Dual-phase nano-glass-hydrides overcome the strength-ductility trade-off and magnetocaloric bottlenecks of rare earth based amorphous alloys.

Metal-hydrogen systems have attracted intense interest for diverse energy-related applications. However, metals usually reduce their ductility after hydrogenation. Here, we show that hydrogen can take the form of nano-sized ordered hydrides (NOH) homogeneously dispersed in a stable glassy shell, leading to remarkable enhancement in both strength and ductility. The yield strength is enhanced by 44% and the plastic strain is substantially improved from almost zero to over 70%, which is attributed to the created NOH and their interplay with the glassy shell. Moreover, the hydride-glass composite GdCoAlH possesses a giant magnetic entropy change (-ΔSM) of 18.7 J kg-1K-1 under a field change of 5 T, which is 105.5% larger than the hydrogen-free sample and is the largest value among amorphous alloys and related composites. The prominent ΔSM-ductility combination overcomes the bottlenecks of amorphous alloys as magnetic refrigerants. These results provide a promising strategy for property breakthrough of structural-functional alloys.

Differences in the EEG Power Spectrum and Cross-Frequency Coupling Patterns between Young and Elderly Patients during Sevoflurane Anesthesia.

Electroencephalography (EEG) is widely used for monitoring the depth of anesthesia in surgical patients. Distinguishing age-related EEG features under general anesthesia will help to optimize anesthetic depth monitoring during surgery for elderly patients. This retrospective cohort study included 41 patients aged from 18 to 79 years undergoing noncardiac surgery under general anesthesia. We compared the power spectral signatures and phase-amplitude coupling patterns of the young and elderly groups under baseline and surgical anesthetic depth. General anesthesia by sevoflurane significantly increased the spectral power of delta, theta, alpha, and beta bands and strengthened the cross-frequency coupling both in young and elderly patients. However, the variation in EEG power spectral density and the modulation of alpha amplitudes on delta phases was relatively weaker in elderly patients. In conclusion, the EEG under general anesthesia using sevoflurane exhibited similar dynamic features between young and elderly patients, and the weakened alteration of spectral power and cross-frequency coupling patterns could be utilized to precisely quantify the depth of anesthesia in elderly patients.

Effects of intra-operative administration of subanesthetic s-ketamine on emergence from sevoflurane anesthesia: a randomized double-blind placebo-controlled study.

BACKGROUND: Ketamine is administered in the perioperative period for its benefits in analgesia, anti-agitation and anti-depression when administered at a small dose. However, it is not clear whether the intra-operative administration of ketamine would affect emergence under sevoflurane anesthesia. To investigate this effect, we designed this trial. METHODS: In this randomized, double-blind, placebo-controlled study, we enrolled 44 female patients aged 18-60 who were scheduled to elective laparoscopic gynecological surgeries. All patients were randomly assigned to saline or s-ketamine group. In s-ketamine group, patients received 0.125 mg/kg s-ketamine 30 min after the start of surgery. In saline group, patients were administered the same volume of saline. Sevoflurane and remifentanil were used to maintain general anesthesia. The primary outcome was emergence time. We also assessed postoperative agitation, cognitive function, and delirium. In addition, we collected and analyzed prefrontal electroencephalogram (EEG) during and after general anesthesia. RESULTS: There were no significant differences in emergence time between s-ketamine group and saline group (10.80 ± 3.77 min vs. 10.00 ± 2.78 min, P = 0.457). Neither postoperative agitation (4 [3, 4] vs. 4 [3, 4], P = 0.835) nor cognitive function (25.84 ± 2.69 vs. 25.55 ± 2.19, P = 0.412) differed between groups. No postoperative delirium was observed in either group. Subanesthetic s-ketamine resulted in active EEG with decreased power of slow (-0.35 ± 1.13 dB vs. -1.63 ± 1.03 dB, P = 0.003), delta (-0.22 ± 1.11 dB vs. -1.32 ± 1.09 dB, P = 0.011) and alpha (-0.31 ± 0.71 dB vs. -1.71 ± 1.34 dB, P = 0.0003) waves and increased power of beta-gamma bands (-0.30 ± 0.89 dB vs. 4.20 ± 2.08 dB, P < 0.0001) during sevoflurane anesthesia, as well as an increased alpha peak frequency (-0.16 ± 0.48 Hz vs. 0.31 ± 0.73 Hz, P = 0.026). EEG patterns did not differ during the recovery period after emergence between groups. CONCLUSION: Ketamine administered during sevoflurane anesthesia had no apparent influence on emergence time in young and middle-aged female patients undergoing laparoscopic surgery. Subanesthetic s-ketamine induced an active prefrontal EEG pattern during sevoflurane anesthesia but did not raise neurological side effects after surgery. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100046479 (date: 16/05/2021).

