CC BY-NC-ND 4.0 · J Neuroanaesth Crit Care 2016; 03(01): 015-024
DOI: 10.4103/2348-0548.173236
Review Article
Thieme Medical and Scientific Publishers Private Ltd.

Basic cellular and molecular mechanisms of anesthetic-induced developmental neurotoxicity: Potential strategies for alleviation

Padmaja Durga
Department of Anaesthesiology and Intensive Care, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India
,
Vidya Yalamanchili
1   Department of Anaesthesiology, Emory University School of Medicine, Atlanta, Georgia, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
03 May 2018 (online)

Abstract

There is an increasing concern regarding the risk of anesthetic-induced developmental neurotoxicity (AIDN) in children. Evidence has shown that exposure to most of the commonly used anaesthetic and sedatives can cause neurodegeneration in the developing brain. Anesthetic effects on the brain during its growth spurt can initiate a cascade of alterations in neurodevelopment, which can be detected structurally or functionally. Anesthetic exposure induces apoptosis and neurodegeneration in a dose and time-dependent fashion consistent with the pattern of N-methyl D-aspartate antagonism and gamma-amino butyric acid type A activation by these drugs. Understanding the cellular and molecular mechanisms of AIDN may help in developing methods that are safe and do not interfere with the beneficial properties of anaesthetic drugs and yet inactivate the intracellular signals that trigger neuroapoptosis.

 
  • REFERENCES

  • 1 Borsook D, George E, Kussman B, Becerra L. Anesthesia and perioperative stress: Consequences on neural networks and postoperative behaviors. Prog Neurobiol 2010; 92: 601-12
  • 2 de la Rosa EJ, de Pablo F. Cell death in early neural development: Beyond the neurotrophic theory. Trends Neurosci 2000; 23: 454-8
  • 3 Zou X, Patterson TA, Divine RL, Sadovova N, Zhang X, Hanig JP. et al. Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain. Int J Dev Neurosci 2009; 27: 727-31
  • 4 Young C, Jevtovic-Todorovic V, Qin YQ, Tenkova T, Wang H, Labruyere J. et al. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol 2005; 146: 189-97
  • 5 Creeley C, Dikranian K, Dissen G, Martin L, Olney J, Brambrink A. Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. Br J Anaesth 2013; 110 Suppl (Suppl. 01) i29-38
  • 6 Savage S, Ma D. The neurotoxicity of nitrous oxide: The facts and “putative” mechanisms. Brain Sci 2014; 4: 73-90
  • 7 Istaphanous GK, Howard J, Nan X, Hughes EA, McCann JC, McAuliffe JJ. et al. Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice. Anesthesiology 2011; 114: 578-87
  • 8 Liang G, Ward C, Peng J, Zhao Y, Huang B, Wei H. Isoflurane causes greater neurodegeneration than an equivalent exposure of sevoflurane in the developing brain of neonatal mice. Anesthesiology 2010; 112: 1325-34
  • 9 Kodama M, Satoh Y, Otsubo Y, Araki Y, Yonamine R, Masui K. et al. Neonatal desflurane exposure induces more robust neuroapoptosis than do isoflurane and sevoflurane and impairs working memory. Anesthesiology 2011; 115: 979-91
  • 10 Zhu C, Gao J, Karlsson N, Li Q, Zhang Y, Huang Z. et al. Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult, rodents. J Cereb Blood Flow Metab 2010; 30: 1017-30
  • 11 Soriano SG, Anand KJ, Rovnaghi CR, Hickey PR. Of mice and men: Should we extrapolate rodent experimental data to the care of human neonates?. Anesthesiology 2005; 102: 866-8
  • 12 Slikker Jr W, Zou X, Hotchkiss CE, Divine RL, Sadovova N, Twaddle NC. et al. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci 2007; 98: 145-58
  • 13 Fredriksson A, Pontén E, Gordh T, Eriksson P. Neonatal exposure to a combination of N-methyl-D-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 2007; 107: 427-36
  • 14 Xiong M, Li J, Alhashem HM, Tilak V, Patel A, Pisklakov S. et al. Propofol exposure in pregnant rats induces neurotoxicity and persistent learning deficit in the offspring. Brain Sci 2014; 4: 356-75
