TY  - JOUR
AU  - Atluri, Navya
AU  - Joksimović, Srđan M.
AU  - Oklopcic, Azra
AU  - Milanović, Desanka
AU  - Klawitter, Jelena
AU  - Eggan, Pierce
AU  - Krishnan, Kathiresan
AU  - Covey, Douglas F.
AU  - Todorović, Slobodan M.
AU  - Jevtović-Todorović, Vesna
PY  - 2018
UR  - http://linkinghub.elsevier.com/retrieve/pii/S0007091218300035
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3053
AB  - BACKGROUND More than 4 million children are exposed annually to sedatives and general anaesthetics (GAs) in the USA alone. Recent data suggest that common GAs can be detrimental to brain development causing neurodegeneration and long-term cognitive impairments. Challenged by a recent US Food and Drug Administration (FDA) warning about potentially neurotoxic effects of GAs in children, there is an urgent need to develop safer GAs. METHODS Postnatal Day 7 (P7) rat pups of both sexes were exposed to six (repeated every 2 h) injections of equipotent hypnotic doses of ketamine or the neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) for 12 h. Loss of righting reflex was used to assess hypnotic properties and therapeutic index; quantitative caspase-3 immunohistochemistry was used to assess developmental neuroapoptosis; patch-clamp recordings in acute brain slices were used to assess the effects of 3β-OH on neuronal excitability and synaptic transmission. Cognitive abilities of rats exposed to ketamine, 3β-OH, or vehicle at P7 were assessed in young adulthood using the radial arm maze. RESULTS The neuroactive steroid 3β-OH has a therapeutic index similar to ketamine, a commonly used clinical GA. We report that 3β-OH is safe and, unlike ketamine, does not cause neuroapoptosis or impair cognitive development when administered to P7 rat pups. Interestingly, 3β-OH blocks T-type calcium channels and presynaptically dampens synaptic transmission at hypnotically-relevant brain concentrations, but it lacks a direct effect on γ-aminobutyric acid A or glutamate-gated ion channels. CONCLUSIONS The neurosteroid 3β-OH is a relatively safe hypnotic that warrants further consideration for paediatric anaesthesia.
T2  - British Journal of Anaesthesia
T1  - A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain.
IS  - 4
VL  - 120
DO  - 10.1016/j.bja.2017.12.039
SP  - 768
EP  - 778
ER  - 

@article{
author = "Atluri, Navya and Joksimović, Srđan M. and Oklopcic, Azra and Milanović, Desanka and Klawitter, Jelena and Eggan, Pierce and Krishnan, Kathiresan and Covey, Douglas F. and Todorović, Slobodan M. and Jevtović-Todorović, Vesna",
year = "2018",
abstract = "BACKGROUND More than 4 million children are exposed annually to sedatives and general anaesthetics (GAs) in the USA alone. Recent data suggest that common GAs can be detrimental to brain development causing neurodegeneration and long-term cognitive impairments. Challenged by a recent US Food and Drug Administration (FDA) warning about potentially neurotoxic effects of GAs in children, there is an urgent need to develop safer GAs. METHODS Postnatal Day 7 (P7) rat pups of both sexes were exposed to six (repeated every 2 h) injections of equipotent hypnotic doses of ketamine or the neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) for 12 h. Loss of righting reflex was used to assess hypnotic properties and therapeutic index; quantitative caspase-3 immunohistochemistry was used to assess developmental neuroapoptosis; patch-clamp recordings in acute brain slices were used to assess the effects of 3β-OH on neuronal excitability and synaptic transmission. Cognitive abilities of rats exposed to ketamine, 3β-OH, or vehicle at P7 were assessed in young adulthood using the radial arm maze. RESULTS The neuroactive steroid 3β-OH has a therapeutic index similar to ketamine, a commonly used clinical GA. We report that 3β-OH is safe and, unlike ketamine, does not cause neuroapoptosis or impair cognitive development when administered to P7 rat pups. Interestingly, 3β-OH blocks T-type calcium channels and presynaptically dampens synaptic transmission at hypnotically-relevant brain concentrations, but it lacks a direct effect on γ-aminobutyric acid A or glutamate-gated ion channels. CONCLUSIONS The neurosteroid 3β-OH is a relatively safe hypnotic that warrants further consideration for paediatric anaesthesia.",
journal = "British Journal of Anaesthesia",
title = "A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain.",
number = "4",
volume = "120",
doi = "10.1016/j.bja.2017.12.039",
pages = "768-778"
}

