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John W Olney - One of the best experts on this subject based on the ideXlab platform.
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Developmental Neurotoxicity of Alcohol and Anesthetic Drugs Is Augmented by Co-Exposure to Caffeine
MDPI AG, 2013Co-Authors: Catherine E Creeley, John W Olney, Carla M YuedeAbstract:Anesthetic and anti-epileptic drugs used in pediatric and obstetric medicine and several drugs, including alcohol, that are abused by pregnant women, trigger widespread Neuroapoptosis in the developing brain of several animal species, including non-human primates. Caffeine (CAF) is often administered to premature infants to stimulate respiration, and these infants are also exposed simultaneously to anesthetic drugs for procedural sedation and/or surgical procedures. Pregnant women who abuse alcohol or other apoptogenic drugs also may heavily consume CAF. We administered CAF to infant mice alone or in combination with alcohol, phencyclidine, diazepam, midazolam, ketamine, or isoflurane, which are drugs of abuse and/or drugs frequently used in pediatric medicine, and found that CAF weakly triggers Neuroapoptosis by itself and markedly potentiates the neuroapoptogenic action of each of these other drugs. Exposure of infant mice to CAF + phencyclidine resulted in long-term impairment in behavioral domains relevant to attention deficit/hyperactivity disorder, whereas exposure to CAF + diazepam resulted in long-term learning/memory impairment. At doses used in these experiments, these behavioral impairments either did not occur or were substantially less pronounced in mice exposed to CAF alone or to phencyclidine or diazepam alone. CAF currently enjoys the reputation of being highly beneficial and safe for use in neonatal medicine. Our data suggest the need to consider whether CAF may have harmful as well as beneficial effects on the developing brain, and the need for research aimed at understanding the full advantage of its beneficial effects while avoiding its potentially harmful effects
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Density of AC3-positive profiles is greater when PCP exposure occurs on P2 and P7 (P2+P7) compared to exposure on P7 alone.
2013Co-Authors: Carla M Yuede, Catherine E Creeley, John W Olney, David F Wozniak, George T Taylor, Nuri B FarberAbstract:Density of AC3-positive cell profiles summed across forebrain regions most sensitive to PCP-induced Neuroapoptosis on P7 (retrosplenial cortex, caudate putamen, anterior thalamic nuclei) is significantly (**p = 0.012) greater in mice that were exposed to PCP on P2 and P7 (P2+P7PCP group) compared to that observed in mice that were treated only on P7 (P7PCP). The P7PCP and P2+P7PCP groups each showed significantly greater densities of AC3-positive profiles compared to the saline controls (†p = 0.001; *p
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isoflurane induced apoptosis of oligodendrocytes in the neonatal primate brain
Annals of Neurology, 2012Co-Authors: Ansgar M Brambrink, Gregory A Dissen, Catherine E Creeley, Stephen A Back, Art Riddle, Xi Gong, Matthew Moravec, Krikor Dikranian, John W OlneyAbstract:Objective Previously we reported that exposure of 6-day old (P6) rhesus macaques to isoflurane for 5 hours triggers a robust Neuroapoptosis response in developing brain. We have also observed (unpublished) that isoflurane causes apoptosis of cellular profiles in the white matter that resemble glia. We analyzed the cellular identity of the apoptotic white matter profiles and determined the magnitude of this cell death response to isoflurane.