  • 15 Davidson A, Flick RP. Neurodevelopmental implications of the use of sedation and analgesia in neonates. Clin Perinatol 2013; 40: 559-73
  • 16 Yon JH, Daniel-Johnson J, Carter LB, Jevtovic-Todorovic V. Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways. Neuroscience 2005; 135: 815-27
  • 17 Qin L, Crews FT. NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration. J Neuroinflammation 2012; 9: 5
  • 18 Liu F, Paule MG, Ali S, Wang C. Ketamine-induced neurotoxicity and changes in gene expression in the developing rat brain. Curr Neuropharmacol 2011; 9: 256-61
  • 19 Zou X, Liu F, Zhang X, Patterson TA, Callicott R, Liu S. et al. Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey. Neurotoxicol Teratol 2011; 33: 592-7
  • 20 Jin J, Gong K, Zou X, Wang R, Lin Q, Chen J. The blockade of NMDA receptor ion channels by ketamine is enhanced in developing rat cortical neurons. Neurosci Lett 2013; 539: 11-5
  • 21 Bhutta AT, Schmitz ML, Swearingen C, James LP, Wardbegnoche WL, Lindquist DM. et al. Ketamine as a neuroprotective and anti-inflammatory agent in children undergoing surgery on cardiopulmonary bypass: A pilot randomized, double-blind, placebo-controlled trial. Pediatr Crit Care Med 2012; 13: 328-37
  • 22 Dong C, Anand KJ. Developmental neurotoxicity of ketamine in pediatric clinical use. Toxicol Lett 2013; 220: 53-60
  • 23 Yan J, Jiang H. Dual effects of ketamine: Neurotoxicity versus neuroprotection in anesthesia for the developing brain. J Neurosurg Anesthesiol 2014; 26: 155-60
  • 24 Yan J, Li YR, Zhang Y, Lu Y, Jiang H. Repeated exposure to anesthetic ketamine can negatively impact neurodevelopment in infants: A prospective preliminary clinical study. J Child Neurol 2014; 29: 1333-8
  • 25 Ben-Ari Y. Excitatory actions of gaba during development: The nature of the nurture. Nat Rev Neurosci 2002; 3: 728-39
  • 26 Zhao YL, Xiang Q, Shi QY, Li SY, Tan L, Wang JT. et al. GABAergic excitotoxicity injury of the immature hippocampal pyramidal neurons’ exposure to isoflurane. Anesth Analg 2011; 113: 1152-60
  • 27 Zhang X, Paule MG, Wang C, Slikker Jr W. Application of microPET imaging approaches in the study of pediatric anesthetic-induced neuronal toxicity. J Appl Toxicol 2013; 33: 861-8
  • 28 Zhang Y, Dong Y, Wu X, Lu Y, Xu Z, Knapp A. et al. The mitochondrial pathway of anesthetic isoflurane-induced apoptosis. J Biol Chem 2010; 285: 4025-37
  • 29 Boscolo A, Starr JA, Sanchez V, Lunardi N, DiGruccio MR, Ori C. et al. The abolishment of anesthesia-induced cognitive impairment by timely protection of mitochondria in the developing rat brain: The importance of free oxygen radicals and mitochondrial integrity. Neurobiol Dis 2012; 45: 1031-41
  • 30 Zhang Y, Xu Z, Wang H, Dong Y, Shi HN, Culley DJ. et al. Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory. Ann Neurol 2012; 71: 687-98
  • 31 Kajimoto M, Atkinson DB, Ledee DR, Kayser EB, Morgan PG, Sedensky MM. et al. Propofol compared with isoflurane inhibits mitochondrial metabolism in immature swine cerebral cortex. J Cereb Blood Flow Metab 2014; 34: 514-21
  • 32 Komita M, Jin H, Aoe T. The effect of endoplasmic reticulum stress on neurotoxicity caused by inhaled anesthetics. Anesth Analg 2013; 117: 1197-204
  • 33 Gao ZY, Chen M, Collins HW, Matschinsky FM, Lee VM, Wolf BA. Mechanisms of spontaneous cytosolic Ca2+ transients in differentiated human neuronal cells. Eur J Neurosci 1998; 10: 2416-25
  • 34 Sinner B, Friedrich O, Zink W, Zausig Y, Graf BM. The toxic effects of s(+)-ketamine on differentiating neurons in vitro as a consequence of suppressed neuronal Ca2+ oscillations. Anesth Analg 2011; 113: 1161-9
  • 35 Dong Y, Wu X, Xu Z, Zhang Y, Xie Z. Anesthetic isoflurane increases phosphorylated tau levels mediated by caspase activation and Aß generation. PLoS One 2012; 7: e39386
  • 36 Wu X, Lu Y, Dong Y, Zhang G, Zhang Y, Xu Z. et al. The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-α, IL-6, and IL-1ß. Neurobiol Aging 2012; 33: 1364-78