Atluri, N., Joksimović, S. M., Oklopcic, A., Milanović, D., Klawitter, J., Eggan, P., Krishnan, K., Covey, D. F., Todorović, S. M.,& Jevtović-Todorović, V.. (2018). A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain.. in British Journal of Anaesthesia, 120(4), 768-778.
https://doi.org/10.1016/j.bja.2017.12.039

Atluri N, Joksimović SM, Oklopcic A, Milanović D, Klawitter J, Eggan P, Krishnan K, Covey DF, Todorović SM, Jevtović-Todorović V. A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain.. in British Journal of Anaesthesia. 2018;120(4):768-778.
doi:10.1016/j.bja.2017.12.039 .

Atluri, Navya, Joksimović, Srđan M., Oklopcic, Azra, Milanović, Desanka, Klawitter, Jelena, Eggan, Pierce, Krishnan, Kathiresan, Covey, Douglas F., Todorović, Slobodan M., Jevtović-Todorović, Vesna, "A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain." in British Journal of Anaesthesia, 120, no. 4 (2018):768-778,
https://doi.org/10.1016/j.bja.2017.12.039 . .

TY  - JOUR
AU  - Milanović, Desanka
AU  - Pešić, Vesna
AU  - Lončarević-Vasiljković, Nataša
AU  - Avramović, Vladimir
AU  - Tešić, Vesna
AU  - Jevtović-Todorović, Vesna
AU  - Kanazir, Selma
AU  - Ruždijić, Sabera
PY  - 2017
UR  - http://link.springer.com/10.1007/s12640-017-9730-0
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2741
AB  - Propofol is a general anesthetic commonly used in pediatric clinical practices. Experimental findings demonstrate that anesthetics induce widespread apoptosis and cognitive decline in a developing brain. Although anesthesia-mediated neurotoxicity is the most prominent during intense period of synaptogenesis, the effects of an early anesthesia exposure on the synapses are not well understood. The aim of this study was to examine the effects of neonatal propofol anesthesia on the expression of key proteins that participate in synaptogenesis and synaptic plasticity and to evaluate long-term neurobehavioral abnormalities in the mature adult brain. Propofol-injected 7-day-old rats were maintained under 2-, 4-, and 6-h-long anesthesia and sacrificed 0, 4, 16, and 24 h after the termination of each exposure. We showed that propofol anesthesia strongly influenced spatiotemporal expression and/or proteolytic processing of crucial presynaptic (GAP-43, synaptophysin, α-synuclein), trans-synaptic (N-cadherin), and postsynaptic (drebrin, MAP-2) proteins in the cortex and thalamus. An overall decrease of synaptophysin, α-synuclein, N-cadherin, and drebrin indicated impaired function and structure of the synaptic contacts immediately after anesthesia cessation. GAP-43 and MAP-2 adult and juvenile isoforms are upregulated following anesthesia, suggesting compensatory mechanism in the maintaining of the structural integrity and stabilization of developing axons and dendritic arbors. Neonatal propofol exposure significantly altered spontaneous motor activity (increased stereotypic/repetitive movements) and changed emotional behavior (reduced anxiety-like response) in the adulthood, 6 months later. These findings suggest that propofol anesthesia is synaptotoxic in the developing brain, disturbing synaptic dynamics and producing neuroplastic changes permanently incorporated into existing networks with long-lasting functional consequences.
T2  - Neurotoxicity Research
T1  - Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats
VL  - 32
DO  - 10.1007/s12640-017-9730-0
SP  - 247
EP  - 263
ER  - 

