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 . .