Orexinergic innervations at GABAergic neurons of the lateral habenula mediates the anesthetic potency of sevoflurane.

AIMS: The circuitry mechanism associated with anesthesia-induced unconsciousness is still largely unknown. It has been reported that orexinergic neurons of the lateral hypothalamus (LHA) facilitate the emergence from anesthesia through their neuronal projections to the arousal-promoting brain areas. However, the lateral habenula (LHb), as one of the orexin downstream targets, is known for its anesthesia-promoting effect. Therefore, the current study aimed to explore whether and how the orexinergic projections from the LHA to the LHb have a regulatory effect on unconsciousness induced by general anesthesia. METHODS: We applied optogenetic, chemogenetic, or pharmacological approaches to regulate the orexinergicLHA-LHb pathway. Fiber photometry was used to assess neuronal activity. Loss or recovery of the righting reflex was used to evaluate the induction or emergence time of general anesthesia. The burst-suppression ratio and electroencephalography spectra were used to measure the anesthetic depth. RESULTS: We found that activation of the orexinergicLHA-LHb pathway promoted emergence and reduced anesthetic depth during sevoflurane anesthesia. Surprisingly, the arousal-promoting effect of the orexinergicLHA-LHb pathway was mediated by excitation of glutamate decarboxylase (GAD2)-expressing neurons, but not glutamatergic neurons in the LHb. CONCLUSION: The orexinergicLHA-LHb pathway facilitates emergence from sevoflurane anesthesia, and this effect was mediated by OxR2 in GAD2-expressing GABA neurons.

Combined-Acupoint Electroacupuncture Induces Better Analgesia via Activating the Endocannabinoid System in the Spinal Cord.

Electroacupuncture (EA) therapy has been widely reported to alleviate neuropathic pain with few side effects in both clinical practice and animal studies worldwide. However, little is known about the comparison of the therapeutic efficacy among the diverse EA schemes used for neuropathic pain. The present study is aimed at investigating the therapeutic efficacy discrepancy between the single and combined-acupoint EA and to reveal the difference of mechanisms behind them. Electroacupuncture was given at both Zusanli (ST36) and Huantiao (GB30) in the combined group or ST36 alone in the single group. Paw withdrawal mechanical threshold (PWMT) was measured to determine the pain level. Electrophysiology was performed to detect the effects of EA on synaptic transmission in the spinal dorsal horn of the vGlut2-tdTomato mice. Spinal contents of endogenous opioids, endocannabinoids, and their receptors were examined. Inhibitors of CBR (cannabinoid receptor) and opioid receptors were used to study the roles of opioid and endocannabinoid system (ECS) in EA analgesia. We found that combined-acupoint acupuncture provide stronger analgesia than the single group did, and the former inhibited the synaptic transmission at the spinal level to a greater extent than later. Besides, the high-intensity stimulation at ST36 or normal stimulation at two sham acupoints did not mimic the similar efficacy of analgesia in the combined group. Acupuncture stimulation in single and combined groups both activated the endogenous opioid system. The ECS was only activated in the combined group. Naloxone totally blocked the analgesic effect of single-acupoint EA; however, it did not attenuate that of combined-acupoint EA unless coadministered with CBR antagonists. Hence, in the CCI-induced neuropathic pain model, combined-acupoint EA at ST36 and GB30 is more effective in analgesia than the single-acupoint EA at ST36. EA stimulation at GB30 alone neither provided a superior analgesic effect to EA treatment at ST36 nor altered the content of AEA, 2-AG, CB1 receptor, or CB2 receptor compared with the CCI group. Activation of the ECS is the main contributor of the better analgesia by the combined acupoint stimulation than that induced by single acupoint stimulation.

