Ketamine inhibits neuronal differentiation by regulating brain-derived neurotrophic factor (BDNF) signaling.

Ketamine is widely used in pediatric anesthesia, perioperative sedation, and analgesia. Knowledge of anesthesia neurotoxicity in humans is currently limited by the difficulty of obtaining neurons and performing developmental toxicity studies in fetal and pediatric populations. However, mouse embryonic stem cells (mESCs) derived from embryos at the preimplantation stage demonstrate an unlimited ability to self-renew and generate different cell types and are a valuable tool for clinical research. Thus, in this study, a model was employed to investigate the mechanism by which ketamine (200 nM) influences the neuronal differentiation of mESCs. Mouse ESCs were treated with an anesthetic dose of ketamine, and neuronal differentiation was significantly inhibited on day 5. Downregulation of brain-derived neurotrophic factor (BDNF) by shRNA was found to have the same inhibitory effect. Furthermore, a rescue experiment indicated that BDNF overexpression markedly restored the neuronal differentiation inhibited by ketamine in the ketamine/BDNF group on day 5. Taken together, these data suggested that ketamine inhibited the neuronal differentiation of mESCs, possibly by interfering with BDNF. The results of the current study may provide novel ideas for preventing ketamine toxicity in the developing fetus.

Dexmedetomidine improves cardiac function and protects against maladaptive remodeling following myocardial infarction.

Dexmedetomidine (DEX), a highly specific and selective α2 adrenergic receptor agonist, has been demonstrated to possess potential cardioprotective effects. However, the mechanisms underlying this process remain to be fully illuminated. In the present study, a myocardial infarction (MI) animal model was generated by permanently ligating the left anterior descending coronary artery in mice. Cardiac function and collagen content were evaluated by transthoracic echocardiography and picrosirius red staining, respectively. Apoptosis was determined by the relative expression levels of Bax and Bcl­2 and the myocardial caspase­3 activity. Additionally, nicotinamide adenine dinucleotide phosphate oxidase (NOX)­derived oxidative stress was evaluated by the relative expression of Nox2 and Nox4, along with the myocardial contents of malondialdehyde (MDA) and superoxide dismutase (SOD) activity. It was demonstrated that intraperitoneal DEX treatment (20 µg/kg/day) improved the systolic function of the left ventricle, and decreased the fibrotic changes in post­myocardial infarction mice, which was paralleled by a decrease in the levels of apoptosis. Subsequent experiments indicated that the restoration of redox signaling was achieved by DEX administration, and the over­activation of NOXs, including Nox2 and Nox4, was markedly inhibited. In conclusion, this present study suggested that DEX was cardioprotective and limited the excess production of NOX­derived ROS in ischemic heart disease, implying that DEX is a promising novel drug, especially for patients who have suffered MI.

Specific detection of hypochlorite based on the size-selective effect of luminophore integrated MOF-801 synthesized by a one-pot strategy.

Hypochlorous acid (HClO), as one of the reactive oxygen species, plays a key role in a variety of physiological and pathological processes, while its accurate and specific in vitro monitoring remains a profound challenge. Herein, a novel luminescent metal-organic framework with high chemical stability has been designed for the specific detection of intracellular ClO-. The specificity was realized by the size-selective effect of MOF-801 with an ultra-small aperture, which can inhibit the entry of large-sized interferents into the cages of MOFs. A universal "ship in a bottle" approach has been proposed to construct this novel sensory platform, in which a large class of luminescent molecules containing carboxylic groups serve as modulators and combine with Zr6 clusters, eventually becoming the luminescent genes of these novel designed MOF-801. Luminescent molecules were readily locked in the framework since they were larger than the small pore entrance of MOF-801, skillfully solving the possible issue of dye leakage. By introducing active sites of 5-aminofluorescein (AF) into MOF-801 (AF@MOF-801) as an example, an excellent ClO- sensing probe was fabricated, which showed strong reliability and excellent sensing performance toward intracellular ClO- with an ultrahigh linear correlation of the Stern-Volmer equation, a rapid response time as short as 30 s and a limit of detection (LOD) as low as 0.05172 µM. Compared with the free AF molecular probe, the specificity of AF@MOF-801 NPs toward ClO- was scarcely affected by other possibly coexistent large-sized interferents in biosystems. The in vitro monitoring of ClO- was also tested with these newly developed AF@MOF-801 NPs, prefiguring their great promise as a robust imaging tool to disclose the complexities of ClO- homeostasis and its pathophysiological contributions.

Clinical efficacy of xenon versus propofol: A systematic review and meta-analysis.

