TY  - JOUR
AU  - Opačić, Miloš
AU  - Ristić, Aleksandar J.
AU  - Sokić, Dragoslav
AU  - Baščarević, Vladimir
AU  - Raičević, Savo
AU  - Savić, Slobodan
AU  - Zorović, Maja
AU  - Živin, Marko
AU  - Šelih, Vid Simon
AU  - Spasojević, Ivan
AU  - Savić, Danijela
PY  - 2021
UR  - https://onlinelibrary.wiley.com/doi/10.1002/brb3.1986
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4403
AB  - Introduction Disruption of copper homeostasis and dysfunction of mitochondria have been documented in sclerotic hippocampi (HS) of patients with mesial temporal lobe epilepsy (mTLE). However, a potential link between these pathological changes has not been tackled so far. Herein, we analyzed regional distribution of neuron somata density, copper concentration, and the activity of cytochrome c oxidase (CCO), a component of mitochondrial electron transport chain and copper-containing metalloprotein, in HS. Methods Histochemical staining and laser ablation inductively coupled plasma mass spectrometry were carried out to construct comparable maps of these parameters in coronal sections of hippocampi of 3 mTLE-HS patients and 3 control subjects. Results Copper levels were decreased in all regions of HS with pyramidal neuron somata. CCO activity was significantly reduced in stratum pyramidale (PY) 1 and cornu Ammonis field 4, the two regions with significant reduction in neuron somata density. CCO activity was also lower in layers that contain apical dendrites of pyramidal neurons and mossy fibers. It appears that copper deficiency in PY2 and PY3 comes before CCO activity reduction and neuronal loss. A strong positive correlation was found between neuron density, Cu concentration, and CCO activity. Conclusions Presented results imply that pathological alterations in Cu and energy metabolism could be involved in the development of HS. A limitation of this study was the relatively small number of patients. However, presented results underline copper deficiency as a component of pathological mechanisms of epilepsy and warrant further investigation of cuproproteins and members of copper transport machinery.
T2  - Brain and Behavior
T1  - Regional distribution of cytochrome c oxidase activity and copper in sclerotic hippocampi of epilepsy patients
IS  - 2
VL  - 11
DO  - 10.1002/brb3.1986
SP  - e01986
ER  - 

@article{
author = "Opačić, Miloš and Ristić, Aleksandar J. and Sokić, Dragoslav and Baščarević, Vladimir and Raičević, Savo and Savić, Slobodan and Zorović, Maja and Živin, Marko and Šelih, Vid Simon and Spasojević, Ivan and Savić, Danijela",
year = "2021",
abstract = "Introduction Disruption of copper homeostasis and dysfunction of mitochondria have been documented in sclerotic hippocampi (HS) of patients with mesial temporal lobe epilepsy (mTLE). However, a potential link between these pathological changes has not been tackled so far. Herein, we analyzed regional distribution of neuron somata density, copper concentration, and the activity of cytochrome c oxidase (CCO), a component of mitochondrial electron transport chain and copper-containing metalloprotein, in HS. Methods Histochemical staining and laser ablation inductively coupled plasma mass spectrometry were carried out to construct comparable maps of these parameters in coronal sections of hippocampi of 3 mTLE-HS patients and 3 control subjects. Results Copper levels were decreased in all regions of HS with pyramidal neuron somata. CCO activity was significantly reduced in stratum pyramidale (PY) 1 and cornu Ammonis field 4, the two regions with significant reduction in neuron somata density. CCO activity was also lower in layers that contain apical dendrites of pyramidal neurons and mossy fibers. It appears that copper deficiency in PY2 and PY3 comes before CCO activity reduction and neuronal loss. A strong positive correlation was found between neuron density, Cu concentration, and CCO activity. Conclusions Presented results imply that pathological alterations in Cu and energy metabolism could be involved in the development of HS. A limitation of this study was the relatively small number of patients. However, presented results underline copper deficiency as a component of pathological mechanisms of epilepsy and warrant further investigation of cuproproteins and members of copper transport machinery.",
journal = "Brain and Behavior",
title = "Regional distribution of cytochrome c oxidase activity and copper in sclerotic hippocampi of epilepsy patients",
number = "2",
volume = "11",
doi = "10.1002/brb3.1986",
pages = "e01986"
}