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ketamine induced Neuroapoptosis in the fetal and neonatal rhesus macaque brain
Anesthesiology, 2012Co-Authors: Ansgar M Brambrink, Alex S Evers, Michael S Avidan, Nuri B Farber, Derek J Smith, Lauren Drew Martin, Gregory A Dissen, Catherine E Creeley, John W OlneyAbstract:Background: Exposure of rhesus macaque fetuses for 24 h or neonates fo r9ht oketamine anesthesia causes Neuroapoptosis in the developing brain. The current study clarifies the minimum exposure required for and the extent and spatial distribution of ketamine-induced Neuroapoptosis in rhesus fetuses and neonates. Method: Ketamine was administered by IV infusion for 5 h to postnatal day 6 rhesus neonates or to pregnant rhesus females at 120 days’ gestation (full term 165 days). Three hours later, fetuses were delivered by cesarean section, and the fetal and neonatal brains were studied for evidence of apoptotic neurodegeneration, as determined by activated caspase-3 staining. Results: Both the fetal (n 3) and neonatal (n 4) ketamine-exposed brains had a significant increase in apoptotic profiles compared with drug-naive controls (fetal n 4; neonatal n 5). Loss of neurons attributable to ketamine exposure was 2.2 times greater in fetuses than in neonates. The pattern of neurodegeneration in fetuses was different from that in neonates, and all subjects exposed at either age had a pattern characteristic for that age. Conclusion: The developing rhesus macaque brain is sensitive to the apoptogenic action of ketamine at both a fetal and neonatal age, and exposure duration o f5hi ssufficient to induce a significant Neuroapoptosis response at either age. The pattern of neurodegeneration induced by ketamine in fetuses was different from that in neonates, and loss of neurons attributable to ketamine exposure was 2.2 times greater in the fetal than neonatal brains.
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alcohol induced Neuroapoptosis in the fetal macaque brain
Neurobiology of Disease, 2010Co-Authors: Nuri B Farber, Catherine E Creeley, John W OlneyAbstract:The ability of brief exposure to alcohol to cause widespread Neuroapoptosis in the developing rodent brain and subsequent long-term neurocognitive deficits has been proposed as a mechanism underlying the neurobehavioral deficits seen in fetal alcohol spectrum disorder (FASD). It is unknown whether brief exposure to alcohol causes apoptosis in the fetal primate brain. Pregnant fascicularis macaques at various stages of gestation (G105 to G155) were exposed to alcohol for 8h, then the fetuses were delivered by caesarean section and their brains perfused with fixative and evaluated for apoptosis. Compared to saline control brains, the ethanol-exposed brains displayed a pattern of Neuroapoptosis that was widespread and similar to that caused by alcohol in infant rodent brain. The observed increase in apoptosis was on the order of 60-fold. We propose that the apoptogenic action of alcohol could explain many of the neuropathological changes and long-term neuropsychiatric disturbances associated with human FASD.
Chainllie Young - One of the best experts on this subject based on the ideXlab platform.
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lithium protects against anesthesia induced developmental Neuroapoptosis
Anesthesiology, 2009Co-Authors: Megan M W Straiko, Derek J Smith, Catherine E Creeley, Chainllie Young, Davide Cattano, Haihui Wang, Stephen A Johnson, John W OlneyAbstract:Background Ethanol and anesthetic drugs trigger Neuroapoptosis in the developing mouse brain. Recently, it was found that ethanol-induced Neuroapoptosis is preceded by suppressed phosphorylation of extracellular signal-regulated protein kinase (ERK), and lithium counteracts both the phosphorylated ERK suppressant action and ethanol-induced Neuroapoptosis. The present study was undertaken to address the following questions: 1) Do ketamine and propofol mimic ethanol in suppressing ERK phosphorylation? 2) If they do, does lithium prevent this suppressant action, and also prevent these anesthetic drugs from triggering Neuroapoptosis?
