Sevoflurane Acts on Ubiquitination–Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice

Abstract

Background Children with multiple exposures to anesthesia and surgery may have an increased risk of developing cognitive impairment. Sevoflurane, a commonly used anesthetic in children, has been reported to decrease levels of postsynaptic density 95 protein. However, the upstream mechanisms and downstream consequences of the sevoflurane-induced reduction in postsynaptic density 95 protein levels remains largely unknown. We therefore set out to assess whether sevoflurane acts on ubiquitination–proteasome pathway to facilitate postsynaptic density 95 protein degradation. Methods Six-day-old wild-type mice received anesthesia with 3% sevoflurane 2 h daily for 3 days starting on postnatal day 6. We determined the effects of the sevoflurane anesthesia on mRNA, protein and ubiquitinated levels of postsynaptic density 95 protein in neurons, and synaptosomes and hippocampus of young mice. Cognitive function in the mice was determined at postnatal day 31 by using a Morris water maze. Proteasome inhibitor MG132 and E3 ligase mouse double mutant 2 homolog inhibitor Nutlin-3 were used for the interaction studies. Results The sevoflurane anesthesia decreased protein, but not mRNA, levels of postsynaptic density 95, and reduced ubiquitinated postsynaptic density 95 protein levels in neurons, synaptosomes, and hippocampus of young mice. Both MG132 and Nutlin-3 blocked these sevoflurane-induced effects. Sevoflurane promoted the interaction of mouse double mutant 2 homolog and postsynaptic density 95 protein in neurons. Finally, MG132 and Nutlin-3 ameliorated the sevoflurane-induced cognitive impairment in the mice. Conclusions These data suggest that sevoflurane acts on the ubiquitination–proteasome pathway to facilitate postsynaptic density 95 protein degradation, which then decreases postsynaptic density 95 protein levels, leading to cognitive impairment in young mice. These studies would further promote the mechanistic investigation of anesthesia neurotoxicity in the developing brain.

Effects of Sevoflurane Exposure During Mid-Pregnancy on Learning and Memory in Offspring Rats: Beneficial Effects of Maternal Exercise

“…The reduction of synaptic markers has been shown to be associated with decreases in synapse number or synaptic loss. Our results are consistent with the notion that anesthetic-induced reduction in GAP43 and PSD 95 may lead to decreased neuroplasticity and cognitive impairments in developing brain (Wang et al, 2012 ; Zhang et al, 2015 ; Lu et al, 2017 ).…”

Resveratrol Mitigates Sevoflurane-Induced Neurotoxicity by the SIRT1-Dependent Regulation of BDNF Expression in Developing Mice

“…In particular, synapsin1, vesicular glutamate transporters (VGluT1), PSD95, and Homer1a are classical markers of presynaptic and postsynaptic proteins, which play an important role in synaptic activity [54][55][56][57][58][59]. Previous research has reported that the repeated sevoflurane exposure downregulates synaptic proteins such as postsynaptic protein PSD95 in the hippocampus of developing mice [60,61]. In the present study, we detect the effect of sevoflurane and resveratrol on the expression of these proteins.…”

Dexmedetomidine Attenuates Neurotoxicity in Developing Rats Induced by Sevoflurane through Upregulating BDNF-TrkB-CREB and Downregulating ProBDNF-P75NRT-RhoA Signaling Pathway

“…Thus, 25 μg/kg of dexmedetomidine was sufficient to induce neuroprotection. As many studies have shown that the main reason for the changes in learning and memory ability caused by inhaled anesthetics is mainly due to the prominent plasticity of brain neurons such as synaptic density or reticular formation rather than neuronal abnormalities caused by apoptosis or oxidative stress [31,32]. BDNF plays an important role in the regulation of synaptic plasticity, which is the basis of the brain's ability in learning and remembering.…”