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

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.

The Role of Neurotrophin Signaling in Age-Related Cognitive Decline and Cognitive Diseases

“…Consistently, downregulation of BDNF/TrkB and NT-3/TrkC were observed due to treatment with 3% sevoflurane. As expected, hippocampal BDNF or NT-3 microinjection partially improved the cognitive impairment and decreased hippocampal neurogenesis caused by sevoflurane, suggesting that a downregulation of these neurotrophins contributes to the onset of PND [48].…”

“…However, sevoflurane has a risk of causing perioperative neurocognitive disorders (PND). Xu et al (2022) showed that a 3% sevoflurane exposure induced cognitive impairment and the inhibition of adult hippocampal neurogenesis in the DG of aged (18-month-old) mice, but not adult (8-month-old) mice [ 48 ]. Consistently, downregulation of BDNF/TrkB and NT-3/TrkC were observed due to treatment with 3% sevoflurane.…”

Early life adversity as a risk factor for cognitive impairment and Alzheimer’s disease

“…Using state-of-the-art tissue processing methods, Moreno-Jimenez et al observed immature neurons with variable degrees of maturation in the DG from neurologically healthy human subjects; however, the number and maturation of these neurons progressively declined alongside AD development [ 169 ]. Additionally, AHN depletion exacerbated cognitive deficits in AD and contributed to cognitive impairment in normal individuals [ 170 , 171 ]. Conversely, pharmacological induction of AHN improved cognitive function in a mouse model of AD, suggesting a critical role of AHN in supporting cognitive function [ 172 ].…”

Minocycline Attenuates Sevoflurane-Induced Postoperative Cognitive Dysfunction in Aged Mice by Suppressing Hippocampal Apoptosis and the Notch Signaling Pathway-Mediated Neuroinflammation

“…Thus, neurogenesis has a strong association with synaptic plasticity. Emerging evidence indicates sevoflurane has an inhibitory effect on hippocampal neurogenesis [ 25 , 26 ]. To confirm this notion and examine the therapeutic effect of minocycline, we used the nucleotide analog BrdU to label neural stem cells to observe the effects of sevoflurane on neurogenesis.…”