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ethanol causes and lithium prevents Neuroapoptosis and suppression of perk in the infant mouse brain
Neurobiology of Disease, 2008Co-Authors: Chainllie Young, Catherine E Creeley, Megan M W Straiko, Stephen A Johnson, John W OlneyAbstract:Transient exposure of immature animals during the brain growth spurt period to ethanol triggers Neuroapoptosis in the developing brain. Here we report that lithium, when administered in a single, well-tolerated dose to infant mice, suppresses spontaneous Neuroapoptosis that occurs naturally in the developing brain, and prevents ethanol from triggering Neuroapoptosis. To explore lithium's mechanism of action, we focused on kinase signaling systems (ERK, Akt, JNK) that are believed to play a regulatory role in cell survival, and found that very rapidly after ethanol administration there is a suppression of ERK phosphorylation, and that lithium stimulates ERK phosphorylation and prevents ethanol from suppressing this phosphorylation process. Ethanol also suppressed pAKT, but lithium did not counteract this effect. We also found that ethanol activates the JNK system, but this cannot explain the neurotoxic action of ethanol, because JNK activation did not occur in the same neuronal populations that are killed by ethanol.
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potential of xenon to induce or to protect against Neuroapoptosis in the developing mouse brain
Canadian Journal of Anaesthesia-journal Canadien D Anesthesie, 2008Co-Authors: Davide Cattano, Alex S Evers, Michael S Avidan, John W Olney, Peter Williamson, Kimiko Fukui, Chainllie YoungAbstract:Purpose: Drugs that suppress neuronal activity, including all general anesthetics that have been tested thus far (ketamine, midazolam, isoflurane, propofol, and a cocktail of midazolam, nitrous oxide and isoflurane), trigger Neuroapoptosis in the developing rodent brain. Combinations of nitrous oxide and isoflurane, or ketamine and propofol, cause more severe Neuroapoptosis than any single agent by itself, which suggests a positive correlation between increased levels of anesthesia and increased severity of Neuroapoptosis. In contrast, there is evidence that the rare gas, xenon, which has anesthetic properties, protects against isoflurane-induced Neuroapoptosis in the infant rat brain, while not inducing Neuroapoptosis by itself. The present study was undertaken to evaluate the potential of xenon to induce Neuroapoptosis or to protect against Neuroapoptosis induced by isoflurane in the infant mouse brain. Methods: Seven-day-old C57BL/6 mice were exposed to one of four conditions: air (control); 0.75% isoflurane; 70% xenon; or 0.75% isoflurane +70% xenon for four hours. For histopathological evaluation of the brains, all pups were euthanized two hours later using activated caspase-3 immunohistochemical staining to detect apoptotic neurons. Under each condition, quantitative assessment of the number of apoptotic neurons in the cerebral cortex (CC) and in the caudate/putamen (C/P) was performed by unbiased stereology. Results: The combination of xenon + isoflurane produced a deeper level of anesthesia than either agent alone. Both xenon alone (p<0.003 in CC;p<0.02 in C/P) and isoflurane alone (p<0.001 in both CC and C/P) induced a significant increase in Neuroapoptosis compared to controls. The neuroapoptotic response to isoflurane was substantially more robust than the response to xenon. When xenon was administered together with isoflurane, the apoptotic response was reduced to a level lower than that for isoflurane alone (p<0.01 in CP; marginally non-significant in CC). Conclusions: We conclude that xenon, in the infant mouse brain, has paradoxical properties. It triggers Neuroapoptosis, and when combined with isoflurane, it increases the depth of anesthesia, and retains its own apoptogenic activity. However, it suppresses, rather than augments, isoflurane’s apoptogenic activity.
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subanesthetic doses of propofol induce Neuroapoptosis in the infant mouse brain
Anesthesia & Analgesia, 2008Co-Authors: Davide Cattano, Chainllie Young, Megan M W Straiko, John W OlneyAbstract:Drugs that block N-methyl-d-aspartate glutamate receptors or that promote gamma-aminobutyric acid type A inhibition trigger Neuroapoptosis in the developing rodent brain. Propofol reportedly interacts with both gamma-aminobutyric acid type A and N-methyl-d-aspartate glutamate receptors, but has not been adequately evaluated for its ability to induce developmental Neuroapoptosis. Here we determined that the intraperitoneal (i.p.) dose of propofol required to induce a surgical plane of anesthesia in the infant mouse is 200 mg/kg. We then administered graduated doses of propofol (25-300 mg/kg i.p.) and found that doses >or=50 mg/kg induce a significant Neuroapoptosis response. We conclude that propofol induces Neuroapoptosis at 1/4 the dose required for surgical anesthesia.