@article{
author = "Milanović, Desanka and Pešić, Vesna and Lončarević-Vasiljković, Nataša and Avramović, Vladimir and Tešić, Vesna and Jevtović-Todorović, Vesna and Kanazir, Selma and Ruždijić, Sabera",
year = "2017",
abstract = "Propofol is a general anesthetic commonly used in pediatric clinical practices. Experimental findings demonstrate that anesthetics induce widespread apoptosis and cognitive decline in a developing brain. Although anesthesia-mediated neurotoxicity is the most prominent during intense period of synaptogenesis, the effects of an early anesthesia exposure on the synapses are not well understood. The aim of this study was to examine the effects of neonatal propofol anesthesia on the expression of key proteins that participate in synaptogenesis and synaptic plasticity and to evaluate long-term neurobehavioral abnormalities in the mature adult brain. Propofol-injected 7-day-old rats were maintained under 2-, 4-, and 6-h-long anesthesia and sacrificed 0, 4, 16, and 24 h after the termination of each exposure. We showed that propofol anesthesia strongly influenced spatiotemporal expression and/or proteolytic processing of crucial presynaptic (GAP-43, synaptophysin, α-synuclein), trans-synaptic (N-cadherin), and postsynaptic (drebrin, MAP-2) proteins in the cortex and thalamus. An overall decrease of synaptophysin, α-synuclein, N-cadherin, and drebrin indicated impaired function and structure of the synaptic contacts immediately after anesthesia cessation. GAP-43 and MAP-2 adult and juvenile isoforms are upregulated following anesthesia, suggesting compensatory mechanism in the maintaining of the structural integrity and stabilization of developing axons and dendritic arbors. Neonatal propofol exposure significantly altered spontaneous motor activity (increased stereotypic/repetitive movements) and changed emotional behavior (reduced anxiety-like response) in the adulthood, 6 months later. These findings suggest that propofol anesthesia is synaptotoxic in the developing brain, disturbing synaptic dynamics and producing neuroplastic changes permanently incorporated into existing networks with long-lasting functional consequences.",
journal = "Neurotoxicity Research",
title = "Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats",
volume = "32",
doi = "10.1007/s12640-017-9730-0",
pages = "247-263"
}

Milanović, D., Pešić, V., Lončarević-Vasiljković, N., Avramović, V., Tešić, V., Jevtović-Todorović, V., Kanazir, S.,& Ruždijić, S.. (2017). Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats. in Neurotoxicity Research, 32, 247-263.
https://doi.org/10.1007/s12640-017-9730-0

Milanović D, Pešić V, Lončarević-Vasiljković N, Avramović V, Tešić V, Jevtović-Todorović V, Kanazir S, Ruždijić S. Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats. in Neurotoxicity Research. 2017;32:247-263.
doi:10.1007/s12640-017-9730-0 .

Milanović, Desanka, Pešić, Vesna, Lončarević-Vasiljković, Nataša, Avramović, Vladimir, Tešić, Vesna, Jevtović-Todorović, Vesna, Kanazir, Selma, Ruždijić, Sabera, "Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats" in Neurotoxicity Research, 32 (2017):247-263,
https://doi.org/10.1007/s12640-017-9730-0 . .

TY  - JOUR
AU  - Milanović, Desanka
AU  - Pešić, Vesna
AU  - Lončarević-Vasiljković, Nataša
AU  - Pavković, Željko
AU  - Popić, Jelena
AU  - Kanazir, Selma
AU  - Jevtović-Todorović, Vesna
AU  - Ruždijić, Sabera
PY  - 2016
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5457
AB  - A number of experimental studies have reported that exposure to common, clinically used anesthetics induce extensive neuroapoptosis and cognitive impairment when applied to young rodents, up to 2 weeks old, in phase of rapid synaptogenesis. Propofol is the most used general anesthetic in clinical practice whose mechanisms of neurotoxicity on the developing brain remains to be examined in depth. This study investigated effects of different exposures to propofol anesthesia on Fas receptor and Fas ligand expressions, which mediate proapoptotic and proinflammation signaling in the brain. Propofol (20 mg/kg) was administered to 7-day-old rats in multiple doses sufficient to maintain 2-, 4- and 6-h duration of anesthesia. Animals were sacrificed at 0, 4, 16 and 24 h after termination of anesthesia. It was found that propofol anesthesia induced Fas/FasL and downstream caspase-8 expression more prominently in the thalamus than in the cortex. Opposite, Bcl-2 and caspase-9, markers of intrinsic pathway activation, were shown to be more influenced by propofol treatment in the cortex. Further, we have established upregulation of caspase-1 and IL-1β cytokine transcription as well as subsequent activation of microglia that is potentially associated with brain inflammation. Behavioral analyses revealed that P35 and P60 animals, neonatally exposed to propofol, had significantly higher motor activity during three consecutive days of testing in the open field, though formation of the intersession habituation was not prevented. This data, together with our previous results, contributes to elucidation of complex mechanisms of propofol toxicity in developing brain.
PB  - New York: Springer
T2  - Neurotoxicity Research
T1  - The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats
IS  - 3
VL  - 30
DO  - 10.1007/s12640-016-9629-1
SP  - 434
EP  - 452
ER  - 