Opačić, M., Ristić, A. J., Sokić, D., Baščarević, V., Raičević, S., Savić, S., Zorović, M., Živin, M., Šelih, V. S., Spasojević, I.,& Savić, D.. (2021). Regional distribution of cytochrome c oxidase activity and copper in sclerotic hippocampi of epilepsy patients. in Brain and Behavior, 11(2), e01986.
https://doi.org/10.1002/brb3.1986

Opačić M, Ristić AJ, Sokić D, Baščarević V, Raičević S, Savić S, Zorović M, Živin M, Šelih VS, Spasojević I, Savić D. Regional distribution of cytochrome c oxidase activity and copper in sclerotic hippocampi of epilepsy patients. in Brain and Behavior. 2021;11(2):e01986.
doi:10.1002/brb3.1986 .

Opačić, Miloš, Ristić, Aleksandar J., Sokić, Dragoslav, Baščarević, Vladimir, Raičević, Savo, Savić, Slobodan, Zorović, Maja, Živin, Marko, Šelih, Vid Simon, Spasojević, Ivan, Savić, Danijela, "Regional distribution of cytochrome c oxidase activity and copper in sclerotic hippocampi of epilepsy patients" in Brain and Behavior, 11, no. 2 (2021):e01986,
https://doi.org/10.1002/brb3.1986 . .

TY  - CONF
AU  - Savić, Danijela
AU  - Opačić, Miloš
AU  - Brkljačić, Jelena
AU  - Ristić, Aleksandar
AU  - Sokić, Dragoslav
AU  - Baščarević, Vladimir
AU  - Raičević, Savo
AU  - Savić, Slobodan
AU  - Zorović, Maja
AU  - Živin, Marko
AU  - Šelih, Vid Simon
AU  - Spasić, Snežana
AU  - Spasojević, Ivan
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5882
AB  - More and more studies are identifying the regulation of metal homeostasis as one of the key points of central nervous system’s
well-being. Epilepsy is a particularly interesting neurological condition when viewed in terms of the correlation between the
amount of metals and the development of a seizure. This lecture will present contribution of our group to the field of metal
biology in epilepsy by mapping brain metals in sclerotic hippocampus resected from drug resistant mesial temporal lobe
epilepsy (mTLE) patients as surgical therapeutic approach. Direct insight into this epileptogenic area, by two powerful techniques,
optical emission and mass spectrometry, has led us to investigation of copper turnover. Namely, among the examined metals,
we found the deficiency of copper in sclerotic hippocampus on two levels: (i) in whole structure (ii) and locally in the areas of
neuronal loss, with significant correlation between copper concentration and neuron density. Furthermore, analysis of copper
metalloproteins showed: (i) significant increase or decrease in levels of protein that is participating in copper transport into
the cell (CTR1) depending on the degree of hippocampal neuronal loss; (ii) and lower activity of an enzyme in which copper
is part of the active site, cytochrome c oxidase, in sclerotic hippocampi of patients compared to control tissue. In our further
investigations it remained to be determined whether changes in copper concentrations and copper metalloproteins are causal
to pathology of mTLE or they represent epiphenomenon.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
T1  - The importance of copper in pathology of mesial temporal lobe epilepsy
SP  - 46
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5882
ER  - 