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subanesthetic doses of propofol induce Neuroapoptosis in the infant mouse brain
Anesthesia & Analgesia, 2008Co-Authors: Davide Cattano, Chainllie Young, Megan M W Straiko, John W OlneyAbstract:Drugs that block N-methyl-d-aspartate glutamate receptors or that promote γ-aminobutyric acid type A inhibition trigger Neuroapoptosis in the developing rodent brain. Propofol reportedly interacts with both γ-aminobutyric acid type A and N-methyl-d-aspartate glutamate receptors, but has not been ade
Catherine E Creeley - One of the best experts on this subject based on the ideXlab platform.
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from drug induced developmental Neuroapoptosis to pediatric anesthetic neurotoxicity where are we now
Brain Sciences, 2016Co-Authors: Catherine E CreeleyAbstract:The fetal and neonatal periods are critical and sensitive periods for neurodevelopment, and involve rapid brain growth in addition to natural programmed cell death (i.e., apoptosis) and synaptic pruning. Apoptosis is an important process for neurodevelopment, preventing redundant, faulty, or unused neurons from cluttering the developing brain. However, animal studies have shown massive neuronal cell death by apoptosis can also be caused by exposure to several classes of drugs, namely gamma-aminobutyric acid (GABA) agonists and N-methyl-d-aspartate (NMDA) antagonists that are commonly used in pediatric anesthesia. This form of neurotoxic insult could cause a major disruption in brain development with the potential to permanently shape behavior and cognitive ability. Evidence does suggest that psychoactive drugs alter neurodevelopment and synaptic plasticity in the animal brain, which, in the human brain, may translate to permanent neurodevelopmental changes associated with long-term intellectual disability. This paper reviews the seminal animal research on drug-induced developmental apoptosis and the subsequent clinical studies that have been conducted thus far. In humans, there is growing evidence that suggests anesthetics have the potential to harm the developing brain, but the long-term outcome is not definitive and causality has not been determined. The consensus is that there is more work to be done using both animal models and human clinical studies.
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Developmental Neurotoxicity of Alcohol and Anesthetic Drugs Is Augmented by Co-Exposure to Caffeine
MDPI AG, 2013Co-Authors: Catherine E Creeley, John W Olney, Carla M YuedeAbstract:Anesthetic and anti-epileptic drugs used in pediatric and obstetric medicine and several drugs, including alcohol, that are abused by pregnant women, trigger widespread Neuroapoptosis in the developing brain of several animal species, including non-human primates. Caffeine (CAF) is often administered to premature infants to stimulate respiration, and these infants are also exposed simultaneously to anesthetic drugs for procedural sedation and/or surgical procedures. Pregnant women who abuse alcohol or other apoptogenic drugs also may heavily consume CAF. We administered CAF to infant mice alone or in combination with alcohol, phencyclidine, diazepam, midazolam, ketamine, or isoflurane, which are drugs of abuse and/or drugs frequently used in pediatric medicine, and found that CAF weakly triggers Neuroapoptosis by itself and markedly potentiates the neuroapoptogenic action of each of these other drugs. Exposure of infant mice to CAF + phencyclidine resulted in long-term impairment in behavioral domains relevant to attention deficit/hyperactivity disorder, whereas exposure to CAF + diazepam resulted in long-term learning/memory impairment. At doses used in these experiments, these behavioral impairments either did not occur or were substantially less pronounced in mice exposed to CAF alone or to phencyclidine or diazepam alone. CAF currently enjoys the reputation of being highly beneficial and safe for use in neonatal medicine. Our data suggest the need to consider whether CAF may have harmful as well as beneficial effects on the developing brain, and the need for research aimed at understanding the full advantage of its beneficial effects while avoiding its potentially harmful effects
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Density of AC3-positive profiles is greater when PCP exposure occurs on P2 and P7 (P2+P7) compared to exposure on P7 alone.