Estrogen Receptor-A in Medial Preoptic Area Contributes to Sex Difference of Mice in Response to Sevoflurane Anesthesia.

A growing number of studies have identified sex differences in response to general anesthesia; however, the underlying neural mechanisms are unclear. The medial preoptic area (MPA), an important sexually dimorphic structure and a critical hub for regulating consciousness transition, is enriched with estrogen receptor alpha (ERα), particularly in neuronal clusters that participate in regulating sleep. We found that male mice were more sensitive to sevoflurane. Pharmacological inhibition of ERα in the MPA abolished the sex differences in sevoflurane anesthesia, in particular by extending the induction time and facilitating emergence in males but not in females. Suppression of ERα in vitro inhibited GABAergic and glutamatergic neurons of the MPA in males but not in females. Furthermore, ERα knockdown in GABAergic neurons of the male MPA was sufficient to eliminate sex differences during sevoflurane anesthesia. Collectively, MPA ERα positively regulates the activity of MPA GABAergic neurons in males but not in females, which contributes to the sex difference of mice in sevoflurane anesthesia.

Esketamine increases neurotransmitter releases but simplifies neurotransmitter networks in mouse prefrontal cortex.

General anesthesia induces a profound but reversible unconscious state, which is accompanied by changes in various neurotransmitters in the cortex. Unlike the "brain silencing" effect of γ-aminobutyric acid (GABA) receptor potentiator anesthesia, ketamine anesthesia leads the brain to a paradoxical active state with higher cortical activity, which is manifested as dissociative anesthesia. However, how the overall neurotransmitter network evolves across conscious states after ketamine administration remains unclear. Using in vivo microdialysis, high-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis, and electroencephalogram (EEG) recording technique, we continuously measured the concentrations of six neurotransmitters and the EEG signals during anesthesia with esketamine, an S-enantiomer of ketamine racemate. We found that there was an increase in the release of five cortical neurotransmitters after the administration of esketamine. The correlation of cortical neurotransmitters was dynamically simplified along with behavioral changes until full recovery after anesthesia. The esketamine-increased gamma oscillation power was positively correlated only with the concentration of 5-hydroxytryptamine (5-HT) in the medial prefrontal cortex. This study suggests that the transformation of the neurotransmitter network rather than the concentrations of neurotransmitters could be more indicative of the consciousness shift during esketamine anesthesia.NEW & NOTEWORTHY In this study, we found that esketamine significantly increased the cortical concentration of multiple neurotransmitters in mice. However, esketamine dynamically simplified the overall network of cortical neurotransmitters at different behavioral states during the perianesthesia period. The concentration of 5-HT in the medial prefrontal cortex (mPFC) was highly correlated with the esketamine-increased gamma oscillation. These findings suggested that the transformation of the neurotransmitter network rather than the concentrations of neurotransmitters could be more indicative of the consciousness shift during esketamine anesthesia.

De novo Lipogenesis in Astrocytes Promotes the Repair of Blood-Brain Barrier after Transient Cerebral Ischemia Through Interleukin-33.

