Comparison of the Neuroapoptotic Properties of Equipotent Anesthetic Concentrations of Desflurane, Isoflurane, or Sevoflurane in Neonatal Mice

Istaphanous, George K.; Howard, Jennifer; Nan, Xinyu; Hughes, Elizabeth; McCann, John; McAuliffe, John J.; Danzer, Steve C.; Loepke, Andreas W.

doi:10.1097/aln.0b013e3182084a70

Cited by 244 publications

(170 citation statements)

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“…In fact, blockade of NMDA receptors with MK801 resulted in widespread apoptosis in the brains of 7-day-old rats [3]. Subsequently, many other studies demonstrated accelerated neuronal apoptosis in newborn rodents after they were exposed only to general anaesthetics such as ketamine, propofol, nitrous oxide, sevoflurane, isoflurane, desflurane, and benzodiazepines, without any other insults [2,[4][5][6][7][8][9][10]. In rats, the effect of anesthetics on apoptosis was greatest in 5-7 day olds.…”

Section: Effects Seen In Animal Studiesmentioning

confidence: 99%

Anesthesia and Apoptosis in the Developing Brain: An Update

Davidson

deGraaff

2012

Curr Anesthesiol Rep

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There is an increasing concern regarding the risk of anaesthetic neurotoxicity in children. Numerous animal and in vitro studies have demonstrated that general anaesthetics cause a variety of potentially harmful effects on the developing brain. An increased level of neuronal apoptosis is one such effect. In some studies, exposed animals have experienced long-lasting neurobehavioural changes. These effects occur at very specific stages of development and are dose-dependent. There are several plausible mechanisms for these deleterious effects; however, the exact mechanism remains unclear. Most importantly, histological and behavioral effects have been demonstrated in non-human primates. Human research evaluating the long-term effects of anaesthesia on brain development is limited and, to date, has been limited to retrospective observational cohort studies. The results of these studies have not been consistent, with some demonstrating an association between surgery and adverse neurobehavioral outcome and others showing no association. Furthermore, these cohort studies have numerous weaknesses and limitations. An ongoing randomized clinical trial aims to provide clear evidence regarding the clinical safety of anesthetics up to 1 h in neonates and older children.

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Section: Effects Seen In Animal Studiesmentioning

confidence: 99%

Anesthesia and Apoptosis in the Developing Brain: An Update

Davidson

deGraaff

2012

Curr Anesthesiol Rep

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“…Caspase-3 serves a vital role in the apoptotic pathway (41), and in previous studies, cleaved caspase-3 expression levels were used as a marker of apoptotic cell death (2,4,5,33). Rutin effectively downregulated the expression levels of activated caspase-3, in addition to the apoptotic cell count.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated the potential detrimental effects of anesthetic exposure to neonatal animals in terms of causing neurohistopathological changes and long-term behavior deficits and cognitive dysfunctions (6,32,33). Apoptotic cell death is an essential part of normal brain development and maturation, leading to the elimination of ~50-70% of neurons and progenitor cells during the development of the central nervous system (34,35).…”

Section: Discussionmentioning

confidence: 99%

Rutin attenuates isoflurane-induced neuroapoptosis via modulating JNK and p38 MAPK pathways in the hippocampi of neonatal rats

Zhao

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. An increasing number of infants and children undergo surgery and are exposed to anesthesia as a part of medical care each year. Isoflurane is a commonly used anesthetic in the pediatric population. However, previous studies have reported widespread isoflurane-induced neuroapoptosis and cognitive impairments in neonatal animal models, raising concerns over the administration of isoflurane in the pediatric population. The current study investigated the effects of rutin, a flavonoid, on isoflurane-induced neuroapoptosis in a neonatal rodent model. Groups of neonatal rat pups were administered rutin at doses of 10, 20 or 40 mg/kg body weight from postnatal day 1 (P1) to P15. On P7, pups were exposed to 0.75% isoflurane for 6 h. Rat pups in the control groups did not receive rutin, and did not receive anesthesia in one group. Neuroapoptosis following isoflurane exposure was determined by TUNEL assay. The expression levels of cleaved caspase-3, apoptotic pathway proteins [Bcl2-associated agonist of cell death (Bad), phospho-Bad, Bax, B-cell lymphoma 2 (Bcl-2) and Bcl-xL and mitogen-activated protein kinases (MAPK)] signalling pathway proteins [c-Jun N-terminal kinase (JNK), phospho-JNK, extracellular-signal-regulated kinase 1/2 (ERK1/2), phosphoERK1/2, p38, phospho-p38 and phospho-c-Jun], were determined by western blot analysis. The Morris water maze test was used to assess the learning and memory of pups on P30 and P31. The present study found that rutin at the tested doses of 10, 20 and 40 mg significantly reduced (P<0.05) the isoflurane-induced elevation in apoptotic cell count. The expression levels of caspase-3, Bad, Bax and MAPK proteins, which were increased following isoflurane treatment, were rescued by rutin treatment. Furthermore, rutin prevented the increase in Bcl-xL, Bcl-2 and phospho-Bad expression following isoflurane treatment, and enhanced the memory of the rats. Rutin provided neuroprotection against isoflurane-induced neuronal apoptosis and improved the learning and memory of rats by effectively regulating the expression levels of proteins in the MAPK pathway.