2013Co-Authors: Carla M Yuede, Catherine E Creeley, John W Olney, David F Wozniak, George T Taylor, Nuri B FarberAbstract:Density of AC3-positive cell profiles summed across forebrain regions most sensitive to PCP-induced Neuroapoptosis on P7 (retrosplenial cortex, caudate putamen, anterior thalamic nuclei) is significantly (**p = 0.012) greater in mice that were exposed to PCP on P2 and P7 (P2+P7PCP group) compared to that observed in mice that were treated only on P7 (P7PCP). The P7PCP and P2+P7PCP groups each showed significantly greater densities of AC3-positive profiles compared to the saline controls (†p = 0.001; *p
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isoflurane induced apoptosis of oligodendrocytes in the neonatal primate brain
Annals of Neurology, 2012Co-Authors: Ansgar M Brambrink, Gregory A Dissen, Catherine E Creeley, Stephen A Back, Art Riddle, Xi Gong, Matthew Moravec, Krikor Dikranian, John W OlneyAbstract:Objective Previously we reported that exposure of 6-day old (P6) rhesus macaques to isoflurane for 5 hours triggers a robust Neuroapoptosis response in developing brain. We have also observed (unpublished) that isoflurane causes apoptosis of cellular profiles in the white matter that resemble glia. We analyzed the cellular identity of the apoptotic white matter profiles and determined the magnitude of this cell death response to isoflurane.
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ketamine induced Neuroapoptosis in the fetal and neonatal rhesus macaque brain
Anesthesiology, 2012Co-Authors: Ansgar M Brambrink, Alex S Evers, Michael S Avidan, Nuri B Farber, Derek J Smith, Lauren Drew Martin, Gregory A Dissen, Catherine E Creeley, John W OlneyAbstract:Background: Exposure of rhesus macaque fetuses for 24 h or neonates fo r9ht oketamine anesthesia causes Neuroapoptosis in the developing brain. The current study clarifies the minimum exposure required for and the extent and spatial distribution of ketamine-induced Neuroapoptosis in rhesus fetuses and neonates. Method: Ketamine was administered by IV infusion for 5 h to postnatal day 6 rhesus neonates or to pregnant rhesus females at 120 days’ gestation (full term 165 days). Three hours later, fetuses were delivered by cesarean section, and the fetal and neonatal brains were studied for evidence of apoptotic neurodegeneration, as determined by activated caspase-3 staining. Results: Both the fetal (n 3) and neonatal (n 4) ketamine-exposed brains had a significant increase in apoptotic profiles compared with drug-naive controls (fetal n 4; neonatal n 5). Loss of neurons attributable to ketamine exposure was 2.2 times greater in fetuses than in neonates. The pattern of neurodegeneration in fetuses was different from that in neonates, and all subjects exposed at either age had a pattern characteristic for that age. Conclusion: The developing rhesus macaque brain is sensitive to the apoptogenic action of ketamine at both a fetal and neonatal age, and exposure duration o f5hi ssufficient to induce a significant Neuroapoptosis response at either age. The pattern of neurodegeneration induced by ketamine in fetuses was different from that in neonates, and loss of neurons attributable to ketamine exposure was 2.2 times greater in the fetal than neonatal brains.
Nuri B Farber - One of the best experts on this subject based on the ideXlab platform.