BACKGROUND: Interest in the anesthetic use of xenon, a noble gas, has waxed and waned for decades, and the clinical effects of xenon are still debated. We performed a meta-analysis to compare the clinical efficacy of xenon with that of propofol. METHODS: Electronic searches were performed through December 2017 using various databases, including PubMed, Embase, and the Cochrane Library. We identified thirteen trials that included a total of 817 patients. RESULTS: Patients treated with xenon had a lower bispectral index (BIS) (weighted mean difference (WMD): -6.26, 95% confidence interval (CI): -11.33 to -1.18, P = .02), a higher mean arterial blood pressure (MAP) (WMD: 7.00, 95% CI: 2.32-11.68, P = .003) and a lower heart rate (HR) (WMD: -9.45, 95% CI: -12.28 to -6.63, P < 0.00001) than propofol-treated patients. However, there were no significant differences between the 2 treatment groups in the effects of nondepolarizing muscular relaxants, the duration spent in the postanesthesia care unit (PACU) (WMD: -0.94, 95% CI: -8.79-6.91, P = .81), or the incidence of perioperative complications [assessed using the outcomes of postoperative nausea and vomiting (PONV) (relative risk (RR): 2.01, 95% CI: 0.79-5.11, P = .14), hypotension (RR: 0.62, 95% CI: 0.27 to 1.40, P = .25), hypertension (RR: 1.27, 95% CI: 0.73-2.21, P = .39) and bradycardia (RR: 1.00, 95% CI: 0.36-2.74, P = 1.00)]. CONCLUSION: In this meta-analysis of randomized controlled trials, we found that xenon treatment resulted in a higher MAP, a lower HR, and a smaller BIS index than treatment with propofol.

Consciousness loss during epileptogenesis: implication for VLPO-PnO circuits.

There is a growing concern about consciousness loss during epileptic seizures. Understanding neural mechanisms could lead to a better comprehension of cerebral circuit function in the control of consciousness loss in intractable epilepsy. We propose that ventrolateral preoptic area (VLPO)- PnO (nucleus pontis oralis) circuits may serve a major role in the loss of consciousness in drug-refractory epilepsy. Future behavioural and neuroimaging studies are clearly needed to understand the functional connectivity between the VLPO and PnO during loss of consciousness in drug-refractory epilepsy, to greatly prevent unconsciousness in this disorder and improve the quality of life in patients with intractable epilepsy.

Tanshinone IIA Attenuates Sevoflurane Neurotoxicity in Neonatal Mice.

BACKGROUND: Sevoflurane is the most widely used inhalational anesthetic in pediatric medicine. Despite this, sevoflurane has been reported to exert potentially neurotoxic effects on the developing brain. Clinical interventions and treatments for these effects are limited. Tanshinone IIA (Tan IIA), extracted from Salvia miltiorrhiza (Danshen), has been documented to alleviate cognitive decline in traditional applications. Therefore, we hypothesized that preadministration of Tan IIA may attenuate sevoflurane-induced neurotoxicity, suggesting that Tan IIA is a new and promising drug capable of counteracting the effects of cognitive dysfunction produced by general anesthetics. METHODS: To test this hypothesis, neonatal C57 mice (P6) were exposed to 3% sevoflurane for 2 hours with or without Tan IIA pretreatment at a dose of 10 mg/kg or 20 mg/kg for 3 consecutive days. Cognitive behavior tests such as open field tests and fear conditioning were performed to evaluate locomotor and cognitive function at P31 and P32. At P8, other separate tests, including TdT mediated dUTP Nick End Labeling (TUNEL) assay, immunohistochemistry, Western blotting, enzyme-linked immunosorbent assay, and electron microscopy, were performed. The mean differences among groups were compared using 1-way analysis of variance followed by Bonferroni post hoc multiple comparison tests. RESULTS: Repeated exposure to sevoflurane leads to significant cognitive impairment in mice, which may be explained by increased apoptosis, overexpression of neuroinflammatory markers, and changes in synaptic ultrastructure. Interestingly, preadministration of Tan IIA ameliorated these neurocognitive deficits, as shown by increased freezing percentages on the fear conditioning test (sevoflurane+Tan IIA [20 mg/kg] versus sevoflurane, mean difference, 19, 99% confidence interval for difference, 6.4-31, P < .0001, n = 6). The treatment also reduced the percentage of TUNEL-positive nuclei (sevoflurane versus sevoflurane+Tan IIA [20 mg/kg], 2.6, 0.73-4.5, P = .0004, n = 6) and the normalized expression of cleaved caspase-3 (sevoflurane versus sevoflurane+Tan IIA [20 mg/kg], 0.27, 0.02-0.51, P = .0046, n = 5). Moreover, it attenuated the production of the neuroinflammatory mediators interleukin (IL)-1ß and IL-6 (normalized sevoflurane versus sevoflurane+Tan IIA [20 mg/kg]: IL-1ß: 0.75, 0.47-1.0; P < .0001; IL-6: 0.66, 0.35-0.97; P < .0001; n = 10 per group). Finally, based on measurements of postsynaptic density, the treatment preserved synaptic ultrastructure (sevoflurane+Tan IIA [20 mg/kg] versus sevoflurane, 42, 20-66; P < .0001; n = 12 per group). CONCLUSIONS: These results indicate that Tan IIA can alleviate sevoflurane-induced neurobehavioral abnormalities and may decrease neuroapoptosis and neuroinflammation.

Docosahexaenoic Acid Rescues Synaptogenesis Impairment and Long-Term Memory Deficits Caused by Postnatal Multiple Sevoflurane Exposures.

