TY  - JOUR
AU  - Opačić, Miloš
AU  - Ristic, Aleksandar J
AU  - Sokic, Dragoslav
AU  - Baščarević, Vladimir
AU  - Raicević, Savo
AU  - Savić, Slobodan
AU  - Zorović, Maja
AU  - Zivin, Marko
AU  - Selih, Vid Simon
AU  - Spasojević, Ivan
AU  - Savić, Danijela Z
PY  - 2021
UR  - http://rimsi.imsi.bg.ac.rs/handle/123456789/1515
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.
PB  - Wiley, Hoboken
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
ER  - 

@article{
author = "Opačić, Miloš and Ristic, Aleksandar J and Sokic, Dragoslav and Baščarević, Vladimir and Raicević, Savo and Savić, Slobodan and Zorović, Maja and Zivin, Marko and Selih, Vid Simon and Spasojević, Ivan and Savić, Danijela Z",
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.",
publisher = "Wiley, Hoboken",
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"
}

Opačić, M., Ristic, A. J., Sokic, D., Baščarević, V., Raicević, S., Savić, S., Zorović, M., Zivin, M., Selih, V. S., Spasojević, I.,& Savić, D. Z.. (2021). Regional distribution of cytochrome c oxidase activity and copper in sclerotic hippocampi of epilepsy patients. in Brain and Behavior
Wiley, Hoboken., 11(2).
https://doi.org/10.1002/brb3.1986

Opačić M, Ristic AJ, Sokic D, Baščarević V, Raicević S, Savić S, Zorović M, Zivin M, Selih VS, Spasojević I, Savić DZ. Regional distribution of cytochrome c oxidase activity and copper in sclerotic hippocampi of epilepsy patients. in Brain and Behavior. 2021;11(2).
doi:10.1002/brb3.1986 .

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

TY  - CONF
AU  - Savic, Danijela
AU  - Opačić, Miloš
AU  - Nestorov, Jelena
AU  - Ristic, Aleksandar J
AU  - Sokic, Dragoslav
AU  - Bascarevic, Vladimir
AU  - Raičević, Savo
AU  - Savić, Slobodan
AU  - Zorović, Maja
AU  - Živin, Marko
AU  - Selih, Vid Simon
AU  - Spasic, Snezana
AU  - Spasojević, Ivan
PY  - 2019
UR  - http://rimsi.imsi.bg.ac.rs/handle/123456789/2841
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  - FENS
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_rimsi_2841
ER  - 

@conference{
author = "Savic, Danijela and Opačić, Miloš and Nestorov, Jelena and Ristic, Aleksandar J and Sokic, Dragoslav and Bascarevic, Vladimir and Raičević, Savo and Savić, Slobodan and Zorović, Maja and Živin, Marko and Selih, Vid Simon and Spasic, Snezana 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 = "FENS",
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_rimsi_2841"
}

Savic, D., Opačić, M., Nestorov, J., Ristic, A. J., Sokic, D., Bascarevic, V., Raičević, S., Savić, S., Zorović, M., Živin, M., Selih, V. S., Spasic, 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
FENS., 46.
https://hdl.handle.net/21.15107/rcub_rimsi_2841

Savic D, Opačić M, Nestorov J, Ristic AJ, Sokic D, Bascarevic V, Raičević S, Savić S, Zorović M, Živin M, Selih VS, Spasic 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_rimsi_2841 .

Savic, Danijela, Opačić, Miloš, Nestorov, Jelena, Ristic, Aleksandar J, Sokic, Dragoslav, Bascarevic, Vladimir, Raičević, Savo, Savić, Slobodan, Zorović, Maja, Živin, Marko, Selih, Vid Simon, Spasic, Snezana, 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_rimsi_2841 .

TY  - CHAP
AU  - Opačić, Miloš
AU  - Ristic, Aleksandar J
AU  - Savic, Danijela
AU  - Selih, Vid Simon
AU  - Zivin, Marko
AU  - Sokic, Dragoslav
AU  - Raičević, Savo
AU  - Bascarevic, Vladimir
AU  - Spasojević, Ivan
PY  - 2017
UR  - http://rimsi.imsi.bg.ac.rs/handle/123456789/2938
AB  - Mesial temporal lobe epilepsy (mTLE) represents the most common subtype of human
focal epilepsies and perhaps the best-characterized disorder of this type 1
. Hippocampal
sclerosis (HS) is the most common histopathologic abnormality found in adults with drugresistant mTLE 2
. The histopathologic hallmark of HS is segmental pyramidal cell loss,
which can affect any field of the cornu Ammonis (CA1-4). Hippocampal neuronal cell loss
is always associated with a severe pattern of astrogliosis 3
. Therewithal, disturbed
homeostasis of metals is implicated in the pathology of mTLE-HS. Zinc has been
considered to play a major role in epileptogenesis in relation to its involvement in the
modulation of excitability and synaptic plasticity 4,5. Further, it has been shown that
epileptogenic hippocampi are exposed to oxidative stress and that the development of prooxidative conditions in the CNS usually involves the loss of homeostasis of iron 6,7. Low
brain levels of copper and manganese have been reported in patients with Menkes disease
and in animal models of epilepsy, and linked to seizure development 8,9. Ristić et al. were
the first to conduct a case-control study of total concentration of metals in tissue of human
HS, and report lower concentrations of copper and manganese 10.
PB  - Biohemijsko društvo Srbije
T2  - Biochemistry of Control in Life and Technology
T1  - Imaging and regional distribution of copper, zinc, manganese and iron in sclerotic hippocampi of patients with mesial temporal lobe epilepsy
EP  - 181
SP  - 179
UR  - https://hdl.handle.net/21.15107/rcub_rimsi_2938
ER  - 