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lithium protects against glucocorticoid induced neural progenitor cell apoptosis in the developing cerebellum
Brain Research, 2014Co-Authors: Omar H Cabrera, Nuri B Farber, Joseph D Dougherty, Sukrit Singh, Brant S Swiney, Kevin K NoguchiAbstract:Abstract Respiratory dysfunction is one of the most common causes of death associated with premature birth ( Barton et al., 1999 ). In the United States, 7–10% of pregnant women receive antenatal glucocorticoid (GC) therapy ( Matthews et al., 2004 ), while approximately 19% of very low birth weight infants receive postnatal GC therapy ( Jobe, 2009 ). Clinical research suggests that GC treatment causes permanent neuromotor and cognitive deficits ( Yeh et al., 2004 ) and stunts cerebellar growth ( Parikh et al., 2007 , Tam et al., 2011 ). We previously reported that GC-mediated neural progenitor cell (NPC) apoptosis may be responsible for cerebellar neuropathology ( Maloney et al., 2011 , Noguchi et al., 2008 , Noguchi et al., 2011 ). The goal of the current study was to determine whether lithium protects NPCs from GC Neuroapoptosis in vivo and in vitro. Given that it protects against a range of brain insults, we hypothesized that lithium would significantly attenuate GC induced NPC toxicity. We report that acute lithium pretreatment provides potent, cell-intrinsic neuroprotection against GC induced NPC toxicity in vivo and in vitro.
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Density of AC3-positive profiles is greater when PCP exposure occurs on P2 and P7 (P2+P7) compared to exposure on P7 alone.
2013Co-Authors: Carla M Yuede, Catherine E Creeley, John W Olney, David F Wozniak, George T Taylor, Nuri B FarberAbstract:Density of AC3-positive cell profiles summed across forebrain regions most sensitive to PCP-induced Neuroapoptosis on P7 (retrosplenial cortex, caudate putamen, anterior thalamic nuclei) is significantly (**p = 0.012) greater in mice that were exposed to PCP on P2 and P7 (P2+P7PCP group) compared to that observed in mice that were treated only on P7 (P7PCP). The P7PCP and P2+P7PCP groups each showed significantly greater densities of AC3-positive profiles compared to the saline controls (†p = 0.001; *p
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ketamine induced Neuroapoptosis in the fetal and neonatal rhesus macaque brain
Anesthesiology, 2012Co-Authors: Ansgar M Brambrink, Alex S Evers, Michael S Avidan, Nuri B Farber, Derek J Smith, Lauren Drew Martin, Gregory A Dissen, Catherine E Creeley, John W OlneyAbstract:Background: Exposure of rhesus macaque fetuses for 24 h or neonates fo r9ht oketamine anesthesia causes Neuroapoptosis in the developing brain. The current study clarifies the minimum exposure required for and the extent and spatial distribution of ketamine-induced Neuroapoptosis in rhesus fetuses and neonates. Method: Ketamine was administered by IV infusion for 5 h to postnatal day 6 rhesus neonates or to pregnant rhesus females at 120 days’ gestation (full term 165 days). Three hours later, fetuses were delivered by cesarean section, and the fetal and neonatal brains were studied for evidence of apoptotic neurodegeneration, as determined by activated caspase-3 staining. Results: Both the fetal (n 3) and neonatal (n 4) ketamine-exposed brains had a significant increase in apoptotic profiles compared with drug-naive controls (fetal n 4; neonatal n 5). Loss of neurons attributable to ketamine exposure was 2.2 times greater in fetuses than in neonates. The pattern of neurodegeneration in fetuses was different from that in neonates, and all subjects exposed at either age had a pattern characteristic for that age. Conclusion: The developing rhesus macaque brain is sensitive to the apoptogenic action of ketamine at both a fetal and neonatal age, and exposure duration o f5hi ssufficient to induce a significant Neuroapoptosis response at either age. The pattern of neurodegeneration induced by ketamine in fetuses was different from that in neonates, and loss of neurons attributable to ketamine exposure was 2.2 times greater in the fetal than neonatal brains.