Sevoflurane exposures were demonstrated to induce neurotoxicity in the developing brain in both human and animal studies. However, there is no effective approach to reverse it. The present study aimed to evaluate the feasibility of utilizing docosahexaenoic acid (DHA) to prevent sevoflurane-induced neurotoxicity. P6 (postnatal 6 days) mice were administrated DHA after exposure to 3% sevoflurane for two hours daily in three consecutive days. Molecular expressions of synaptic makers (PSD95, synaptophysin) and synaptic morphological changes were investigated by Western blot analysis and transmission electron microscopy, respectively. Meanwhile, Morris water maze test was used to assess spatial memory of mice at P31 (postnatal 31 days). DHA restored sevoflurane-induced decreased level of PSD95 and synaptophysin expressions and increased PSD areas and also improved long-term spatial memory. These results suggest that DHA could rescue synaptogenesis impairment and long-term memory deficits in postnatal caused by multiple sevoflurane exposures.

Isoflurane Is More Deleterious to Developing Brain Than Desflurane: The Role of the Akt/GSK3ß Signaling Pathway.

Demand is increasing for safer inhalational anesthetics for use in pediatric anesthesia. In this regard, researchers have debated whether isoflurane is more toxic to the developing brain than desflurane. In the present study, we compared the effects of postnatal exposure to isoflurane with those of desflurane on long-term cognitive performance and investigated the role of the Akt/GSK3ß signaling pathway. Postnatal day 6 (P6) mice were exposed to either isoflurane or desflurane, after which the phosphorylation levels of Akt/GSK3ß and learning and memory were assessed at P8 or P31. The phosphorylation levels of Akt/GSK3ß and learning and memory were examined after intervention with lithium. We found that isoflurane, but not desflurane, impaired spatial learning and memory at P31. Accompanied by behavioral change, only isoflurane decreased p-Akt (ser473) and p-GSK3ß (ser9) expressions, which led to GSK3ß overactivation. Lithium prevented GSK3ß overactivation and alleviated isoflurane-induced cognitive deficits. These results suggest that isoflurane is more likely to induce developmental neurotoxicity than desflurane in context of multiple exposures and that the Akt/GSK3ß signaling pathway partly participates in this process. GSK3ß inhibition might be an effective way to protect against developmental neurotoxicity.

Sevoflurane induces tau phosphorylation and glycogen synthase kinase 3ß activation in young mice.

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. The authors therefore assessed the effects of sevoflurane on Tau phosphorylation and the underlying mechanisms in young mice. METHODS: Six-day-old wild-type and Tau knockout mice were exposed to sevoflurane. The authors determined the effects of sevoflurane anesthesia on Tau phosphorylation, levels of the kinases and phosphatase related to Tau phosphorylation, interleukin-6 and postsynaptic density protein-95 in hippocampus, and cognitive function in both young wild-type and Tau knockout mice. RESULTS: Anesthesia with 3% sevoflurane 2 h daily for 3 days induced Tau phosphorylation (257 vs. 100%, P = 0.0025, n = 6) and enhanced activation of glycogen synthase kinase 3ß, which is the kinase related to Tau phosphorylation in the hippocampus of postnatal day-8 wild-type mice. The sevoflurane anesthesia decreased hippocampus postsynaptic density protein-95 levels and induced cognitive impairment in the postnatal day-31 mice. Glycogen synthase kinase 3ß inhibitor lithium inhibited the sevoflurane-induced glycogen synthase kinase 3ß activation, Tau phosphorylation, increased levels of interleukin-6, and cognitive impairment in the wild-type young mice. Finally, the sevoflurane anesthesia did not induce an increase in interleukin-6 levels, reduction in postsynaptic density protein-95 levels in hippocampus, or cognitive impairment in Tau knockout young mice. CONCLUSIONS: These data suggested that sevoflurane induced Tau phosphorylation, glycogen synthase kinase 3ß activation, increase in interleukin-6 and reduction in postsynaptic density protein-95 levels in hippocampus of young mice, and cognitive impairment in the mice. Future studies will dissect the cascade relation of these effects.

Upregulation of miR-370 contributes to the progression of gastric carcinoma via suppression of FOXO1.

FOXO1 is downregulated in a number of cancers. However, the underlying mechanisms are poorly understood. In this study, we report that the expression of miR-370 was upregulated in gastric cancer cell lines and gastric cancer tissues. Overexpression of miR-370 in gastric cancer cells promoted the cell proliferation and anchorage-independent growth, while silencing of miR-370 showed opposite effects. miR-370-induced proliferation was correlated with the downregulation of cyclin-dependent kinase inhibitors, p27(Kip1) and p21(Cip1), and the upregulation of the cell cycle regulator cyclin D1. Furthermore, we identified that FOXO1 is the functional target of miR-370. Restored expression of FOXO1 together with miR-370 strongly abrogated miR-370-induced cell proliferation. Taken together, our results revealed a novel mechanism of FOXO1 suppression mediated by miR-370 in gastric cancer.