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
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4516
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  - John Wiley and Sons Inc
T2  - Neuropathology and Applied Neurobiology
T1  - The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
VL  - 49
IS  - 1
DO  - 10.1111/nan.12867
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",
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 = "John Wiley and Sons Inc",
journal = "Neuropathology and Applied Neurobiology",
title = "The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia",
volume = "49",
number = "1",
doi = "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, R. F., Ingelman-Sundberg, M.,& Jukić, M.. (2023). The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia. in Neuropathology and Applied Neurobiology
John Wiley and Sons Inc., 49(1).
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 M. The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia. in Neuropathology and Applied Neurobiology. 2023;49(1).
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, "The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia" in Neuropathology and Applied Neurobiology, 49, no. 1 (2023),
https://doi.org/10.1111/nan.12867 . .