  • 37 Shu Y, Zhou Z, Wan Y, Sanders RD, Li M, Pac-Soo CK. et al. Nociceptive stimuli enhance anesthetic-induced neuroapoptosis in the rat developing brain. Neurobiol Dis 2012; 45: 743-50
  • 38 Lu LX, Yon JH, Carter LB, Jevtovic-Todorovic V. General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain. Apoptosis 2006; 11: 1603-15
  • 39 Popic J, Pesic V, Milanovic D, Todorovic S, Kanazir S, Jevtovic-Todorovic V. et al. Propofol-induced changes in neurotrophic signaling in the developing nervous system in vivo . PLoS One 2012; 7: e34396
  • 40 Olney JW, Young C, Wozniak DF, Ikonomidou C, Jevtovic-Todorovic V. Anesthesia-induced developmental neuroapoptosis. Does it happen in humans? Anesthesiology 2004; 101: 273-5
  • 41 Head BP, Patel HH, Niesman IR, Drummond JC, Roth DM, Patel PM. Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system. Anesthesiology 2009; 110: 813-25
  • 42 Hirasawa T, Wada H, Kohsaka S, Uchino S. Inhibition of NMDA receptors induces delayed neuronal maturation and sustained proliferation of progenitor cells during neocortical development. J Neurosci Res 2003; 74: 676-87
  • 43 Tung A, Herrera S, Fornal CA, Jacobs BL. The effect of prolonged anesthesia with isoflurane, propofol, dexmedetomidine, or ketamine on neural cell proliferation in the adult rat. Anesth Analg 2008; 106: 1772-7
  • 44 Culley DJ, Boyd JD, Palanisamy A, Xie Z, Kojima K, Vacanti CA. et al. Isoflurane decreases self-renewal capacity of rat cultured neural stem cells. Anesthesiology 2011; 115: 754-63
  • 45 Crampton SJ, Collins LM, Toulouse A, Nolan YM, O'Keeffe GW. Exposure of foetal neural progenitor cells to IL-1ß impairs their proliferation and alters their differentiation – A role for maternal inflammation?. J Neurochem 2012; 120: 964-73
  • 46 Erasso DM, Chaparro RE, Quiroga Del Rio CE, Karlnoski R, Camporesi EM, Saporta S. Quantitative assessment of new cell proliferation in the dentate gyrus and learning after isoflurane or propofol anesthesia in young and aged rats. Brain Res 2012; 1441: 38-46
  • 47 Vutskits L, Gascon E, Tassonyi E, Kiss JZ. Effect of ketamine on dendritic arbor development and survival of immature GABAergic neurons in vitro . Toxicol Sci 2006; 91: 540-9
  • 48 De Roo M, Klauser P, Briner A, Nikonenko I, Mendez P, Dayer A. et al. Anesthetics rapidly promote synaptogenesis during a critical period of brain development. PLoS One 2009; 4: e7043
  • 49 Briner A, Nikonenko I, De Roo M, Dayer A, Muller D, Vutskits L. Developmental Stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology 2011; 115: 282-93
  • 50 Vutskits L, Gascon E, Potter G, Tassonyi E, Kiss JZ. Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture. Toxicology 2007; 234: 216-26
  • 51 Woodall AJ, Naruo H, Prince DJ, Feng ZP, Winlow W, Takasaki M. et al. Anesthetic treatment blocks synaptogenesis but not neuronal regeneration of cultured Lymnaea neurons. J Neurophysiol 2003; 90: 2232-9
  • 52 Onizuka S, Takasaki M, Syed NI. Long-term exposure to local but not inhalation anesthetics affects neurite regeneration and synapse formation between identified lymnaea neurons. Anesthesiology 2005; 102: 353-63
  • 53 Lunardi N, Hucklenbruch C, Latham JR, Scarpa J, Jevtovic-Todorovic V. Isoflurane impairs immature astroglia development in vitro: The role of actin cytoskeleton. J Neuropathol Exp Neurol 2011; 70: 281-91
  • 54 Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive performance in children: No evidence for a causal relationship. Twin Res Hum Genet 2009; 12: 246-53
  • 55 Sprung J, Flick RP, Wilder RT, Katusic SK, Pike TL, Dingli M. et al. Anesthesia for cesarean delivery and learning disabilities in a population-based birth cohort. Anesthesiology 2009; 111: 302-10
  • 56 Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C. et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 2009; 110: 796-804
  • 57 Davidson AJ. Anesthesia and neurotoxicity to the developing brain: The clinical relevance. Paediatr Anaesth 2011; 21: 716-21
  • 58 DiMaggio C, Sun LS, Li G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg 2011; 113: 1143-51
