Multiple sevoflurane anesthesia in pregnant mice inhibits neurogenesis of fetal hippocampus via repressing transcription factor Pax6

Fang, Fang; Song, Ruixue; Ling, Xiaomin; Peng, Mengyuan; Zhao, Xue; Cang, Jing

doi:10.1016/j.lfs.2017.03.003

Cited by 42 publications

(40 citation statements)

References 28 publications

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“…Although sevoflurane has smaller potency to cause neurotoxicity to the developing brain compared with other general anesthetic such as isoflurane [ 7 ], there were still some preclinical studies reported that sevoflurane could cause neurological deficits [ 8 , 9 ]. While neurogenesis abnormality is thought to play a vital role [ 10 – 12 ], the concrete impact of sevoflurane on fetal brain development remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

“…Most studies on the sevoflurane-induced neurotoxicity have focused on the change in the development of the hippocampus [ 10 , 13 ]. It is worth noting that the third trimester is a stage at which there are high levels of neurogenesis throughout the cortex and that the development of the prefrontal cortex (PFC), a seat of the highest-order cognitive functions, plays critical roles in the onset and development of many neurodevelopmental deficits [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Former in vitro studies have shown that self-renewal capacity and the subsequent differentiation of neural progenitors could be disturbed by sevoflurane [ 12 , 17 ]. Our earlier study has also shown a significant proliferation inhibition in neural progenitors after sevoflurane exposure [ 10 ]. Cell cycle dynamics, including the progression and exit of cell cycle, is important in cell fate decisions during neurogenesis [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Maternal Sevoflurane Exposure Causes Abnormal Development of Fetal Prefrontal Cortex and Induces Cognitive Dysfunction in Offspring

Song

Ling

Peng

et al. 2017

Stem Cells International

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Maternal sevoflurane exposure during pregnancy is associated with increased risk for behavioral deficits in offspring. Several studies indicated that neurogenesis abnormality may be responsible for the sevoflurane-induced neurotoxicity, but the concrete impact of sevoflurane on fetal brain development remains poorly understood. We aimed to investigate whether maternal sevoflurane exposure caused learning and memory impairment in offspring through inducing abnormal development of the fetal prefrontal cortex (PFC). Pregnant mice at gestational day 15.5 received 2.5% sevoflurane for 6 h. Learning function of the offspring was evaluated with the Morris water maze test at postnatal day 30. Brain tissues of fetal mice were subjected to immunofluorescence staining to assess differentiation, proliferation, and cell cycle dynamics of the fetal PFC. We found that maternal sevoflurane anesthesia impaired learning ability in offspring through inhibiting deep-layer immature neuron output and neuronal progenitor replication. With the assessment of cell cycle dynamics, we established that these effects were mediated through cell cycle arrest in neural progenitors. Our research has provided insights into the cell cycle-related mechanisms by which maternal sevoflurane exposure can induce neurodevelopmental abnormalities and learning dysfunction and appeals people to consider the neurotoxicity of anesthetics when considering the benefits and risks of nonobstetric surgical procedures.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Maternal Sevoflurane Exposure Causes Abnormal Development of Fetal Prefrontal Cortex and Induces Cognitive Dysfunction in Offspring

Song

Ling

Peng

et al. 2017

Stem Cells International

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“…Hui Zheng et al found that 2.5% sevoflurane anesthesia on G18 had adverse effects on rat fetuses' brains (Zheng et al, 2013). Multiple exposures to 2.5% sevoflurane during late gestation caused learning and memory impairment in offspring (Fang et al, 2017). One animal study showed that mater-nal exposure to 1.5% sevoflurane for 6 hr on E17 did not cause short-term learning and memory impairment in offspring (Suehara et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Suberoylanilide hydroxamic acid (SAHA) alleviates the learning and memory impairment in rat offspring caused by maternal sevoflurane exposure during late gestation

