Brain regional vulnerability to anaesthesia-induced neuroapoptosis shifts with age at exposure and extends into adulthood for some regions

Deng, Mengying; Hofacer, Rylon D.; Jiang, Connie; Joseph, Bernadin; Hughes, Elizabeth; Jia, Bing; Danzer, Steve C.; Loepke, Andreas W.

doi:10.1093/bja/aet469

Cited by 87 publications

(62 citation statements)

References 38 publications

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“…The hippocampus serves a crucial role in regulating the cognitive function (11). A previous study demonstrated that the hippocampus is vulnerable to adverse events, including hypoxemia, exposure to inhaled anesthetics and surgical trauma (12). Evidence from magnetic resonance imaging studies indicated that decreased hippocampal volume is significantly associated with mild cognitive impairment in various neuropsychiatric diseases (13,14).…”

Section: Introductionmentioning

confidence: 99%

Sevoflurane exposure in postnatal rats induced long-term cognitive impairment through upregulating caspase-3/cleaved-poly (ADP-ribose) polymerase pathway

Ling

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The association of anesthetic exposure in infants or young children with the long-term impairment of neurologic functions has been reported previously; however, the underlying mechanisms remain largely unknown. In order to identify dysregulated gene expression underlying long-term cognitive impairment caused by sevoflurane exposure at the postnatal stage, the present study initially performed behavioral tests on adult Wistar rats, which received 3% sevoflurane at postnatal day 7 (P7) for different time course. Subsequently, transcriptome profiling of hippocampal tissues from experimental and control rats was performed. Significant impairment of the working memory was observed in adult rats with sevoflurane exposure for 4-6 h, when compared with the control rats. The results indicated that a total of 264 genes were aberrantly expressed (51 downregulated and 213 upregulated; fold change >2.0; P<0.05; false discovery rate <0.05) in the hippocampus of experimental adult rats compared with those from control rats. Particularly, the expression of caspase-3 gene (CASP3), encoding caspase-3 protein, presented the most significant upregulation, which was further validated by quantitative polymerase chain reaction and immunohistochemical analysis. Further analysis revealed that CASP3 expression level was negatively correlated with the rats' spatial working memory performance, as indicated by the Y-maze test. The level of cleaved-poly (ADP-ribose) polymerase (PARP), a substrate of caspase-3, was also increased in the hippocampus of experimental adult rats. Thus, the present study revealed that upregulation of caspase-3/cleaved-PARP may be involved in long-term cognitive impairment caused by sevoflurane exposure in infants, which may be useful for the clinical prevention of cognitive impairment.

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Section: Introductionmentioning

confidence: 99%

Sevoflurane exposure in postnatal rats induced long-term cognitive impairment through upregulating caspase-3/cleaved-poly (ADP-ribose) polymerase pathway

Ling

et al. 2017

Experimental and Therapeutic Medicine

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“…Exposure to isoflurane, however, led to a dramatic increase in the number of caspase-3 immunoreactive cells in the dentate gyrus ( Fig.1), consistent with previous studies. 13,14 Moreover, quantification of caspase-3 immunolabeling in GFP-expressing cells revealed a five-fold increase in double-labeled cells relative to controls. Specifically, in 21-day-old control animals, 2.05±0.75% of GFPexpressing cells co-labeled with caspase-3, while 11.03±1.75% of cells in the P21 anesthesia group expressed caspase-3 ( Fig.1; P<0.001, t-test).…”

Section: Resultsmentioning

confidence: 98%

“…11,12 A second complicating factor is the potential for compensatory neurogenesis among certain neuronal populations sensitive to anesthesia-induced death. Specifically, we and others have recently demonstrated that hippocampal dentate granule cells are especially vulnerable to anesthesia-induced neurotoxicity in 21 day-old (P21) mice, 13,14,15 a brain maturational stage comparable to human infants. 16 Granule cells, however, are produced throughout life in animals and humans, 17 so it is conceivable that the dentate could regenerate lost cells.…”

Section: Introductionmentioning

confidence: 87%

Long-term Fate Mapping to Assess the Impact of Postnatal Isoflurane Exposure on Hippocampal Progenitor Cell Productivity

Jiang

Tong

Hofacer

et al. 2017

Survey of Anesthesiology

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“…In newborn mice, general anaesthesia with 1.5 Vol.% isoflurane has been found to cause a 4-11 fold increase of neuronal death in various brain regions, as compared to controls. [10,28,29] A 6-hour isoflurane exposure eliminates approximately 2% of cortical neurons [14]. Apoptosis appears to be the predominant mode of isoflurane-induced death, as evidenced by caspase-3 cleavage [10].…”

Section: Resultsmentioning

confidence: 99%

Isoflurane but not Fentanyl Causes Apoptosis in Immature Primary Neuronal Cells

Berns¹,

Wolter²,

Bührer³

et al. 2017

TOATJ

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Background:Anaesthetics are widely used in new-borns and preterm infants, although it is known that they may adversely affect the developing brain. Objective:We assessed the impact of the volatile anaesthetic, isoflurane, and the intravenous analgesic, fentanyl, on immature and mature embryonic neuronal cells. Methods:Primary neuronal cultures from embryonic rats (E18) cultured for 5 (immature) or 15 days (mature) in vitro (DIV), respectively, were exposed to isoflurane (1.5 Vol.%) or fentanyl (0.8 -200 ng/ml) for 24 hours. Experiments were repeated in the presence of the γ-amino butyric acid-A (GABA A ) receptor antagonists, bicuculline or picrotoxin (0.1 mmol/l), or the pancaspase inhibitor zVAD-fmk (20 nmol/l). Cell viability was assessed by methyltetrazolium (MTT) metabolism or lactate dehydrogenase (LDH) release. Results:Isoflurane reduced cell viability significantly in primary neuronal cells cultured for 5 DIV (Δ MTT -28 ±13%, Δ LDH +143 ±15%). Incubation with bicuculline, picrotoxin or zVAD-fmk protected the cells mostly from isoflurane toxicity. After 15 DIV, cell viability was not reduced by isoflurane. Viability of primary neurons cultured for 5 DIV did not change with fentanyl over the wide range of concentrations tested. Conclusion:Immature primary neurons may undergo apoptosis following exposure to isoflurane but are unaffected by fentanyl. Mature primary neurons were not affected by isoflurane exposure.

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Brain regional vulnerability to anaesthesia-induced neuroapoptosis shifts with age at exposure and extends into adulthood for some regions

Cited by 87 publications

References 38 publications

Sevoflurane exposure in postnatal rats induced long-term cognitive impairment through upregulating caspase-3/cleaved-poly (ADP-ribose) polymerase pathway

Sevoflurane exposure in postnatal rats induced long-term cognitive impairment through upregulating caspase-3/cleaved-poly (ADP-ribose) polymerase pathway

Long-term Fate Mapping to Assess the Impact of Postnatal Isoflurane Exposure on Hippocampal Progenitor Cell Productivity

Isoflurane but not Fentanyl Causes Apoptosis in Immature Primary Neuronal Cells

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