  • 59 Hansen TG, Pedersen JK, Henneberg SW, Pedersen DA, Murray JC, Morton NS. et al. Academic performance in adolescence after inguinal hernia repair in infancy: A nationwide cohort study. Anesthesiology 2011; 114: 1076-85
  • 60 Ludman L, Spitz L, Wade A. Educational attainments in early adolescence of infants who required major neonatal surgery. J Pediatr Surg 2001; 36: 858-62
  • 61 Kalkman CJ, Peelen L, Moons KG, Veenhuizen M, Bruens M, Sinnema G. et al. Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology 2009; 110: 805-12
  • 62 Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD. et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics 2011; 128: e1053-61
  • 63 Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von Ungern-Sternberg BS. et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics 2012; 130: e476-85
  • 64 Palanisamy A. Maternal anesthesia and fetal neurodevelopment. Int J Obstet Anesth 2012; 21: 152-62
  • 65 Hansen TG, Pedersen JK, Henneberg SW, Morton NS, Christensen K. Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: A nationwide cohort study. Paediatr Anaesth 2013; 23: 883-90
  • 66 Davidson AJ, McCann ME, Morton NS, Myles PS. Anesthesia and outcome after neonatal surgery: The role for randomized trials. Anesthesiology 2008; 109: 941-4
  • 67 Sun LS, Li G, DiMaggio CJ, Byrne MW, Ing C, Miller TL. et al. Feasibility and pilot study of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) project. J Neurosurg Anesthesiol 2012; 24: 382-8
  • 68 Miller TL, Park R, Sun LS. Report of the third PANDA symposium on “Anesthesia and Neurodevelopment in Children”. J Neurosurg Anesthesiol 2012; 24: 357-61
  • 69 Dzietko M, Felderhoff-Mueser U, Sifringer M, Krutz B, Bittigau P, Thor F. et al. Erythropoietin protects the developing brain against N-methyl-D-aspartate receptor antagonist neurotoxicity. Neurobiol Dis 2004; 15: 177-87
  • 70 Straiko MM, Young C, Cattano D, Creeley CE, Wang H, Smith DJ. et al. Lithium protects against anesthesia-induced developmental neuroapoptosis. Anesthesiology 2009; 110: 862-8
  • 71 Zhao L, Wang F, Gui B, Hua F, Qian Y. Prophylactic lithium alleviates postoperative cognition impairment by phosphorylating hippocampal glycogen synthase kinase-3ß (Ser9) in aged rats. Exp Gerontol 2011; 46: 1031-6
  • 72 Yon JH, Carter LB, Reiter RJ, Jevtovic-Todorovic V. Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain. Neurobiol Dis 2006; 21: 522-30
  • 73 Wang C, Sadovova N, Patterson TA, Zou X, Fu X, Hanig JP. et al. Protective effects of 7-nitroindazole on ketamine-induced neurotoxicity in rat forebrain culture. Neurotoxicology 2008; 29: 613-20
  • 74 Zou X, Sadovova N, Patterson TA, Divine RL, Hotchkiss CE, Ali SF. et al. The effects of L-carnitine on the combination of, inhalation anesthetic-induced developmental, neuronal apoptosis in the rat frontal cortex. Neuroscience 2008; 151: 1053-65
  • 75 Edwards DA, Shah HP, Cao W, Gravenstein N, Seubert CN, Martynyuk AE. Bumetanide alleviates epileptogenic and neurotoxic effects of sevoflurane in neonatal rat brain. Anesthesiology 2010; 112: 567-75
  • 76 Lim BG, Shen FY, Kim YB, Kim WB, Kim YS, Han HC. et al. Possible role of GABAergic depolarization in neocortical neurons in generating hyperexcitatory behaviors during emergence from sevoflurane anesthesia in the rat. ASN Neuro. 2014 6.. pii: e00141
  • 77 Sanders RD, Sun P, Patel S, Li M, Maze M, Ma D. Dexmedetomidine provides cortical neuroprotection: Impact on anaesthetic-induced neuroapoptosis in the rat developing brain. Acta Anaesthesiol Scand 2010; 54: 710-6
  • 78 Degos V, Charpentier TL, Chhor V, Brissaud O, Lebon S, Schwendimann L. et al. Neuroprotective effects of dexmedetomidine against glutamate agonist-induced neuronal cell death are related to increased astrocyte brain-derived neurotrophic factor expression. Anesthesiology 2013; 118: 1123-32
  • 79 Ma D, Williamson P, Januszewski A, Nogaro MC, Hossain M, Ong LP. et al. Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. Anesthesiology 2007; 106: 746-53