@conference{
author = "Savić, Danijela and Opačić, Miloš and Brkljačić, Jelena and Ristić, Aleksandar and Sokić, Dragoslav and Baščarević, Vladimir and Raičević, Savo and Savić, Slobodan and Zorović, Maja and Živin, Marko and Šelih, Vid Simon and Spasić, Snežana and Spasojević, Ivan",
year = "2019",
abstract = "More and more studies are identifying the regulation of metal homeostasis as one of the key points of central nervous system’s
well-being. Epilepsy is a particularly interesting neurological condition when viewed in terms of the correlation between the
amount of metals and the development of a seizure. This lecture will present contribution of our group to the field of metal
biology in epilepsy by mapping brain metals in sclerotic hippocampus resected from drug resistant mesial temporal lobe
epilepsy (mTLE) patients as surgical therapeutic approach. Direct insight into this epileptogenic area, by two powerful techniques,
optical emission and mass spectrometry, has led us to investigation of copper turnover. Namely, among the examined metals,
we found the deficiency of copper in sclerotic hippocampus on two levels: (i) in whole structure (ii) and locally in the areas of
neuronal loss, with significant correlation between copper concentration and neuron density. Furthermore, analysis of copper
metalloproteins showed: (i) significant increase or decrease in levels of protein that is participating in copper transport into
the cell (CTR1) depending on the degree of hippocampal neuronal loss; (ii) and lower activity of an enzyme in which copper
is part of the active site, cytochrome c oxidase, in sclerotic hippocampi of patients compared to control tissue. In our further
investigations it remained to be determined whether changes in copper concentrations and copper metalloproteins are causal
to pathology of mTLE or they represent epiphenomenon.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia",
title = "The importance of copper in pathology of mesial temporal lobe epilepsy",
pages = "46",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5882"
}

Savić, D., Opačić, M., Brkljačić, J., Ristić, A., Sokić, D., Baščarević, V., Raičević, S., Savić, S., Zorović, M., Živin, M., Šelih, V. S., Spasić, S.,& Spasojević, I.. (2019). The importance of copper in pathology of mesial temporal lobe epilepsy. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 46.
https://hdl.handle.net/21.15107/rcub_ibiss_5882

Savić D, Opačić M, Brkljačić J, Ristić A, Sokić D, Baščarević V, Raičević S, Savić S, Zorović M, Živin M, Šelih VS, Spasić S, Spasojević I. The importance of copper in pathology of mesial temporal lobe epilepsy. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia. 2019;:46.
https://hdl.handle.net/21.15107/rcub_ibiss_5882 .

Savić, Danijela, Opačić, Miloš, Brkljačić, Jelena, Ristić, Aleksandar, Sokić, Dragoslav, Baščarević, Vladimir, Raičević, Savo, Savić, Slobodan, Zorović, Maja, Živin, Marko, Šelih, Vid Simon, Spasić, Snežana, Spasojević, Ivan, "The importance of copper in pathology of mesial temporal lobe epilepsy" in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia (2019):46,
https://hdl.handle.net/21.15107/rcub_ibiss_5882 .

TY  - CONF
AU  - Ristić, Aleksandar
AU  - Savić, Danijela
AU  - Bogdanović Pristov, Jelena
AU  - Brkljačić, Jelena
AU  - Baščarević, Vladimir
AU  - Raičević, Savo
AU  - Savić, Slobodan
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5991
AB  - Mesial temporal lobe epilepsy associated with hippocampal sclerosis (mTLE-HS) is probably the single most frequent human focal epilepsy. The involvement of redox processes in the pathological mechanisms of mTLE-HS has been implicated  by mitochondrial dysfunction and oxidative damage, and by different metabolic abnormalities that have been observed in sclerotic hippocampi, such as altered metabolism of redox-active metals. The strongest proof came with the analysis of enzymatic antioxidative system. Sclerotic hippocampi show drastically increased activity and levels of hydrogen peroxide–removing enzymes – catalase and glutathione peroxidase/reductase. Catalase is located mainly in neurons in both, controls and HS. Sclerotic hippocampi are depleted of glutathione peroxidase-positive blood vessels that are present in control hippocampi. Pertinent to this, it has been documented that hippocampi of mTLE-HS patients show increased blood vessel density, but most of the vessels represent atrophic vascular structures. On the other hand, HS showes specific glutathione peroxidase-rich loci that are present in gyrus dentatus, CA regions, and alveus, and appear to represent bundles of astrocytes. These loci are probably sites of excessive (neuronal) production of hydrogen peroxide that is counteracted by astrocytes. Finally, protein levels of mitochondrial enzyme manganese superoxide dismutase are higher in HS than controls. Neurons with abnormal morphology and strong superoxide dismutase immunofluorescence are present in all neuronal layers in HS. In close, antioxidative system is upregulated in HS implying that epileptogenic hippocampi are exposed to oxidative stress. The involvement of redox alterations in the pathology of epilepsy may open new pharmacologic perspectives for mTLE-HS treatment.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
T1  - Hippocampal Antioxidative System in Epilepsy
SP  - 42
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5991
ER  - 