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“…Apoptosis has been observed to occur acutely in the period immediately following anesthesia (Jevtovic-Todorovic et al, 2003;Istaphanous et al, 2011;Shih et al, 2012), and the thalamus and hippocampus are known areas susceptible to extensive neurodegeneration (JevtovicTodorovic et al, 2003;Satomoto et al, 2009;Shih et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Effects of vitamin C on inhalation anesthetic isoflurane-induced developmental, neuronal apoptosis in neonatal rats

Shuai

Wang

Xiong

et al. 2014

Bangladesh J Pharmacol

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Research ArticleEffects of vitamin C on inhalation anesthetic isoflurane-induced developmental, neuronal apoptosis in neonatal rats BJP IntroductionAbout 200 million patients worldwide are exposed to anesthesia and undergo surgery each year (Weiser et al., 2008;Moonesinghe et al., 2011). Volatile anesthetics such as isoflurane and sevoflurane are used in millions of young children each year during surgical procedures and imaging studies (Istaphanous and Loepke, 2009). Exposure to anesthetic cocktails (Yon et al., 2005;Lu et al., 2006;Sanders et al., 2009) or volatile agents such as isoflurane even as a single anesthetic (Yon et al., 2005;Ma et al., 2007) has been reported to be associated with widespread apoptotic neurodegeneration in the developing brains and contributes to the post-operative cognitive dysfunction (POCD) (Jevtovic-Todorovic et al., 2003;Satomoto et al., 2009;Brambrink et al., 2010;Kong et al., 2011;Paule et al., 2011; Li et al., 2013a,b).In rodent models, the effects of anesthesia have been evaluated following exposure during a time of peak brain development and synaptogenesis, typically at postnatal day 7 (P7) (Jevtovic-Todorovic et al., 2003;Stratmann et al., 2009b;Shih et al., 2012). Apoptosis has been observed to occur acutely in the period immediately following anesthesia (Jevtovic-Todorovic et al., 2003;Istaphanous et al., 2011;Shih et al., 2012), and the thalamus and hippocampus are known areas susceptible to extensive neurodegeneration (JevtovicTodorovic et al., 2003;Satomoto et al., 2009;Shih et al., 2012). AbstractDevelopmental abnormalities, neuronal apoptosis and associated cognitive impairment following isoflurane exposure in neonatal rodents have been reported. The study was undertaken to investigate the effect of vitamin C supplementation against isoflurane-induced neurotoxicity. Seven day old rats were exposed to 1.1% isoflurane, or air for 6 hours. Treatment groups were administered with vitamin C (30 mg/kg, orally) from postnatal day 1 (P1) to P10 and were exposed to isoflurane on P7. Isoflurane exposure induced apoptosis was determined by Fluoro-Jade C and terminal deoxynucleotidyltransferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling assay. Vitamin C considerably improved memory and learning impairments, modulated neuroapoptosis and improved expressions of brain-derived neurotrophic factor, nerve growth factor, Bcl-xL and decreased activated caspase-3 expressions. Thus, vitamin C effectively offered protection against isoflurane-induced neuronal apoptosis, learning and memory disturbances. Article Info

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Comparison of the Neuroapoptotic Properties of Equipotent Anesthetic Concentrations of Desflurane, Isoflurane, or Sevoflurane in Neonatal Mice

Abstract: In neonatal mice, equipotent doses of the three commonly used inhaled anesthetics demonstrated similar neurotoxic profiles, suggesting that developmental neurotoxicity is a common feature of all three drugs and cannot be avoided by switching to newer agents.

Cited by 244 publications

References 59 publications

Anesthesia and Apoptosis in the Developing Brain: An Update

Anesthesia and Apoptosis in the Developing Brain: An Update

Rutin attenuates isoflurane-induced neuroapoptosis via modulating JNK and p38 MAPK pathways in the hippocampi of neonatal rats

Effects of vitamin C on inhalation anesthetic isoflurane-induced developmental, neuronal apoptosis in neonatal rats

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