokić A, Blagojević D, Milovanović M, Munjiza A, Jukić MM, Pešić V, Lečić-Toševski D, Spasić M. Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients.. in Psychiatry research. 2018;269:746-752.
doi:10.1016/j.psychres.2018.09.009 .

Miljević, Čedo D., Nikolić-Kokić, Aleksandra, Blagojević, Duško, Milovanović, Maja, Munjiza, Ana, Jukić, Marin M, Pešić, Vesna, Lečić-Toševski, Dušica, Spasić, Mihajlo, "Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients." in Psychiatry research, 269 (2018):746-752,
https://doi.org/10.1016/j.psychres.2018.09.009 . .