@article{
author = "Milanović, Desanka and Pešić, Vesna and Lončarević-Vasiljković, Nataša and Pavković, Željko and Popić, Jelena and Kanazir, Selma and Jevtović-Todorović, Vesna and Ruždijić, Sabera",
year = "2016",
abstract = "A number of experimental studies have reported that exposure to common, clinically used anesthetics induce extensive neuroapoptosis and cognitive impairment when applied to young rodents, up to 2 weeks old, in phase of rapid synaptogenesis. Propofol is the most used general anesthetic in clinical practice whose mechanisms of neurotoxicity on the developing brain remains to be examined in depth. This study investigated effects of different exposures to propofol anesthesia on Fas receptor and Fas ligand expressions, which mediate proapoptotic and proinflammation signaling in the brain. Propofol (20 mg/kg) was administered to 7-day-old rats in multiple doses sufficient to maintain 2-, 4- and 6-h duration of anesthesia. Animals were sacrificed at 0, 4, 16 and 24 h after termination of anesthesia. It was found that propofol anesthesia induced Fas/FasL and downstream caspase-8 expression more prominently in the thalamus than in the cortex. Opposite, Bcl-2 and caspase-9, markers of intrinsic pathway activation, were shown to be more influenced by propofol treatment in the cortex. Further, we have established upregulation of caspase-1 and IL-1β cytokine transcription as well as subsequent activation of microglia that is potentially associated with brain inflammation. Behavioral analyses revealed that P35 and P60 animals, neonatally exposed to propofol, had significantly higher motor activity during three consecutive days of testing in the open field, though formation of the intersession habituation was not prevented. This data, together with our previous results, contributes to elucidation of complex mechanisms of propofol toxicity in developing brain.",
publisher = "New York: Springer",
journal = "Neurotoxicity Research",
title = "The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats",
number = "3",
volume = "30",
doi = "10.1007/s12640-016-9629-1",
pages = "434-452"
}

Milanović, D., Pešić, V., Lončarević-Vasiljković, N., Pavković, Ž., Popić, J., Kanazir, S., Jevtović-Todorović, V.,& Ruždijić, S.. (2016). The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats. in Neurotoxicity Research
New York: Springer., 30(3), 434-452.
https://doi.org/10.1007/s12640-016-9629-1

Milanović D, Pešić V, Lončarević-Vasiljković N, Pavković Ž, Popić J, Kanazir S, Jevtović-Todorović V, Ruždijić S. The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats. in Neurotoxicity Research. 2016;30(3):434-452.
doi:10.1007/s12640-016-9629-1 .

Milanović, Desanka, Pešić, Vesna, Lončarević-Vasiljković, Nataša, Pavković, Željko, Popić, Jelena, Kanazir, Selma, Jevtović-Todorović, Vesna, Ruždijić, Sabera, "The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats" in Neurotoxicity Research, 30, no. 3 (2016):434-452,
https://doi.org/10.1007/s12640-016-9629-1 . .

