Distinct long-term neurocognitive outcomes after equipotent sevoflurane or isoflurane anaesthesia in immature rats

Ramage, Tatiana M.; Chang, Flora L.; Shih, Jennifer; Alvi, Rehan S.; Quitoriano, G. R.; Rau, Vinuta; Barbour, Kyle; Elphick, Sophie A.; Kong, Christina; Tantoco, Nicole; Ben-Tzur, Dana; Kang, Hongjun; McCreery, M. S.; Huang, Pamela; Park, A.; Uy, Judy Grace Laurilla; Rossi, Meghan; Zhao, Chao; Geronimo, R. T. Di; Stratmann, Greg; Sall, Jeffrey W.

doi:10.1093/bja/aet103

Cited by 57 publications

(45 citation statements)

References 29 publications

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“…This is consistent with Zhu and colleagues’ finding that adult rats and mice that received 35 minutes of 1.7% isoflurane daily, for five consecutive days, from postnatal day 14 were cognitively impaired in comparison to control group [25]. The same cognitive impairment was also observed in rats that had single 4-h exposure to isoflurane [22]. The cognitive impairment seems to be correlated with persistent decrease in the hippocampal neural stem cell pool and neurogenesis [25].…”

Section: New Evidence On Anaesthetics Induced Neuronal Cell Death supporting

confidence: 90%

Anaesthetics-Induced Neurotoxicity in Developing Brain: An Update on Preclinical Evidence

Zhou

2014

Brain Sciences

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Every year millions of young people are treated with anaesthetic agents for surgery and sedation in a seemingly safe manner. However, growing and convincing preclinical evidence in rodents and nonhuman primates, together with recent epidemiological observations, suggest that exposure to anaesthetics in common clinical use can be neurotoxic to the developing brain and lead to long-term neurological sequelae. These findings have seriously questioned the safe use of general anaesthetics in obstetric and paediatric patients. The mechanisms and human applicability of anaesthetic neurotoxicity and neuroprotection have remained under intense investigation over the past decade. Ongoing pre-clinical investigation may have significant impact on clinical practice in the near future. This review represents recent developments in this rapidly emerging field. The aim is to summarise recently available laboratory data, especially those being published after 2010, in the field of anaesthetics-induced neurotoxicity and its impact on cognitive function. In addition, we will discuss recent findings in mechanisms of early-life anaesthetics-induced neurotoxicity, the role of human stem cell-derived models in detecting such toxicity, and new potential alleviating strategies.

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Section: New Evidence On Anaesthetics Induced Neuronal Cell Death supporting

confidence: 90%

Anaesthetics-Induced Neurotoxicity in Developing Brain: An Update on Preclinical Evidence

Zhou

2014

Brain Sciences

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“…However, increasing experimental data in neonatal rodents and nonhuman primates settings have shown that early exposure to commonly used general anesthetics impaired brain development such as inhibiting neurogenesis, inducing widespread neuroapoptosis and longterm neurocognitive deficits [1][2][3]. Epidemiological studies indicated that young children underwent general anesthesia were possibly associated with potential neurocognitive impairment later in life [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Wang¹,

Lu²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Isoflurane inhibited neurogenesis and induced subsequent neurocognitive deficits in developing brain. Simvastatin exerts neuroprotection in a wide range of brain injury models. In the present study, we investigated whether simvastatin could attenuate neurogenetic inhibition and cognitive deficits induced by isoflurane exposure in neonatal rats. Methods: Sprague-Dawley rats at postnatal day (PND) 7 and neural stem cells (NSCs) were treated with either gas mixture, isoflurane, or simvastatin 60 min prior to isoflurane exposure, respectively. The rats were decapitated at PND 8 and PND 10 for detection of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunostaining. NSC proliferation, viability and apoptosis were assessed by immunohistochemistry, CCK-8 and TUNEL, respectively. The protein expressions of caspase-3, p-Akt and p-GSK-3β both in vivo and vitro were assessed by western blotting. Cognitive functions were assessed by Morris Water Maze test and context fear conditioning test at the adult. Results: Isoflurane exposure inhibited neurogenesis in the SVZ and SGZ, decreased NSC proliferation and viability, promoted NSC apoptosis and led to late cognitive deficits. Furthermore, isoflurane increased caspase-3 expression and decreased protein expressions of p-Akt and p-GSK-3β both in vivo and in vitro. Pretreatment with simvastatin attenuated isoflurane-elicited changes in NSCs and cognitive function. Co-treatment with LY294002 reversed the effect of simvastatin on NSCs in vitro. Conclusion: We for the first time showed that simvastatin, by upregulating Akt/GSK-3β signaling pathway, alleviated isoflurane-induced neurogenetic damage and neurocognitive deficits in developing rat brain.

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“…Numerous animal experiments have documented neuronal death following exposure to volatile anesthetics 4,6,7 . In addition, factors influencing cell death have been researched extensively, including duration of anesthesia and the specific anesthetic agent that is delivered 6,8,9 . Various mechanisms have even been proposed to account for the process of anesthetic-induced neuroapoptosis 10,11 .…”

Section: Introductionmentioning

confidence: 99%

“…Cell death occurs acutely in the period immediately following anesthesia 4,8,21 , and the thalamus and hippocampus are areas known to be susceptible to extensive neurodegeneration 4,7,21 . Long-term behavior is separately assessed in adolescence or adulthood using a range of tasks 4,6,7,9 .…”

Section: Introductionmentioning

confidence: 99%

Isoflurane exposure in newborn rats induces long-term cognitive dysfunction in males but not females

et al. 2014

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Volatile anesthetics are used widely for achieving a state of unconsciousness, yet these agents are incompletely understood in their mechanisms of action and effects on neural development. There is mounting evidence that children exposed to anesthetic agents sustain lasting effects on learning and memory. The explanation for these behavioral changes remains elusive, although acute neuronal death after anesthesia is commonly believed to be a principal cause. Rodent models have shown that isoflurane exposure in newborns induces acute neuroapoptosis and long-term cognitive impairment. However, the assessment of predisposing factors is lacking. We investigated the role of sex by delivering isoflurane to postnatal day (P)7 male and female Sprague Dawley rats for 4 hours. Brain cell death was assessed 12 h later using FluoroJade C staining in the thalamus, CA1-3 regions of hippocampus, and dentate gyrus. Behavior was assessed separately using a series of object recognition tasks and a test of social memory beginning at P38. We found that isoflurane exposure significantly increased neuronal death in each brain region with no difference between sexes. Behavioral outcome was also equivalent in simple novel object recognition. However, only males were impaired in the recognition of objects in different locations and contexts. Males also exhibited deficient social memory while females were intact. The profound behavioral impairment in males relative to females, in spite of comparable cell death, suggests that males are more susceptible to long-term cognitive effects and this outcome may not be exclusively attributed to neuronal death.

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Distinct long-term neurocognitive outcomes after equipotent sevoflurane or isoflurane anaesthesia in immature rats

Abstract: Both isoflurane and sevoflurane delivered at 1 MAC for 4 h to immature rats caused a deficit in long-term memory. Isoflurane also caused a deficit in short-term memory. Isoflurane might be more detrimental than sevoflurane in very young animals.

Cited by 57 publications

References 29 publications

Anaesthetics-Induced Neurotoxicity in Developing Brain: An Update on Preclinical Evidence

Anaesthetics-Induced Neurotoxicity in Developing Brain: An Update on Preclinical Evidence

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Isoflurane exposure in newborn rats induces long-term cognitive dysfunction in males but not females

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