Astrocytes experience significant metabolic shifts in the "sensitive period" of neurological function recovery following cerebral ischemia. However, the changes in astrocyte lipid metabolism and their implications for neurological recovery remain unknown. In the present study, we employed a mouse middle cerebral artery occlusion model to investigate the changes in de novo lipogenesis and interleukin-33 (IL-33) production in astrocytes and elucidate their role in blood-brain barrier (BBB) repair in the subacute phase of cerebral ischemia. Neurological behavior evaluation was used to assess functional changes in mice. Pharmacological inhibition and astrocyte-specific downregulation of fatty acid synthase (FASN) were used to evaluate the role of de novo lipogenesis in brain injury. Intracerebroventricular administration of recombinant IL-33 was performed to study the contribution of IL-33 to BBB disruption. Extravasation of Evans blue dye, dextran and IgG were used to assess BBB integrity. Western blotting of tight junction proteins ZO-1, Occludin, and Claudin-5 were performed at defined time points to evaluate changes in BBB. It was found that de novo lipogenesis was activated, and IL-33 production increased in astrocytes at the subacute stage of cerebral ischemia injury. Inhibition of lipogenesis in astrocytes decreased IL-33 production in the peri-infarct area, deteriorated BBB damage and interfered with neurological recovery. In addition, supplementation of IL-33 alleviated BBB destruction and improved neurological recovery worsened by lipogenesis inhibition. These findings indicate that astrocyte lipogenesis increases the production of IL-33 in the peri-infarct area, which promotes BBB repair in the subacute phase of cerebral ischemia injury and improves long-term functional recovery.

Neural Substrates for the Regulation of Sleep and General Anesthesia.

General anesthesia has been successfully used in clinics for over 170 years, but its mechanisms of effect remain unclear. Behaviorally, general anesthesia is similar to sleep as it produces a reversible transition between wakefulness and the state of being unaware of one's surroundings. A discussion regarding the common circuits of sleep and general anesthesia has been ongoing as an increasing number of sleep-arousal regulatory nuclei are reported to participate in the consciousness shift occurring during general anesthesia. Recently, with progress in research technology, both positive and negative evidence for overlapping neural circuits between sleep and general anesthesia has emerged. This article provides a review of the latest evidence on the neural substrates for sleep and general anesthesia regulation by comparing the roles of pivotal nuclei in sleep and anesthesia.

Sevoflurane preconditioning protects experimental ischemic stroke by enhancing anti-inflammatory microglia/macrophages phenotype polarization through GSK-3ß/Nrf2 pathway.

AIMS: Sevoflurane preconditioning (SPC) results in cerebral ischemic tolerance; however, the mechanism remains unclear. Promoting microglia/macrophages polarization from pro-inflammatory state to anti-inflammatory phenotype has been indicated as a potential treatment target against ischemic stroke. In this study, we aimed to assess the effect of SPC on microglia polarization after stroke and which signaling pathway was involved in this transition. METHODS: Mouse primary microglia with SPC were challenged by oxygen-glucose deprivation (OGD) or lipopolysaccharide (LPS), and mice with SPC were subjected to middle cerebral artery occlusion (MCAO). Then, the mRNA and protein levels of pro-inflammatory/anti-inflammatory factors were analyzed. GSK-3ß phosphorylation and Nrf2 nuclear translocation were measured. The mRNA and protein expression of pro-inflammatory/anti-inflammatory factors, neurological scores, infarct volume, cellular apoptosis, the proportion of pro-inflammatory/anti-inflammatory microglia/macrophages, and the generation of super-oxidants were examined after SPC or GSK-3ß inhibitor TDZD treatment with or without Nrf2 deficiency. RESULTS: Sevoflurane preconditioning promoted anti-inflammatory and inhibited pro-inflammatory microglia/macrophages phenotype both in vitro and in vivo. GSK-3ß phosphorylation at Ser9 was increased after SPC. Both SPC and TDZD administration enhanced Nrf2 nuclear translocation, reduced pro-inflammatory microglia/macrophages markers expression, promoted anti-inflammatory markers level, and elicited a neuroprotective effect. Nrf2 deficiency abolished the promoted anti-inflammatory microglia/macrophages polarization and ischemic tolerance induced by TDZD treatment. The reduced percentage of pro-inflammatory positive cells and super-oxidants generation induced by SFC or TDZD was also reversed by Nrf2 knockdown. CONCLUSIONS: Our results indicated that SPC exerts brain ischemic tolerance and promotes anti-inflammatory microglia/macrophages polarization by GSK-3ß-dependent Nrf2 activation, which provides a novel mechanism for SPC-induced neuroprotection.

