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.

Lichi Xu,Wei Sun,Jiangnan Wu,Xinlei Li,Gongming Wang,Yanjing Guo,Mengyuan Zhang,Jingjing Li,Guoqing Sun

doi:10.3389/fnagi.2022.782932

Abstract

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.

Highlights

Nowadays, more and more elderly patients need surgical treatments
Through a series of in vivo studies, we demonstrated that sevoflurane-induced cognitive impairment in aged mice depended on the inhibition of Adult hippocampal neurogenesis (AHN) in the subgranular zone (SGZ) through the Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (TrkB) and NT-3/tropomyosin receptor kinase C (TrkC) pathways
In order to explore the potential mechanisms of sevoflurane-induced cognitive impairment and AHN inhibition, we evaluated the effects of sevoflurane exposure on the expression levels of BDNF/TrkB and NT-3/TrkC in the hippocampal tissues of aged mice

Summary

Introduction

More and more elderly patients need surgical treatments. Sevoflurane is a commonly anesthetics for elderly patients which has many advantages such as easy-control, analgesia and muscle relaxation (Zhang Y. et al, 2018). PND prolongs the length of hospital stay and increases the cost of inpatient and out-of-hospital care. It affects the prognosis of patients and increases the postoperative mortality rate (Monk et al, 2008). Reports on the effect of sevoflurane on cognition are conflicting (Monk et al, 2008; Herling et al, 2017; Tian et al, 2018; Yang and Yuan, 2018; Zhang H. et al, 2018; Zhang Y. et al, 2018). The different studies showed that many factors could influence the research conclusions above, such as different inhalation concentrations, times of exposure, periods of exposure, and brain backgrounds (Bedford, 1955; Monk et al, 2008; Herling et al, 2017; Tian et al, 2018; Yang and Yuan, 2018; Zhang H. et al, 2018; Zhang Y. et al, 2018). The basic studies have demonstrated that sevoflurane-induced cognitive impairment in young rats was dependent on the rats’ age and inhalation of 1.5% sevoflurane had no effect on cognition in adult rats but inhalation of both 2 and 3% sevoflurane produced significant cognitive impairment in aged rats (Shen et al, 2013; Tian et al, 2018; Yang and Yuan, 2018; Li et al, 2019)

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Conclusion