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Ketamineinduced Neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology 116
2012Co-Authors: Ansgar M Brambrink, Alex S Evers, Michael S Avidan, Nuri B Farber, Derek J Smith, Lauren Drew Martin, Gregory A Dissen, Ph. DAbstract:Background: Exposure of rhesus macaque fetuses for 24 h or neonates for 9 h to ketamine anesthesia causes neuroapo-ptosis in the developing brain. The current study clarifies the minimum exposure required for and the extent and spatial distribution of ketamine-induced Neuroapoptosis in rhesus fetuses and neonates. Method: Ketamine was administered by IV infusion for 5 h to postnatal day 6 rhesus neonates or to pregnant rhesus females at 120 days ’ gestation (full term 165 days). Three hours later, fetuses were delivered by cesarean section, and the fetal and neonatal brains were studied for evidence of apoptotic neurodegeneration, as determined by activated caspase-3 staining. Results: Both the fetal (n 3) and neonatal (n 4) ket
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alcohol induced Neuroapoptosis in the fetal macaque brain
Neurobiology of Disease, 2010Co-Authors: Nuri B Farber, Catherine E Creeley, John W OlneyAbstract:The ability of brief exposure to alcohol to cause widespread Neuroapoptosis in the developing rodent brain and subsequent long-term neurocognitive deficits has been proposed as a mechanism underlying the neurobehavioral deficits seen in fetal alcohol spectrum disorder (FASD). It is unknown whether brief exposure to alcohol causes apoptosis in the fetal primate brain. Pregnant fascicularis macaques at various stages of gestation (G105 to G155) were exposed to alcohol for 8h, then the fetuses were delivered by caesarean section and their brains perfused with fixative and evaluated for apoptosis. Compared to saline control brains, the ethanol-exposed brains displayed a pattern of Neuroapoptosis that was widespread and similar to that caused by alcohol in infant rodent brain. The observed increase in apoptosis was on the order of 60-fold. We propose that the apoptogenic action of alcohol could explain many of the neuropathological changes and long-term neuropsychiatric disturbances associated with human FASD.
Vesna Jevtovictodorovic - One of the best experts on this subject based on the ideXlab platform.
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a neurosteroid analogue with t type calcium channel blocking properties is an effective hypnotic but is not harmful to neonatal rat brain
BJA: British Journal of Anaesthesia, 2018Co-Authors: Navya Atluri, Desanka Milanovic, Srđan M Joksimovic, Azra Oklopcic, Jelena Klawitter, Pierce Eggan, Kathiresan Krishnan, Douglas F Covey, Slobodan M Todorovic, Vesna JevtovictodorovicAbstract: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.
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clinical anesthesia causes permanent damage to the fetal guinea pig brain
Brain Pathology, 2008Co-Authors: S Rizzi, Lisa B Carter, Carlo Ori, Vesna JevtovictodorovicAbstract:Exposure of the immature brain to general anesthesia is common. The safety of this practice has recently been challenged in view of evidence that general anesthetics can damage developing mammalian neurons. Initial reports on immature rats raised criticism regarding the possibly unique vulnerability of this species, short duration of their brain development and a lack of close monitoring of nutritional and cardiopulmonary homeostasis during anesthesia. Therefore, we studied the neurotoxic effects of anesthesia in guinea pigs, whose brain development is longer and is mostly a prenatal phenomenon, so that anesthesia-induced neurotoxicity studies of the fetal brain can be performed by anesthetizing pregnant female pigs. Because of their large size, these animals made invasive monitoring of maternal and, indirectly, fetal well-being technically feasible. Despite adequate maintenance of maternal homeostasis, a single short maternal exposure to isoflurane, whether alone or with nitrous oxide and/or midazolam at the peak of fetal synaptogenesis, induced severe Neuroapoptosis in the fetal guinea pig brain. As detected early in post-natal life, this resulted in the loss of many neurons from vulnerable brain regions, demonstrating that anesthesia-induced Neuroapoptosis can cause permanent brain damage.
