Sevoflurane Induces Tau Phosphorylation and Glycogen Synthase Kinase 3β Activation in Young Mice

Abstract

Background Children with multiple exposures to anesthesia and surgery may have an increased risk of developing cognitive impairment. Sevoflurane is a commonly used anesthetic in children. Tau phosphorylation contributes to cognitive dysfunction. We therefore assessed the effects of sevoflurane on Tau phosphorylation and underlying mechanisms in young mice. Methods Six day-old wild-type (WT) and Tau knockout (KO) mice were exposed to sevoflurane. We determined the effects of the sevoflurane anesthesia on Tau phosphorylation, levels of the kinases and phosphatase related to Tau phosphorylation, interleukin-6, and postsynaptic density protein 95 (PSD-95) in hippocampus, and cognitive function in both young WT and Tau KO mice. Results Anesthesia with 3% sevoflurane two hours daily for three days induced Tau phosphorylation (257% versus 100%, P=0.0025, n=6), enhanced activation of glycogen synthase kinase 3β (GSK3β), the kinase related to Tau phosphorylation in the hippocampus of postnatal day 8 WT mice. The sevoflurane anesthesia decreased hippocampus PSD-95 levels and induced cognitive impairment in the postnatal day 31 mice. GSK3β inhibitor lithium inhibited the sevoflurane-induced GSK3β activation, Tau phosphorylation, elevated levels of interleukin-6 and cognitive impairment in the WT young mice. Finally, the sevoflurane anesthesia did not induce an elevation of interleukin-6 levels, reduction in PSD-5 levels in hippocampus, or cognitive impairment in Tau KO young mice. Conclusions These data suggested that sevoflurane induced Tau phosphorylation, GSK3β activation, elevation of interleukin-6 and reduction of PSD-95 levels in hippocampus of young mice, and cognitive impairment in the mice. Future studies will dissect the cascade relationship of these effects.

Roscovitine, a CDK5 Inhibitor, Alleviates Sevoflurane-Induced Cognitive Dysfunction via Regulation Tau/GSK3β and ERK/PPARγ/CREB Signaling

“…PPARγ has anti-inflammatory, -oxidative, and -apoptotic properties [20, 28]. We found here that CDK5 activation promotes Tau phosphorylation and activates GSK3β signaling, which in turn enhanced neuronal injury and cognitive dysfunction caused by sevoflurane exposure [17]. We propose that inhibiting CDK5 has protective effects following sevoflurane exposure.…”

“…Sevoflurane has been shown to induce Tau phosphorylation and GSK3β activation in young mice, resulting in cognitive impairment [17]. A western blot analysis revealed that sevoflurane anesthesia increased Tau phosphorylation and activation but decreased the p-GSK3β (Ser9)/GSK3β ratio due to a decrease in GSK3β phosphorylation at serine 9, which is known to activate GSK3β.…”

“…CDK5 inhibition activates cyclic AMP response element-binding protein (CREB), peroxisome proliferator-activated receptor (PPAR)γ, and extracellular signal-regulated kinase (ERK), which are important factors modulating neuronal plasticity [13-15]. Sevoflurane-induced cognitive dysfunction has been linked to Tau phosphorylation by CDK5; this activates glycogen synthase kinase (GSK)3β, leading to upregulation of pro-inflammatory cytokines and neuronal damage [8, 16, 17]. …”

Influence of sevoflurane exposure on mitogen-activated protein kinases and Akt/GSK-3β/CRMP-2 signaling pathways in the developing rat brain

“…GSK-3 activation is a critical step in the cascade of detrimental events that occur during the development in AD, preceding the neurofibrillary tangles and neuronal death pathways (19). It has been demonstrated that sevoflurane induces Tau phosphorylation and GSK-3β activation in the hippocampus of developing mice (26). GSK-3β catalytic kinase activity is regulated by the differential phosphorylation of serine/threonine residues, including Ser 21 and Ser 9, which have an inhibitory effect, and tyrosine residues such as Tyr 279 and Tyr 216, which have an activating effect.…”

Can Exposure to Volatile Anesthetics Be a Tipping Point for AD Susceptible Populations?

“…Tau is continually phosphorylated on multiple serine and threonine residues -hyperphosphorylation -an initiating step in the pretangle stages of tau aggregation [29,30]. vGA can accelerate this process by increasing pS and pThr sites directly [31] or through inhibition of PP2A [27]. A principle side effect of vGA exposure during surgical procedures is signifi cant drop in body temperature, hypothermia.…”