Protective effects of Coenzyme Q10 against sevoflurane‐induced cognitive impairment through regulating apolipoprotein E and phosphorylated Tau expression in young mice

Abstract

Children with multiple exposures to anesthesia and surgery may be more likely to develop the learning disability. Coenzyme Q10 (CoQ10) was reported to reduce the multiple sevoflurane treatment‐induced cognitive deficiency in 6‐day‐old young mice. However, its specific mechanisms have not yet been found. This research aimed to reveal the role of ApoE in the pathogenesis of cognitive deficiency caused by sevoflurane anesthesia and the protective mechanism of CoQ10 in a multiple sevoflurane treatment model of young mice. The mice were randomly divided into four groups: Control + corn oil, Sevoflurane + corn oil, Control + CoQ10, and Sevoflurane + CoQ10. Sevoflurane group mice were anesthetized with 3% sevoflurane and 60% oxygen 2 hr a day for 3 days, while control group mice received only 60% oxygen. Mice received an intraperitoneal injection of 50 mg/kg CoQ10 or the same volume of corn oil 30 min before the inhalation of oxygen or sevoflurane for 3 days. Mice received sevoflurane anesthesia or control treatment from the 6th to 8th day after birth. The cortex and hippocampus were harvested on the 8th day. The ATP, MMP, ApoE mRNA, total ApoE, ApoE fragments, Aβ1‐40, Aβ1‐42, Tau5, AT8, and PHF levels were detected. The Morris water maze (MWM) tests were performed from P30 to p36 after anesthesia or control treatment. The results indicated that the injection of CoQ10 ahead of sevoflurane treatment could reverse the anesthesia‐induced energy deficiency, mitochondrial dysfunction, ApoE, and its fragments expression, Aβ1‐42 generation, Tau phosphorylation, and cognitive impairment in young mice. These data reveal that the ApoE and its fragments enhancement may play an important role in the pathogenesis of cognitive deficiency caused by sevoflurane anesthesia. CoQ10 could reduce ApoE expression by improving energy replenishment and mitochondrial functions, thereby alleviating sevoflurane‐induced brain damage and cognitive impairment.

Interaction of Tau, IL-6 and mitochondria on synapse and cognition following sevoflurane anesthesia in young mice

“…Anesthesia and Tau phosphorylation, inflammation and mitochondrial dysfunction in the brain tissues of young mice have been extensively studied ( Vutskits and Xie, 2016 ). Previous studies have shown that sevoflurane can increase Tau phosphorylation ( Hu et al., 2013 ; Huang et al., 2018 ; Tao et al., 2014 ; Yang et al., 2020a , 2020b ; Yu et al., 2009 , Yu et al., 2020 ) and cause IL-6 elevation ( Shen et al., 2013 ; Yang et al., 2020a , 2020b ; Zhang et al., 2013 ; Zheng et al., 2013 ) in brain tissues of young mice. Consistently, the present study also showed that sevoflurane increased the amounts of Tau-PS202/PT205 and IL-6.…”

Gut microbiota mediates cognitive impairment in young mice after multiple neonatal exposures to sevoflurane

“…In addition, the anesthesia group exhibited reduced spatial positioning capability as demonstrated by the results from the probe trial on PND 36, including showing fewer platform-crossing instances (4.80 ± 0.53 vs 2.20 ± 0.49, p = 0.0021; Figure 1E), less time spent in the fourth quadrant (26.10 ± 1.70 s vs 18.31 ± 2.06 s, p = 0.0092; Figure 1F), and longer mean distance from the platform (0.27 ± 0.02 m vs 0.35 ± 0.02 m, p = 0.0041; Figure 1G) compared with those of the control group. These results suggested that the sevoflurane treatment may result in defective memory and cognitive function of the treated mice [19,34].…”

Effects of toxic apolipoprotein E fragments on Tau phosphorylation and cognitive impairment in neonatal mice under sevoflurane anesthesia

“…We only chose female mice in this research since it has previously been shown that females are more vulnerable to anesthetic than males, resulting in long‐term cognitive impairment(Yang et al., 2020 ; Zhang et al., 2017 ). As a result, the mice utilized in this experiment were entirely female in order to generate a consistent cognitive impairment model.…”

“…Hyperphosphorylation of Tau protein is thought to be the source of AD neuropathy and cognitive impairment (Ando et al., 2016 ). In previous studies, we found that anesthesia with 3% sevoflurane administered twice daily for three days could cause neurotoxicity and cognitive impairment in neonatal mice (starting sevoflurane anesthesia on postnatal day 6 [P6]) but not in adult mice (starting sevoflurane anesthesia on postnatal day 60 [P60]), implying that abnormal Tau phosphorylation in the developing brain could be a key cause of anesthesia‐induced cognitive impairment (Yang et al., 2020 ; Yu et al., 2020 ). However, the mechanism through which sevoflurane‐induced Tau phosphorylation causes cognitive impairment in neonatal mice is unclear.…”