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general anesthesia activates bdnf dependent Neuroapoptosis in the developing rat brain
Apoptosis, 2006Co-Authors: Lisa B Carter, Junheum Yon, Vesna JevtovictodorovicAbstract:Brain-derived neurotrophic factor (BDNF) is important in supporting neuronal development. BDNF imbalance due to excessive neuronal inhibition can result in the apoptotic degeneration of developing neurons. Since general anesthetics cause profound depression of neuronal activity and are known to induce widespread degeneration in the developing brain, we studied their potential to activate BDNF-mediated developmental Neuroapoptosis. When P7 rats (at the peak of brain development) were exposed to a commonly-used and highly pro-apoptotic anesthesia protocol (midazolam, isoflurane, nitrous oxide) for a period of 2, 4 or 6 h, we found that anesthesia modulates the key steps in BDNF-activated apoptotic cascade in two of the most vulnerable brain regions--cerebral cortex and thalamus in time-dependent fashion by activating both Trk-dependent (in thalamus) and Trk-independent p75NTR dependent (in cerebral cortex) neurotrophic pathways. beta-estradiol, a sex hormone that upregulates the protein levels of the activated Akt, protects against anesthesia-induced Neuroapoptosis.
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general anesthesia activates bdnf dependent Neuroapoptosis in the developing rat brain
Apoptosis, 2006Co-Authors: Lisa B Carter, Junheum Yon, Vesna JevtovictodorovicAbstract:Brain-derived neurotrophic factor (BDNF) is important in supporting neuronal development. BDNF imbalance due to excessive neuronal inhibition can result in the apoptotic degeneration of developing neurons. Since general anesthetics cause profound depression of neuronal activity and are known to induce widespread degeneration in the developing brain, we studied their potential to activate BDNF-mediated developmental Neuroapoptosis. When P7 rats (at the peak of brain development) were exposed to a commonly-used and highly pro-apoptotic anesthesia protocol (midazolam, isoflurane, nitrous oxide) for a period of 2, 4 or 6 h, we found that anesthesia modulates the key steps in BDNF-activated apoptotic cascade in two of the most vulnerable brain regions—cerebral cortex and thalamus in time-dependent fashion by activating both Trk-dependent (in thalamus) and Trk-independent p75NTR dependent (in cerebral cortex) neurotrophic pathways. β-estradiol, a sex hormone that upregulates the protein levels of the activated Akt, protects against anesthesia-induced Neuroapoptosis.
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potential of ketamine and midazolam individually or in combination to induce apoptotic neurodegeneration in the infant mouse brain
British Journal of Pharmacology, 2005Co-Authors: Chainllie Young, Haihui Wang, Vesna Jevtovictodorovic, Yueqin Qin, Tatyana Tenkova, Joann Labruyere, John W OlneyAbstract:Recently, it was reported that anesthetizing infant rats for 6 h with a combination of anesthetic drugs (midazolam, nitrous oxide, isoflurane) caused widespread apoptotic neurodegeneration in the developing brain, followed by lifelong cognitive deficits. It has also been reported that ketamine triggers Neuroapoptosis in the infant rat brain if administered repeatedly over a period of 9 h. The question arises whether less extreme exposure to anesthetic drugs can also trigger Neuroapoptosis in the developing brain. To address this question we administered ketamine, midazolam or ketamine plus midazolam subcutaneously at various doses to infant mice and evaluated the rate of Neuroapoptosis in various brain regions following either saline or these various drug treatments. Each drug was administered as a single one-time injection in a dose range that would be considered subanesthetic, and the brains were evaluated by unbiased stereology methods 5 h following drug treatment. Neuroapoptosis was detected by immunohistochemical staining for activated caspase-3. It was found that either ketamine or midazolam caused a dose-dependent, statistically significant increase in the rate of Neuroapoptosis, and the two drugs combined caused a greater increase than either drug alone. The apoptotic nature of the neurodegenerative reaction was confirmed by electron microscopy. We conclude that relatively mild exposure to ketamine, midazolam or a combination of these drugs can trigger apoptotic neurodegeneration in the developing mouse brain.