Feng

Huang³

et al. 2019

J. Toxicol. Sci.

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Recent studies have shown that sevoflurane can cause long-term neurotoxicity and learning and memory impairment in developing and progressively neurodegenerative brains. Sevoflurane is a widely used volatile anesthetic in clinical practice. Late gestation is a rapidly developing period in the fetal brain, but whether sevoflurane anesthesia during late gestation affects learning and memory of offspring is not fully elucidated. Histone deacetylase 2 (HDAC2) plays an important regulatory role in learning and memory. This study examined the effect of maternal sevoflurane exposure on learning and memory in offspring and the underlying role of HDAC2. The Morris water maze (MWM) test was used to evaluate learning and memory function. Q-PCR and immunofluorescence staining were used to measure the expression levels of genes related to learning and memory. The results showed that sevoflurane anesthesia during late gestation impaired learning and memory in offspring rats (e.g., showing increase of the escape latency and decrease of the platform-crossing times and target quadrant traveling time in behavior tests) and upregulated the expression of HDAC2, while downregulating the expression of the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the N-methyl-D-aspartate receptor 2 subunit B (NR2B) mRNA and protein in the hippocampus of offspring in a timedependent manner. HDAC2 inhibitor suberoylanilide hydroxamic acid (SAHA) treatment alleviated all of these changes in offspring rats. Therefore, the present study indicates that sevoflurane exposure during late gestation impairs offspring rat's learning and memory via upregulation of the expression of HDAC2 and downregulation of the expression of CREB and NR2B. SAHA can alleviate these impairments.

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“…Anesthesia has been reported to impair neurogenesis in developing brain (Stratmann et al, 2009;Zhu et al, 2010;Shen et al, 2013;Zhang et al, 2013;Yi et al, 2016;Fang et al, 2017). Sevoflurane inhibited neurogenesis of hippocampus neural stem cells in vitro and in rodent models (Engelhard et al, 2007;Zhang et al, 2015;Yi et al, 2016;Fang et al, 2017), and in human embryonic stem cells . However, the underlying mechanism remains mostly unknown.…”

Section: Introductionmentioning

confidence: 99%

Cyclophilin D Contributes to Anesthesia Neurotoxicity in the Developing Brain

Zhang

Lü

Liang

et al. 2020

Front. Cell Dev. Biol.

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Anesthetic sevoflurane induces mitochondrial dysfunction, impairment of neurogenesis, and cognitive impairment in young mice, but the underlying mechanism remains to be determined. Cyclophilin D (CypD) is a modulatory factor for the mitochondrial permeability transition pore (mPTP). We, therefore, set out to evaluate the role of CypD in these sevoflurane-induced changes in vitro and in young mice. Wild-type (WT) and CypD knockout (KO) young (postnatal day 6, 7, and 8) mice received 3% sevoflurane 2 h daily and the neural progenitor cells (NPCs) harvested from the WT or CypD KO mice received 4.1% sevoflurane. We used immunohistochemistry and immunocytochemistry imaging, flow cytometry, Western blot, RT-PCR, co-immunoprecipitation, and Morris Water Maze to assess the interaction of sevoflurane and CypD on mitochondria function, neurogenesis, and cognition in vitro and in WT or CypD KO mice. We demonstrated that the sevoflurane anesthesia induced accumulation of CypD, mitochondrial dysfunction, impairment of neurogenesis, and cognitive impairment in WT mice or NPCs harvested from WT mice, but not in CypD KO mice or NPCs harvested from CypD KO mice. Furthermore, the sevoflurane anesthesia reduced the binding of CypD with Adenine nucleotide translocator, the other component of mPTP. These data suggest that the sevoflurane anesthesia might induce a CypD-dependent mitochondria dysfunction, impairment of neurogenesis, and cognitive impairment in young mice and NPCs.

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Multiple sevoflurane anesthesia in pregnant mice inhibits neurogenesis of fetal hippocampus via repressing transcription factor Pax6

Cited by 42 publications

References 28 publications

Maternal Sevoflurane Exposure Causes Abnormal Development of Fetal Prefrontal Cortex and Induces Cognitive Dysfunction in Offspring

Maternal Sevoflurane Exposure Causes Abnormal Development of Fetal Prefrontal Cortex and Induces Cognitive Dysfunction in Offspring

Suberoylanilide hydroxamic acid (SAHA) alleviates the learning and memory impairment in rat offspring caused by maternal sevoflurane exposure during late gestation

Cyclophilin D Contributes to Anesthesia Neurotoxicity in the Developing Brain

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