@inbook{
author = "Opačić, Miloš and Ristic, Aleksandar J and Savic, Danijela and Selih, Vid Simon and Zivin, Marko and Sokic, Dragoslav and Raičević, Savo and Bascarevic, Vladimir and Spasojević, Ivan",
year = "2017",
abstract = "Mesial temporal lobe epilepsy (mTLE) represents the most common subtype of human
focal epilepsies and perhaps the best-characterized disorder of this type 1
. Hippocampal
sclerosis (HS) is the most common histopathologic abnormality found in adults with drugresistant mTLE 2
. The histopathologic hallmark of HS is segmental pyramidal cell loss,
which can affect any field of the cornu Ammonis (CA1-4). Hippocampal neuronal cell loss
is always associated with a severe pattern of astrogliosis 3
. Therewithal, disturbed
homeostasis of metals is implicated in the pathology of mTLE-HS. Zinc has been
considered to play a major role in epileptogenesis in relation to its involvement in the
modulation of excitability and synaptic plasticity 4,5. Further, it has been shown that
epileptogenic hippocampi are exposed to oxidative stress and that the development of prooxidative conditions in the CNS usually involves the loss of homeostasis of iron 6,7. Low
brain levels of copper and manganese have been reported in patients with Menkes disease
and in animal models of epilepsy, and linked to seizure development 8,9. Ristić et al. were
the first to conduct a case-control study of total concentration of metals in tissue of human
HS, and report lower concentrations of copper and manganese 10.",
publisher = "Biohemijsko društvo Srbije",
journal = "Biochemistry of Control in Life and Technology",
booktitle = "Imaging and regional distribution of copper, zinc, manganese and iron in sclerotic hippocampi of patients with mesial temporal lobe epilepsy",
pages = "181-179",
url = "https://hdl.handle.net/21.15107/rcub_rimsi_2938"
}

Opačić, M., Ristic, A. J., Savic, D., Selih, V. S., Zivin, M., Sokic, D., Raičević, S., Bascarevic, V.,& Spasojević, I.. (2017). Imaging and regional distribution of copper, zinc, manganese and iron in sclerotic hippocampi of patients with mesial temporal lobe epilepsy. in Biochemistry of Control in Life and Technology
Biohemijsko društvo Srbije., 179-181.
https://hdl.handle.net/21.15107/rcub_rimsi_2938

Opačić M, Ristic AJ, Savic D, Selih VS, Zivin M, Sokic D, Raičević S, Bascarevic V, Spasojević I. Imaging and regional distribution of copper, zinc, manganese and iron in sclerotic hippocampi of patients with mesial temporal lobe epilepsy. in Biochemistry of Control in Life and Technology. 2017;:179-181.
https://hdl.handle.net/21.15107/rcub_rimsi_2938 .

Opačić, Miloš, Ristic, Aleksandar J, Savic, Danijela, Selih, Vid Simon, Zivin, Marko, Sokic, Dragoslav, Raičević, Savo, Bascarevic, Vladimir, Spasojević, Ivan, "Imaging and regional distribution of copper, zinc, manganese and iron in sclerotic hippocampi of patients with mesial temporal lobe epilepsy" in Biochemistry of Control in Life and Technology (2017):179-181,
https://hdl.handle.net/21.15107/rcub_rimsi_2938 .