Activation of Orexinergic Neurons Inhibits the Anesthetic Effect of Desflurane on Consciousness State via Paraventricular Thalamic Nucleus in Rats.

BACKGROUND: Orexin, a neuropeptide derived from the perifornical area of the hypothalamus (PeFLH), promotes the recovery of propofol, isoflurane, and sevoflurane anesthesias, without influencing the induction time. However, whether the orexinergic system also plays a similar role in desflurane anesthesia, which is widely applied in clinical practice owing to its most rapid onset and offset time among all volatile anesthetics, has not yet been studied. In the present study, we explored the effect of the orexinergic system on the consciousness state induced by desflurane anesthesia. METHODS: The c-Fos staining was used to observe the activity changes of orexinergic neurons in the PeFLH and their efferent projection regions under desflurane anesthesia. Chemogenetic and optogenetic techniques were applied to compare the effect of PeFLH orexinergic neurons on the induction, emergence, and maintenance states between desflurane and isoflurane anesthesias. Orexinergic terminals in the paraventricular thalamic nucleus (PVT) were manipulated with pharmacologic, chemogenetic, and optogenetic techniques to assess the effect of orexinergic circuitry on desflurane anesthesia. RESULTS: Desflurane anesthesia inhibited the activity of orexinergic neurons in the PeFLH, as well as the neuronal activity in PVT, basal forebrain, dorsal raphe nucleus, and ventral tegmental area, as demonstrated by c-Fos staining. Activation of PeFLH orexinergic neurons prolonged the induction time and accelerated emergence from desflurane anesthesia but only influenced the emergence in isoflurane anesthesia, as demonstrated by chemogenetic and pharmacologic techniques. Meanwhile, optical activation of orexinergic neurons exhibited a long-lasting inhibitory effect on burst-suppression ratio (BSR) under desflurane anesthesia, and the effect may be contributed by the orexinergic PeFLH-PVT circuitry. The orexin-2 receptor (OX2R), but not orexin-1 receptor (OX1R), in the PVT, which had been inhibited most significantly by desflurane, mediated the proemergence effect of desflurane anesthesia. CONCLUSIONS: We discovered, for the first time, that orexinergic neurons in the PeFLH could not only influence the maintenance and emergence from isoflurane and desflurane anesthesias but also affect the induction under desflurane anesthesia. Furthermore, this specific effect is probably mediated by orexinergic PeFLH-PVT circuitry, especially OX2Rs in the PVT.

An MD2-perturbing peptide has therapeutic effects in rodent and rhesus monkey models of stroke.

Studies have failed to translate more than 1000 experimental treatments from bench to bedside, leaving stroke as the second leading cause of death in the world. Thrombolysis within 4.5 hours is the recommended therapy for stroke and cannot be performed until neuroimaging is used to distinguish ischemic stroke from hemorrhagic stroke. Therefore, finding a common and critical therapeutic target for both ischemic and hemorrhagic stroke is appealing. Here, we report that the expression of myeloid differentiation protein 2 (MD2), which is traditionally regarded to be expressed only in microglia in the normal brain, was markedly increased in cortical neurons after stroke. We synthesized a small peptide, Trans-trans-activating (Tat)-cold-inducible RNA binding protein (Tat-CIRP), which perturbed the function of MD2 and strongly protected neurons against excitotoxic injury in vitro. In addition, systemic administration of Tat-CIRP or genetic deletion of MD2 induced robust neuroprotection against ischemic and hemorrhagic stroke in mice. Tat-CIRP reduced the brain infarct volume and preserved neurological function in rhesus monkeys 30 days after ischemic stroke. Tat-CIRP efficiently crossed the blood-brain barrier and showed a wide therapeutic index for stroke because no toxicity was detected when high doses were administered to the mice. Furthermore, we demonstrated that MD2 elicited neuronal apoptosis and necroptosis via a TLR4-independent, Sam68-related cascade. In summary, Tat-CIRP provides robust neuroprotection against stroke in rodents and gyrencephalic nonhuman primates. Further efforts should be made to translate these findings to treat both ischemic and hemorrhagic stroke in patients.

