Sevoflurane induces short‐term changes in proteins in the cerebral cortices of developing rats

Li, Y.; Liu, C.; Zhao, Yifan; Hu, Kun; Zhang, J.; Zeng, Mingtao; Luo, Tao; Jiang, Wei; Wang, Hairong

doi:10.1111/aas.12018

Cited by 38 publications

(29 citation statements)

References 35 publications

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“…Rats were exposed for 6 h to 0.75% isoflurane or 1.2% sevoflurane (approximately 0.3 MAC in P7 rats as determined by Orliaguet et al [24]) in 30% oxygen or air in a temperature-controlled chamber as we described before [7], [25].…”

Section: Methodsmentioning

confidence: 99%

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Dexmedetomidine Reduces Isoflurane-Induced Neuroapoptosis Partly by Preserving PI3K/Akt Pathway in the Hippocampus of Neonatal Rats

et al. 2014

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Prolonged exposure to volatile anesthetics, such as isoflurane and sevoflurane, causes neurodegeneration in the developing animal brains. Recent studies showed that dexmedetomidine, a selective α2-adrenergic agonist, reduced isoflurane-induced cognitive impairment and neuroapoptosis. However, the mechanisms for the effect are not completely clear. Thus, we investigated whether exposure to isoflurane or sevoflurane at an equivalent dose for anesthesia during brain development causes different degrees of neuroapoptosis and whether this neuroapoptosis is reduced by dexmedetomidine via effects on PI3K/Akt pathway that can regulate cell survival. Seven-day-old (P7) neonatal Sprague-Dawley rats were randomly exposed to 0.75% isoflurane, 1.2% sevoflurane or air for 6 h. Activated caspase-3 was detected by immunohistochemistry and Western blotting. Phospho-Akt, phospho-Bad, Akt, Bad and Bcl-xL proteins were detected by Western blotting in the hippocampus at the end of exposure. Also, P7 rats were pretreated with various concentrations of dexmedetomidine alone or together with PI3K inhibitor LY294002, and then exposed to 0.75% isoflurane. Terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL) and activated caspase-3 were used to detect neuronal apoptosis in their hippocampus. Isoflurane, not sevoflurane at the equivalent dose, induced significant neuroapoptosis, decreased the levels of phospho-Akt and phospho-Bad proteins, increased the expression of Bad protein and reduced the ratio of Bcl-xL/Bad in the hippocampus. Dexmedetomidine pretreatment dose-dependently inhibited isoflurane-induced neuroapoptosis and restored protein expression of phospho-Akt and Bad as well as the Bcl-xL/Bad ratio induced by isoflurane. Pretreatment with single dose of 75 µg/kg dexmedetomidine provided a protective effect similar to that with three doses of 25 µg/kg dexmedetomidine. Moreover, LY294002, partly inhibited neuroprotection of dexmedetomidine. Our results suggest that dexmedetomidine pretreatment provides neuroprotection against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats by preserving PI3K/Akt pathway activity.

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Section: Methodsmentioning

confidence: 99%

“…Recent studies have demonstrated that prolonged exposure to isoflurane and sevoflurane causes neurodegeneration in the developing animal brains and persistent learning deficits [2], [3], [4], [5], [6], [7], [8]. Isoflurane at an equivalent dose for anesthesia induces more profound apoptosis than sevoflurane in neonatal rat brains [9].…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine Reduces Isoflurane-Induced Neuroapoptosis Partly by Preserving PI3K/Akt Pathway in the Hippocampus of Neonatal Rats

et al. 2014

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“…Activated calpain may also bind to the apoptosis induced factor (AIF) and thus mediate the caspase-independent apoptotic pathway (35). Indeed, our previous study determined that sevoflurane increases the expression of AIF in the cortex of P7 rats (36). Therefore, it is possible that sevoflurane induces neuroapoptosis by activating the caspase-dependent and -independent pathways.…”

Section: Discussionmentioning

confidence: 99%

Influence of sevoflurane exposure on mitogen-activated protein kinases and Akt/GSK-3β/CRMP-2 signaling pathways in the developing rat brain

Liu

Zeng

et al. 2017

Exp Ther Med

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Abstract. Prolonged exposure to volatile anesthetics causes neurodegeneration in developing animal brains. However, their underlying mechanisms of action remain unclear. The current study investigated the expression of proteins associated with the mitogen-activated protein kinases (MAPK) and protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β)/collapsin response mediator protein 2 (CRMP-2) signaling pathways in the cortices of neonatal mice following exposure to sevoflurane.

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“…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%

“…Western blot analysis was performed to assess the expression levels of various proteins following isoflurane exposure and rutin treatment. Western blot analysis was performed as previously described by Li et al (6,7). Briefly, protein concentrations were determined using a BCA protein assay (Bio-Rad Laboratories, Inc., Hercules, CA, USA).…”

Section: Methodsmentioning

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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Sevoflurane induces short‐term changes in proteins in the cerebral cortices of developing rats

Abstract: These findings suggest that sevoflurane may cause short-term neuronal apoptosis and disturbances of neuronal migration, differentiation and energy metabolism in neonatal rat brains, and that these disturbances may contribute to its neurodegenerative effects.

Cited by 38 publications

References 35 publications

Dexmedetomidine Reduces Isoflurane-Induced Neuroapoptosis Partly by Preserving PI3K/Akt Pathway in the Hippocampus of Neonatal Rats

Dexmedetomidine Reduces Isoflurane-Induced Neuroapoptosis Partly by Preserving PI3K/Akt Pathway in the Hippocampus of Neonatal Rats

Influence of sevoflurane exposure on mitogen-activated protein kinases and Akt/GSK-3β/CRMP-2 signaling pathways in the developing rat brain

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

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