  • 80 Shu Y, Patel SM, Pac-Soo C, Fidalgo AR, Wan Y, Maze M. et al. Xenon pretreatment attenuates anesthetic-induced apoptosis in the developing brain in comparison with nitrous oxide and hypoxia. Anesthesiology 2010; 113: 360-8
  • 81 Men'shanov PN, Bannova AV, Il'inykh FA, Dygalo NN. Negative regulation of caspase-3 expression in the neonatal cerebral cortex by alpha2A-adrenoceptors. Bull Exp Biol Med 2007; 143: 277-9
  • 82 Laudenbach V, Mantz J, Lagercrantz H, Desmonts JM, Evrard P, Gressens P. Effects of alpha(2)-adrenoceptor agonists on perinatal excitotoxic brain injury: Comparison of clonidine and dexmedetomidine. Anesthesiology 2002; 96: 134-41
  • 83 Cattano D, Williamson P, Fukui K, Avidan M, Evers AS, Olney JW. et al. Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain. Can J Anaesth 2008; 55: 429-36
  • 84 Brosnan H, Bickler PE. Xenon neurotoxicity in rat hippocampal slice cultures is similar to isoflurane and sevoflurane. Anesthesiology 2013; 119: 335-44
  • 85 Turner CP, Gutierrez S, Liu C, Miller L, Chou J, Finucane B. et al. Strategies to defeat ketamine-induced neonatal brain injury. Neuroscience 2012; 210: 384-92
  • 86 Wei H, Liang G, Yang H. Isoflurane preconditioning inhibited isoflurane-induced neurotoxicity. Neurosci Lett 2007; 425: 59-62
  • 87 Zhou XF, Huang DD, Wang DF, Fu JQ. The protective effect of propofol pretreatment on glutamate injury of neonatal rat brain slices. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2012; 24: 750-3
  • 88 Anand KJ, Garg S, Rovnaghi CR, Narsinghani U, Bhutta AT, Hall RW. Ketamine reduces the cell death following inflammatory pain in newborn rat brain. Pediatr Res 2007; 62: 283-90
  • 89 Ullah N, Ullah I, Lee HY, Naseer MI, Seok PM, Ahmed J. et al. Protective function of nicotinamide against ketamine-induced apoptotic neurodegeneration in the infant rat brain. J Mol Neurosci 2012; 47: 67-75
  • 90 Lema Tomé CM, Bauer C, Nottingham C, Smith C, Blackstone K, Brown L. et al. MK801-induced caspase-3 in the postnatal brain: Inverse relationship with calcium binding proteins. Neuroscience 2006; 141: 1351-63
  • 91 Naseer MI, Ullah N, Ullah I, Koh PO, Lee HY, Park MS. et al. Vitamin C protects against ethanol and PTZ-induced apoptotic neurodegeneration in prenatal rat hippocampal neurons. Synapse 2011; 65: 562-71
  • 92 Konishi Y, Chui DH, Hirose H, Kunishita T, Tabira T. Trophic effect of erythropoietin and other hematopoietic factors on central cholinergic neurons in vitro and in vivo . Brain Res 1993; 609: 29-35
  • 93 Tsuchimoto T, Ueki M, Miki T, Morishita J, Maekawa N. Erythropoietin attenuates isoflurane-induced neurodegeneration and learning deficits in the developing mouse brain. Paediatr Anaesth 2011; 21: 1209-13
  • 94 Kumral A, Yesilirmak DC, Sonmez U, Baskin H, Tugyan K, Yilmaz O. et al. Neuroprotective effect of the peptides ADNF-9 and NAP on hypoxic-ischemic brain injury in neonatal rats. Brain Res 2006; 1115: 169-78
  • 95 Zhang Y, Dong Y, Xu Z, Xie Z. Propofol and magnesium attenuate isoflurane-induced caspase-3 activation via inhibiting mitochondrial permeability transition pore. Med Gas Res 2012; 2: 20
  • 96 Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Zhang X. et al. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology 2010; 112: 834-41
  • 97 Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C. et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol 2011; 33: 220-30
  • 98 Brambrink AM, Back SA, Riddle A, Gong X, Moravec MD, Dissen GA. et al. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol 2012; 72: 525-35
  • 99 Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Martin LD. et al. Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology 2012; 116: 372-84
  • 100 Creeley CE, Dikranian KT, Dissen GA, Back SA, Olney JW, Brambrink AM. Isoflurane-induced apoptosis of neurons and oligodendrocytes in the fetal rhesus macaque brain. Anesthesiology 2014; 120: 626-38