Dorsal raphe serotonergic neurons promote arousal from isoflurane anesthesia.

AIMS: General anesthesia has been widely applied in surgical or nonsurgical medical procedures, but the mechanism behind remains elusive. Because of shared neural circuits of sleep and anesthesia, whether serotonergic system, which is highly implicated in modulation of sleep and wakefulness, regulates general anesthesia as well is worth investigating. METHODS: Immunostaining and fiber photometry were used to assess the neuronal activities. Electroencephalography spectra and burst-suppression ratio (BSR) were used to measure anesthetic depth and loss or recovery of righting reflex to indicate the induction or emergence time of general anesthesia. Regulation of serotonergic system was achieved through optogenetic, chemogenetic, or pharmacological methods. RESULTS: We found that both Fos expression and calcium activity were significantly decreased during general anesthesia. Activation of 5-HT neurons in the dorsal raphe nucleus (DRN) decreased the depth of anesthesia and facilitated the emergence from anesthesia, and inhibition deepened the anesthesia and prolonged the emergence time. Furthermore, agonism or antagonism of 5-HT 1A or 2C receptors mimicked the effect of manipulating DRN serotonergic neurons. CONCLUSION: Our results demonstrate that 5-HT neurons in the DRN play a regulative role of general anesthesia, and activation of serotonergic neurons could facilitate emergence from general anesthesia partly through 5-HT 1A and 2C receptors.

Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Modulate the Anesthetic Potency of Isoflurane in Mice.

The lateral hypothalamic area (LHA) plays a pivotal role in regulating consciousness transition, in which orexinergic neurons, GABAergic neurons, and melanin-concentrating hormone neurons are involved. Glutamatergic neurons have a large population in the LHA, but their anesthesia-related effect has not been explored. Here, we found that genetic ablation of LHA glutamatergic neurons shortened the induction time and prolonged the recovery time of isoflurane anesthesia in mice. In contrast, chemogenetic activation of LHA glutamatergic neurons increased the time to anesthesia and decreased the time to recovery. Optogenetic activation of LHA glutamatergic neurons during the maintenance of anesthesia reduced the burst suppression pattern of the electroencephalogram (EEG) and shifted EEG features to an arousal pattern. Photostimulation of LHA glutamatergic projections to the lateral habenula (LHb) also facilitated the emergence from anesthesia and the transition of anesthesia depth to a lighter level. Collectively, LHA glutamatergic neurons and their projections to the LHb regulate anesthetic potency and EEG features.

Lateral hypothalamus orexinergic inputs to lateral habenula modulate maladaptation after social defeat stress.

Social stress, a common stressor, causes multiple forms of physical and mental dysfunction. Prolonged exposure to social stress is associated with a higher risk of psychological disorders, including anxiety disorders and major depressive disorder (MDD). The orexinergic system is involved in the regulation of multiple motivated behaviors. The current study examined the regulatory effect of orexinergic projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) in depression- and anxiety-like behaviors after chronic social defeat stress. When mice were defeated during social interaction, both orexinergic neurons in the LHA and glutamatergic neurons in the LHb were strongly activated, as indicated by the FosTRAP strategy. Infusion of orexin in the LHb significantly alleviated social avoidance and depression-like behaviors induced by chronic social defeat stress. Administration of an orexin receptor 2 antagonist in the LHb further aggravated the depressive phenotype. Photoactivation of orexinergic cell bodies in the LHA or terminals in the LHb relieved anxiety-like behaviors induced by chronic social defeat stress. Collectively, we identified the antidepressant and anxiolytic effects of the circuit from LHA orexinergic neurons to the LHb in response to chronic social stress, providing new evidence of the antidepressant properties of LHA orexin circuits.