TY  - JOUR
AU  - Opačić, Miloš
AU  - Ristic, Aleksandar J
AU  - Savić, Danijela Z
AU  - Selih, Vid Simon
AU  - Zivin, Marko
AU  - Sokic, Dragoslav
AU  - Raicević, Savo
AU  - Baščarević, Vladimir
AU  - Spasojević, Ivan
PY  - 2017
UR  - http://rimsi.imsi.bg.ac.rs/handle/123456789/1080
AB  - The loss of metal homeostasis has been implicated in the pathophysiology of mesial temporal lobe epilepsy associated with hippocampal sclerosis (mTLE-HS). Here we applied laser ablation inductively coupled plasma mass spectrometry imaging to establish the spatial distribution of Zn, Fe, Cu and Mn in coronal sections of hippocampi of four patients with drug-resistant mTLE-HS who underwent amygdalohippocampectomy. Detailed maps of the metal concentrations in the different morphological areas/layers were built and analyzed. The highest level of Zn (>20 mu g g(-1)) was found in mossy fiber-rich regions -cornu ammonis field 4 (CA4), gyrus dentatus, and CA3. The distribution of Fe appears to reflect the routes of the main intrahippocampal blood vessels. The highest concentrations of Cu (410 mg g(-1)) and Mn (415 mu g g(-1)) were observed in regions/layers with neuron somata - subiculum, CA4, gyrus dentatus, and stratum pyramidale (SPy) in CA1 and CA2. Alveus and other regions with axons and dendrites generally showed lower levels of Zn, Cu, and Mn. The Cu concentration was decreased in the areas of total neuronal loss in SPy in CA1 (9.73 +/- 0.91 mu g g(-1)), compared to the subiculum (13.32 +/- .29 mu g g(-1); p = 0.043). The Cu and Mn concentrations correlated positively with neuron density in the SPy in CA1 (R = 0.629, p o 0.001; and R = 0.391, p = 0.004). These results provide a deeper insight into hippocampal metabolism of metals, and pave the road for identifying the components of the mechanism of epileptogenesis among Cu and Mn transporters and metalloproteins.
PB  - Royal Soc Chemistry, Cambridge
T2  - Metallomics
T1  - Metal maps of sclerotic hippocampi of patients with mesial temporal lobe epilepsy
EP  - 148
IS  - 2
SP  - 141
VL  - 9
DO  - 10.1039/c6mt00293e
ER  - 

@article{
author = "Opačić, Miloš and Ristic, Aleksandar J and Savić, Danijela Z and Selih, Vid Simon and Zivin, Marko and Sokic, Dragoslav and Raicević, Savo and Baščarević, Vladimir and Spasojević, Ivan",
year = "2017",
abstract = "The loss of metal homeostasis has been implicated in the pathophysiology of mesial temporal lobe epilepsy associated with hippocampal sclerosis (mTLE-HS). Here we applied laser ablation inductively coupled plasma mass spectrometry imaging to establish the spatial distribution of Zn, Fe, Cu and Mn in coronal sections of hippocampi of four patients with drug-resistant mTLE-HS who underwent amygdalohippocampectomy. Detailed maps of the metal concentrations in the different morphological areas/layers were built and analyzed. The highest level of Zn (>20 mu g g(-1)) was found in mossy fiber-rich regions -cornu ammonis field 4 (CA4), gyrus dentatus, and CA3. The distribution of Fe appears to reflect the routes of the main intrahippocampal blood vessels. The highest concentrations of Cu (410 mg g(-1)) and Mn (415 mu g g(-1)) were observed in regions/layers with neuron somata - subiculum, CA4, gyrus dentatus, and stratum pyramidale (SPy) in CA1 and CA2. Alveus and other regions with axons and dendrites generally showed lower levels of Zn, Cu, and Mn. The Cu concentration was decreased in the areas of total neuronal loss in SPy in CA1 (9.73 +/- 0.91 mu g g(-1)), compared to the subiculum (13.32 +/- .29 mu g g(-1); p = 0.043). The Cu and Mn concentrations correlated positively with neuron density in the SPy in CA1 (R = 0.629, p o 0.001; and R = 0.391, p = 0.004). These results provide a deeper insight into hippocampal metabolism of metals, and pave the road for identifying the components of the mechanism of epileptogenesis among Cu and Mn transporters and metalloproteins.",
publisher = "Royal Soc Chemistry, Cambridge",
journal = "Metallomics",
title = "Metal maps of sclerotic hippocampi of patients with mesial temporal lobe epilepsy",
pages = "148-141",
number = "2",
volume = "9",
doi = "10.1039/c6mt00293e"
}

Opačić, M., Ristic, A. J., Savić, D. Z., Selih, V. S., Zivin, M., Sokic, D., Raicević, S., Baščarević, V.,& Spasojević, I.. (2017). Metal maps of sclerotic hippocampi of patients with mesial temporal lobe epilepsy. in Metallomics
Royal Soc Chemistry, Cambridge., 9(2), 141-148.
https://doi.org/10.1039/c6mt00293e

Opačić M, Ristic AJ, Savić DZ, Selih VS, Zivin M, Sokic D, Raicević S, Baščarević V, Spasojević I. Metal maps of sclerotic hippocampi of patients with mesial temporal lobe epilepsy. in Metallomics. 2017;9(2):141-148.
doi:10.1039/c6mt00293e .

Opačić, Miloš, Ristic, Aleksandar J, Savić, Danijela Z, Selih, Vid Simon, Zivin, Marko, Sokic, Dragoslav, Raicević, Savo, Baščarević, Vladimir, Spasojević, Ivan, "Metal maps of sclerotic hippocampi of patients with mesial temporal lobe epilepsy" in Metallomics, 9, no. 2 (2017):141-148,
https://doi.org/10.1039/c6mt00293e . .