Persistent alteration in behavioural reactivity to a mild social stressor in rhesus monkeys repeatedly exposed to sevoflurane in infancy

Raper, Jessica; Biasio, Justin C. De; Murphy, Kathy; Alvarado, Maria C.; Baxter, Mark G.

doi:10.1016/j.bja.2018.01.014

Cited by 81 publications

(84 citation statements)

References 43 publications

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“…In fact, the effect sizes for the current study were small relative to those seen in our earlier report. We note that studies in other laboratories have found behavioral deficits in rhesus macaques reared in complex social groups similar to ours, but these animals were exposed to multiple anesthetic doses in the first few months after birth (Coleman et al, ; Raper et al, ). As such, the present results suggest that the rich environment of the field corral setting might buffer an individual but only up to a point, for example, involving only a single, sedative dose of ketamine postnatally.…”

Section: Discussionsupporting

confidence: 76%

“…Our primary hypothesis was that we would find behavioral differences similar to those reported by Capitanio et al () that were associated with prenatal and early postnatal exposure to sedative doses of ketamine and that were moderated by the low‐activity MAOA‐LPR gene: increased activity, poor performance in a memory task, reduced emotionality, and less contact with novel objects. The BioBehavioral Assessment (BBA), from which the current behavioral data are drawn, includes additional social and emotional tests, such as the human intruder test, which have been shown to be affected by repeated anesthetic doses in the first few months of life in previous studies of nonhuman primates (Coleman et al, ; Raper, Alvarado, Murphy, & Baxter, ; Raper, De Biasio, Murphy, Alvarado, & Baxter, ). For the current study, we chose to base our predictions on the tests that were found to be significantly affected by sedative doses of ketamine in low‐activity MAOA genotype monkeys in the Capitanio et al, study.…”

Section: Introductionmentioning

confidence: 99%

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Behavioral effects of postnatal ketamine exposure in rhesus macaque infants are dependent on MAOA‐LPR genotype

Herrington

Rosso

Capitanio

2019

Developmental Psychobiology

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Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist widely used in pediatric anesthetic and therapeutic practices and veterinary medicine. Previous evidence suggests that exposure to ketamine during sensitive periods of development results in neural apoptosis and atypical behavior. Since monoamine neurotransmitters play important roles in prenatal and early postnatal neural development, and since previous work suggests ketamine can inhibit monoamine transporters, we hypothesized that there would be behavioral consequences of prenatal and early postnatal exposure to ketamine moderated by genotype of the promoter in the monoamine oxidase-A (MAOA) gene. From a large sample of animals (N = 408), we compared groups of rhesus monkeys that had experienced a single exposure to ketamine during prenatal development, an exposure during prenatal development and one postnatal exposure, a postnatal exposure with no prenatal exposure, and no exposures. Animals were classified by putative activity levels for the MAOA genotype and were tested between 3 and 4 months of age on a battery of behavioral tests. Results suggested that animals exposed to ketamine postnatally, at a dose typically used for sedative effects that also had the low-activity variant of MAOA performed poorly on a visual memory test compared to animals with the high-activity variant of the MAOA gene.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Behavioral effects of postnatal ketamine exposure in rhesus macaque infants are dependent on MAOA‐LPR genotype

Herrington

Rosso

Capitanio

2019

Developmental Psychobiology

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“…However, recent data in non-human primates have provided definitive evidence that early postnatal GA exposure can have lasting effects on cognition, including deficits in socioemotional and learning function [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway

Xu¹,

Mathena²,

Xu³

et al. 2018

Preprint

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Human epidemiologic studies and laboratory investigations in animal models suggest that exposure to general anesthetic agents (GAs) have harmful effects on brain development. The mechanism underlying this putative iatrogenic condition is not clear and there are currently no accepted strategies for prophylaxis or treatment. Recent evidence suggests that anesthetics might cause persistent deficits in synaptogenesis by disrupting key events in neurodevelopment. Using an in vitro model consisting of dissociated primary cultured mouse neurons we demonstrate abnormal pre- and post-synaptic marker expression after a clinically relevant isoflurane anesthesia exposure conducted during neuron development. We find that pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) pathway can reverse the observed changes. Isoflurane exposure increases expression of phospho-S6, a marker of mTOR pathway activity, in a concentration-dependent fashion and this effect occurs throughout neuronal development. The mTOR 1 complex (mTORC1) and the mTOR 2 complex (mTORC2) branches of the pathway are both activated by isoflurane exposure and this is reversible with branch-specific inhibitors. Upregulation of mTOR is also seen with sevoflurane and propofol exposure, suggesting that this mechanism of developmental anesthetic neurotoxicity may occur with all the commonly used GAs in pediatric practice. We conclude that GAs disrupt the development of neurons during development by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition.

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“…Every year, millions of children undergo diagnostic or surgical procedures under general anesthesia globally, and the long-term potential neurotoxic effects of general anesthetics (GAs) on the infant brain is a worldwide concern. Solid evidence from rodent and nonhuman primate models has proved that exposure to GAs, especially to those targeting the γ-aminobutyric acid type A receptor and/or the Nmethyl-D-aspartate receptor, during the brain growth spurt period can cause neuroapoptosis, synaptic dysfunction, and long-term behavioral abnormality [1][2][3][4][5][6][7][8][9][10]. Although growing preclinical data has been accumulated, ambiguity still exists in clinical studies [11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Mitigates Sevoflurane-Induced Neurotoxicity by the SIRT1-Dependent Regulation of BDNF Expression in Developing Mice

Tang

Zhao

Zhou

et al. 2020

Oxidative Medicine and Cellular Longevity

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Various lines of evidence suggest that neonatal exposure to general anesthetics, especially repeatedly, results in neuropathological brain changes and long-term cognitive impairment. Although progress has been made in experimental models, the exact mechanism of GA-induced neurotoxicity in the developing brain remains to be clarified. Sirtuin 1 (SIRT1) plays an important role in synaptic plasticity and cognitive performance, and its abnormal reduction is associated with cognitive dysfunction in neurodegenerative diseases. However, the role of SIRT1 in GA-induced neurotoxicity is unclear to date. In this study, we found that the protein level of SIRT1 was inhibited in the hippocampi of developing mice exposed to sevoflurane. Furthermore, the SIRT1 inhibition in hippocampi was associated with brain-derived neurotrophic factor (BDNF) downregulation modulated by methyl-cytosine-phosphate-guanine–binding protein 2 (MeCP2) and cAMP response element-binding protein (CREB). Pretreatment of neonatal mice with resveratrol nearly reversed the reduction in hippocampal SIRT1 expression, which increased the expression of BDNF in developing mice exposed to sevoflurane. Moreover, changes in the levels of CREB and MeCP2, which were considered to interact with BDNF promoter IV, were also rescued by resveratrol. Furthermore, resveratrol improved the cognitive performance in the Morris water maze test of the adult mice with exposure to sevoflurane in the neonatal stage, without changing motor function in the open field test. Taken together, our findings suggested that SIRT1 deficiency regulated BDNF signaling via regulation of the epigenetic activity of MeCP2 and CREB, and resveratrol might be a promising agent for mitigating sevoflurane-induced neurotoxicity in developing mice.

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Persistent alteration in behavioural reactivity to a mild social stressor in rhesus monkeys repeatedly exposed to sevoflurane in infancy

Abstract: Early repeated sevoflurane exposure in infant non-human primates results in an anxious phenotype that was first detected at 6 months, and persists for at least 2 yr of age. This is the first demonstration of such a prolonged impact of early anaesthesia exposure on emotional reactivity.

Cited by 81 publications

References 43 publications

Behavioral effects of postnatal ketamine exposure in rhesus macaque infants are dependent on MAOA‐LPR genotype

Behavioral effects of postnatal ketamine exposure in rhesus macaque infants are dependent on MAOA‐LPR genotype

Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway

Resveratrol Mitigates Sevoflurane-Induced Neurotoxicity by the SIRT1-Dependent Regulation of BDNF Expression in Developing Mice

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