Early-Life Multiple Sevoflurane Exposures Alleviate Long-term Anxiety-Like Behaviors in Mice via the proBDNF/ERK Pathway

Luo, Ruyi; Luo, Cong; Zhong, Feng; Shen, Weiyun; Li, Hui; Zhang, Yanling; Dai, Renke

doi:10.1007/s12035-020-02113-y

Cited by 4 publications

(2 citation statements)

References 42 publications

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“…Previous studies show that the effect of sevoflurane on cognitive function of elderly animals is controversial (Callaway et al, 2012;Liu et al, 2015;Hu et al, 2016;Yang and Yuan, 2018). Due to the complexity of clinical anesthesia and the difference between clinical anesthesia and basic research, we adopted the sevoflurane exposure method referring to Shen et al (2013) and Luo et al (2021) study in order to control the experimental factors.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Adult Hippocampal Neurogenesis Plays a Role in Sevoflurane-Induced Cognitive Impairment in Aged Mice Through Brain-Derived Neurotrophic Factor/Tyrosine Receptor Kinase B and Neurotrophin-3/Tropomyosin Receptor Kinase C Pathways

Guo

Wang

et al. 2022

Front. Aging Neurosci.

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Sevoflurane anesthesia induces cognitive impairment, which may lead to perioperative neurocognitive disorders (PND). However, the factors and molecular mechanism underlying this impairment remains unclear. Adult hippocampal neurogenesis (AHN) in the subgranular zone of the hippocampus has been implicated in cognitive processes. Nonetheless, the direct role of AHN in sevoflurane-induced cognitive impairment has never been demonstrated. In this study, we explored the age and the concentration factors and the role of AHN inhibition in sevoflurane-induced cognitive impairment in sevoflurane inhalation model mice. We found that 3% sevoflurane exposure induced significant cognitive impairment and inhibition of AHN in aged mice but not adult mice. Expression of BDNF/TrkB and NT-3/TrkC was also decreased by 3% sevoflurane exposure in aged mice. Hippocampal brain-derived neurotrophic factor (BDNF) or Neurotrophin-3 (NT-3) microinjection could partially improve the sevoflurane-induced cognitive impairment and AHN inhibition, respectively. These results demonstrate that the cognitive impairment caused by sevoflurane inhalation is related to patient age and sevoflurane concentration. In conclusion, the molecular mechanism of cognitive impairment in the elderly is related to the inhibition of AHN through the BDNF/TrkB and NT-3/TrkC pathways. Thus, sevoflurane inhalation anesthesia may be safe for adult patients, but caution should be exercised when administering it to the elderly.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Adult Hippocampal Neurogenesis Plays a Role in Sevoflurane-Induced Cognitive Impairment in Aged Mice Through Brain-Derived Neurotrophic Factor/Tyrosine Receptor Kinase B and Neurotrophin-3/Tropomyosin Receptor Kinase C Pathways

Guo

Wang

et al. 2022

Front. Aging Neurosci.

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“…The Morris water maze (MWM) is widely utilized for assessing the spatial learning and memory abilities of animals, particularly in relation to neurocognitive disorders [21][22][23]. In the place navigation test, an increase in escape latency indicates a decline in cognitive ability related to spatial memory [24], while an increase in time spent crossing the platform and staying in the target quadrant suggests improved special information processing skills and overall proficiency [25,26].…”

Section: Discussionmentioning

confidence: 99%

Isoflurane-induced neuroinflammation and NKCC1/KCC2 dysregulation result in long-term cognitive disorder in neonatal mice

Xu,

Liu,

Meng

et al. 2024

BMC Anesthesiol

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Background The inhalational anesthetic isoflurane is commonly utilized in clinical practice, particularly in the field of pediatric anesthesia. Research has demonstrated its capacity to induce neuroinflammation and long-term behavioral disorders; however, the underlying mechanism remains unclear [1]. The cation-chloride cotransporters Na+–K+–2Cl−–1 (NKCC1) and K+–2Cl−–2 (KCC2) play a pivotal role in regulating neuronal responses to gamma-aminobutyric acid (GABA) [2]. Imbalances in NKCC1/KCC2 can disrupt GABA neurotransmission, potentially leading to neural circuit hyperexcitability and reduced inhibition following neonatal exposure to anesthesia [3]. Therefore, this study postulates that anesthetics have the potential to dysregulate NKCC1 and/or KCC2 during brain development. Methods We administered 1.5% isoflurane anesthesia to neonatal rats for a duration of 4 h at postnatal day 7 (PND7). Anxiety levels were assessed using the open field test at PND28, while cognitive function was evaluated using the Morris water maze test between PND31 and PND34. Protein levels of NKCC1, KCC2, BDNF, and phosphorylated ERK (P-ERK) in the hippocampus were measured through Western blotting analysis. Pro-inflammatory cytokines IL-1β, IL-6, and TNF-α were quantified using ELISA. Results We observed a decrease in locomotion trajectories within the central region and a significantly shorter total distance in the ISO group compared to CON pups, indicating that isoflurane induces anxiety-like behavior. In the Morris water maze (MWM) test, rats exposed to isoflurane exhibited prolonged escape latency onto the platform. Additionally, isoflurane administration resulted in reduced time spent crossing in the MWM experiment at PND34, suggesting long-term impairment of memory function. Furthermore, we found that isoflurane triggered activation of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α; downregulated KCC2/BDNF/P-ERK expression; and increased the NKCC1/KCC2 ratio in the hippocampus of PND7 rats. Bumetadine (NKCC1 specific inhibitors) reversed cognitive damage and effective disorder induced by isoflurane in neonatal rats by inhibiting TNF-α activation, normalizing IL-6 and IL-1β levels, restoring KCC2 expression levels as well as BDNF and ERK signaling pathways. Based on these findings, it can be speculated that BDNF, P-ERK, IL-1β, IL-6 and TNF - α may act downstream of the NKCC1/KCC2 pathway. Conclusions Our findings provide evidence that isoflurane administration in neonatal rats leads to persistent cognitive deficits through dysregulation of the Cation-Chloride Cotransporters NKCC1 and KCC2, BDNF, p-ERK proteins, as well as neuroinflammatory processes.

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MANF Alleviates Sevoflurane-Induced Cognitive Impairment in Neonatal Mice by Modulating Microglial Activation and Polarization

Gao,

Zhang,

Zhou

et al. 2023

Mol Neurobiol

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Early-Life Multiple Sevoflurane Exposures Alleviate Long-term Anxiety-Like Behaviors in Mice via the proBDNF/ERK Pathway

Cited by 4 publications

References 42 publications

Inhibition of Adult Hippocampal Neurogenesis Plays a Role in Sevoflurane-Induced Cognitive Impairment in Aged Mice Through Brain-Derived Neurotrophic Factor/Tyrosine Receptor Kinase B and Neurotrophin-3/Tropomyosin Receptor Kinase C Pathways

Inhibition of Adult Hippocampal Neurogenesis Plays a Role in Sevoflurane-Induced Cognitive Impairment in Aged Mice Through Brain-Derived Neurotrophic Factor/Tyrosine Receptor Kinase B and Neurotrophin-3/Tropomyosin Receptor Kinase C Pathways

Isoflurane-induced neuroinflammation and NKCC1/KCC2 dysregulation result in long-term cognitive disorder in neonatal mice

MANF Alleviates Sevoflurane-Induced Cognitive Impairment in Neonatal Mice by Modulating Microglial Activation and Polarization

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