@conference{
author = "Ristić, Aleksandar and Savić, Danijela and Bogdanović Pristov, Jelena and Brkljačić, Jelena and Baščarević, Vladimir and Raičević, Savo and Savić, Slobodan",
year = "2019",
abstract = "Mesial temporal lobe epilepsy associated with hippocampal sclerosis (mTLE-HS) is probably the single most frequent human focal epilepsy. The involvement of redox processes in the pathological mechanisms of mTLE-HS has been implicated  by mitochondrial dysfunction and oxidative damage, and by different metabolic abnormalities that have been observed in sclerotic hippocampi, such as altered metabolism of redox-active metals. The strongest proof came with the analysis of enzymatic antioxidative system. Sclerotic hippocampi show drastically increased activity and levels of hydrogen peroxide–removing enzymes – catalase and glutathione peroxidase/reductase. Catalase is located mainly in neurons in both, controls and HS. Sclerotic hippocampi are depleted of glutathione peroxidase-positive blood vessels that are present in control hippocampi. Pertinent to this, it has been documented that hippocampi of mTLE-HS patients show increased blood vessel density, but most of the vessels represent atrophic vascular structures. On the other hand, HS showes specific glutathione peroxidase-rich loci that are present in gyrus dentatus, CA regions, and alveus, and appear to represent bundles of astrocytes. These loci are probably sites of excessive (neuronal) production of hydrogen peroxide that is counteracted by astrocytes. Finally, protein levels of mitochondrial enzyme manganese superoxide dismutase are higher in HS than controls. Neurons with abnormal morphology and strong superoxide dismutase immunofluorescence are present in all neuronal layers in HS. In close, antioxidative system is upregulated in HS implying that epileptogenic hippocampi are exposed to oxidative stress. The involvement of redox alterations in the pathology of epilepsy may open new pharmacologic perspectives for mTLE-HS treatment.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia",
title = "Hippocampal Antioxidative System in Epilepsy",
pages = "42",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5991"
}

Ristić, A., Savić, D., Bogdanović Pristov, J., Brkljačić, J., Baščarević, V., Raičević, S.,& Savić, S.. (2019). Hippocampal Antioxidative System in Epilepsy. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 42.
https://hdl.handle.net/21.15107/rcub_ibiss_5991

Ristić A, Savić D, Bogdanović Pristov J, Brkljačić J, Baščarević V, Raičević S, Savić S. Hippocampal Antioxidative System in Epilepsy. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia. 2019;:42.
https://hdl.handle.net/21.15107/rcub_ibiss_5991 .

Ristić, Aleksandar, Savić, Danijela, Bogdanović Pristov, Jelena, Brkljačić, Jelena, Baščarević, Vladimir, Raičević, Savo, Savić, Slobodan, "Hippocampal Antioxidative System in Epilepsy" in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia (2019):42,
https://hdl.handle.net/21.15107/rcub_ibiss_5991 .

TY  - CONF
AU  - Savić, Danijela
AU  - Opačić, Miloš
AU  - Ristić, Aleksandar
AU  - Sokić, Dragoslav
AU  - Baščarević, Vladimir
AU  - Raičević, Savo
AU  - Savić, Slobodan
AU  - Živin, Marko
AU  - Šelih, Vid Simon
AU  - Spasić, Snežana
AU  - Spasojević, Ivan
PY  - 2018
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5887
AB  - The accumulating evidence on the relation between the disturbed metal homeostasis
and epilepsy urges the need for data regarding the total metal concentrations, as well
as metal distribution in the brain itself, in order to indicate where to direct the
potential therapy, to metal supplementation or chelation. This paper summarizes our
results on the measurements of some important essential metals in hippocampi of
patients with mesial temporal lobe epilepsy (mTLE) who underwent
amigdalohippocampectomy. The key findings point out that levels of copper and
manganese are deficient in hippocampi of mTLE patients, and that their
concentrations correlated positively with neuronal loss in affected regions of sclerotic
hippocampus. In addition, the Cu concentration was decreased in the areas of total
neuronal loss. Iron and zinc total hippocampal levels were neither accumulated nor
deficient compared to control. Our results contribute to deeper insight of metals
biology in the epilepsy and may represent the initial point of new and non-invasive
therapy of drug resistant epilepsy.
PB  - Belgrade: Faculty of Chemistry: Serbian Biochemical Society
C3  - Proceedings: Serbian Biochemical Society Eigth Conference with international participation: Coordination in Biochemistry and Life; 2018 Nov 16; Novi Sad, Serbia
T1  - Distribution and role of metals in sclerotic hippocampi of patients with mesial temporal lobe epilepsy
SP  - 105
EP  - 112
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5887
ER  - 