TY  - JOUR
AU  - Popić, Jelena
AU  - Pešić, Vesna
AU  - Milanović, Desanka
AU  - Todorović, Smilja
AU  - Kanazir, Selma
AU  - Jevtović-Todorović, Vesna
AU  - Ruždijić, Sabera
PY  - 2012
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4125
AB  - Several studies have revealed a role for neurotrophins in anesthesia-induced neurotoxicity in the developing brain. In this study we monitored the spatial and temporal expression of neurotrophic signaling molecules in the brain of 14-day-old (PND14) Wistar rats after the application of a single propofol dose (25 mg/kg i.p). The structures of interest were the cortex and thalamus as the primary areas of anesthetic actions. Changes of the protein levels of the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), their activated receptors tropomyosin-related kinase (TrkA and TrkB) and downstream kinases Akt and the extracellular signal regulated kinase (ERK) were assessed by Western immunoblot analysis at different time points during the first 24 h after the treatment, as well as the expression of cleaved caspase-3 fragment. Fluoro-Jade B staining was used to follow the appearance of degenerating neurons. The obtained results show that the treatment caused marked alterations in levels of the examined neurotrophins, their receptors and downstream effector kinases. However, these changes were not associated with increased neurodegeneration in either the cortex or the thalamus. These results indicate that in the brain of PND14 rats, the interaction between Akt/ERK signaling might be one of important part of endogenous defense mechanisms, which the developing brain utilizes to protect itself from potential anesthesia-induced damage. Elucidation of the underlying molecular mechanisms will improve our understanding of the age-dependent component of anesthesia-induced neurotoxicity.
PB  - San Francisco:the Public Library of Science (PLOS)
T2  - PLoS One
T1  - Propofol-induced changes in neurotrophic signaling in the developing nervous system in vivo
IS  - 4
VL  - 7
DO  - 10.1371/journal.pone.0034396
SP  - e34396
ER  - 

@article{
author = "Popić, Jelena and Pešić, Vesna and Milanović, Desanka and Todorović, Smilja and Kanazir, Selma and Jevtović-Todorović, Vesna and Ruždijić, Sabera",
year = "2012",
abstract = "Several studies have revealed a role for neurotrophins in anesthesia-induced neurotoxicity in the developing brain. In this study we monitored the spatial and temporal expression of neurotrophic signaling molecules in the brain of 14-day-old (PND14) Wistar rats after the application of a single propofol dose (25 mg/kg i.p). The structures of interest were the cortex and thalamus as the primary areas of anesthetic actions. Changes of the protein levels of the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), their activated receptors tropomyosin-related kinase (TrkA and TrkB) and downstream kinases Akt and the extracellular signal regulated kinase (ERK) were assessed by Western immunoblot analysis at different time points during the first 24 h after the treatment, as well as the expression of cleaved caspase-3 fragment. Fluoro-Jade B staining was used to follow the appearance of degenerating neurons. The obtained results show that the treatment caused marked alterations in levels of the examined neurotrophins, their receptors and downstream effector kinases. However, these changes were not associated with increased neurodegeneration in either the cortex or the thalamus. These results indicate that in the brain of PND14 rats, the interaction between Akt/ERK signaling might be one of important part of endogenous defense mechanisms, which the developing brain utilizes to protect itself from potential anesthesia-induced damage. Elucidation of the underlying molecular mechanisms will improve our understanding of the age-dependent component of anesthesia-induced neurotoxicity.",
publisher = "San Francisco:the Public Library of Science (PLOS)",
journal = "PLoS One",
title = "Propofol-induced changes in neurotrophic signaling in the developing nervous system in vivo",
number = "4",
volume = "7",
doi = "10.1371/journal.pone.0034396",
pages = "e34396"
}

Popić, J., Pešić, V., Milanović, D., Todorović, S., Kanazir, S., Jevtović-Todorović, V.,& Ruždijić, S.. (2012). Propofol-induced changes in neurotrophic signaling in the developing nervous system in vivo. in PLoS One
San Francisco:the Public Library of Science (PLOS)., 7(4), e34396.
https://doi.org/10.1371/journal.pone.0034396

Popić J, Pešić V, Milanović D, Todorović S, Kanazir S, Jevtović-Todorović V, Ruždijić S. Propofol-induced changes in neurotrophic signaling in the developing nervous system in vivo. in PLoS One. 2012;7(4):e34396.
doi:10.1371/journal.pone.0034396 .

Popić, Jelena, Pešić, Vesna, Milanović, Desanka, Todorović, Smilja, Kanazir, Selma, Jevtović-Todorović, Vesna, Ruždijić, Sabera, "Propofol-induced changes in neurotrophic signaling in the developing nervous system in vivo" in PLoS One, 7, no. 4 (2012):e34396,
https://doi.org/10.1371/journal.pone.0034396 . .