@conference{
author = "Savić, Danijela and Opačić, Miloš and Ristić, Aleksandar and Sokić, Dragoslav and Baščarević, Vladimir and Raičević, Savo and Savić, Slobodan and Živin, Marko and Šelih, Vid Simon and Spasić, Snežana and Spasojević, Ivan",
year = "2018",
abstract = "The accumulating evidence on the relation between the disturbed metal homeostasis
and epilepsy urges the need for data regarding the total metal concentrations, as well
as metal distribution in the brain itself, in order to indicate where to direct the
potential therapy, to metal supplementation or chelation. This paper summarizes our
results on the measurements of some important essential metals in hippocampi of
patients with mesial temporal lobe epilepsy (mTLE) who underwent
amigdalohippocampectomy. The key findings point out that levels of copper and
manganese are deficient in hippocampi of mTLE patients, and that their
concentrations correlated positively with neuronal loss in affected regions of sclerotic
hippocampus. In addition, the Cu concentration was decreased in the areas of total
neuronal loss. Iron and zinc total hippocampal levels were neither accumulated nor
deficient compared to control. Our results contribute to deeper insight of metals
biology in the epilepsy and may represent the initial point of new and non-invasive
therapy of drug resistant epilepsy.",
publisher = "Belgrade: Faculty of Chemistry: Serbian Biochemical Society",
journal = "Proceedings: Serbian Biochemical Society Eigth Conference with international participation: Coordination in Biochemistry and Life; 2018 Nov 16; Novi Sad, Serbia",
title = "Distribution and role of metals in sclerotic hippocampi of patients with mesial temporal lobe epilepsy",
pages = "105-112",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5887"
}

Savić, D., Opačić, M., Ristić, A., Sokić, D., Baščarević, V., Raičević, S., Savić, S., Živin, M., Šelih, V. S., Spasić, S.,& Spasojević, I.. (2018). Distribution and role of metals in sclerotic hippocampi of patients with mesial temporal lobe epilepsy. in Proceedings: Serbian Biochemical Society Eigth Conference with international participation: Coordination in Biochemistry and Life; 2018 Nov 16; Novi Sad, Serbia
Belgrade: Faculty of Chemistry: Serbian Biochemical Society., 105-112.
https://hdl.handle.net/21.15107/rcub_ibiss_5887

Savić D, Opačić M, Ristić A, Sokić D, Baščarević V, Raičević S, Savić S, Živin M, Šelih VS, Spasić S, Spasojević I. Distribution and role of metals in sclerotic hippocampi of patients with mesial temporal lobe epilepsy. in Proceedings: Serbian Biochemical Society Eigth Conference with international participation: Coordination in Biochemistry and Life; 2018 Nov 16; Novi Sad, Serbia. 2018;:105-112.
https://hdl.handle.net/21.15107/rcub_ibiss_5887 .

Savić, Danijela, Opačić, Miloš, Ristić, Aleksandar, Sokić, Dragoslav, Baščarević, Vladimir, Raičević, Savo, Savić, Slobodan, Živin, Marko, Šelih, Vid Simon, Spasić, Snežana, Spasojević, Ivan, "Distribution and role of metals in sclerotic hippocampi of patients with mesial temporal lobe epilepsy" in Proceedings: Serbian Biochemical Society Eigth Conference with international participation: Coordination in Biochemistry and Life; 2018 Nov 16; Novi Sad, Serbia (2018):105-112,
https://hdl.handle.net/21.15107/rcub_ibiss_5887 .