Selective optogenetic activation of orexinergic terminals in the basal forebrain and locus coeruleus promotes emergence from isoflurane anaesthesia in rats.

BACKGROUND: The neuropeptide orexin promotes arousal from general anaesthesia, however the neuronal circuits that mediate this effect have not been defined. We investigated whether orexinergic neurones modulate the basal forebrain (BF) and locus coeruleus (LC) in emergence from anaesthesia. METHODS: Hcrtcre rats were generated using a CRISPR/Cas9-based approach. Viruses encoding optogenetic probes were injected into the perifornical lateral hypothalamic (PeFLH) area, optogenetic fibres were embedded in the PeFLH, BF, or LC, and changes in anaesthesia state under 1.4 vol% or 0.8 vol% isoflurane were determined. RESULTS: In the PeFLH, 98.8% (0.4%) of orexin-A-positive cells expressed tdTomato, and 91.9% (2.2%) of tdTomato cells were orexin-A-positive. Under 1.4 vol% isoflurane anaesthesia, compared with control groups, burst suppression ratio was less, and emergence time was shorter in groups with optogenetic activation of orexinergic cell bodies in the PeFLH (923 [162] vs 493 [68] s, P=0.0003) or orexinergic terminals in the BF (937 (122) vs 674 (108) s, P=0.0049) or LC (913 [128] vs 742 [76] s, P=0.022). Optical stimulation of orexinergic terminals in the BF and LC also improved the movement scores of rats under 0.8 vol% isoflurane anaesthesia. CONCLUSIONS: Activation of orexinergic terminals in the FB or LC mediates facilitation of emergence from anaesthesia by orexinergic neurones during isoflurane anaesthesia.

Genistein Attenuates Acute Cerebral Ischemic Damage by Inhibiting the NLRP3 Inflammasome in Reproductively Senescent Mice.

Postmenopausal women have a higher incidence of stroke compared to the age-matched males, and the estrogen was thought to be the main cause of such difference. However, estrogen replacement therapy for the prevention of postmenopausal stroke shows controversial results and is widely disputed because of its serious side effects after chronic administration. Genistein (Gen), a natural phytestrogen with fewer side effects, has a protective effect against cerebral ischemia damage. However, whether Gen could effectively prevent postmenopausal stroke has not been elucidated. In the current study, reproductively senescent mice were treated with Gen (10 mg/kg) for 2 weeks before having transient cerebral ischemia insults. Neurological scores, infarct volumes, and cell apoptosis were evaluated 24 h after reperfusion. The levels of inflammatory factors and nod-like receptor protein 3 (NLRP3) inflammasome-related proteins were also examined. The results showed that Gen treatment reduced infarct volumes, improved neurological scores, attenuated apoptosis, and decreased inflammatory factor release. The expression of NLRP3 inflammasome-related proteins in microglia was downregulated by Gen. However, the overexpression of NLRP3 in microglia abrogated the Gen-induced inhibition of inflammatory factor release and reversed the neuroprotective effect of Gen. Taken together, the results suggest that Gen treatment could attenuate the acute injury induced by cerebral ischemia in reproductively senescent mice via the inhibition of the NLRP3 inflammasome in microglia, indicating that Gen could be a candidate drug for the treatment of stroke in postmenopausal women.

Inhibition of chemokine CX3CL1 in spinal cord mediates the electroacupuncture-induced suppression of inflammatory pain.

PURPOSE: Chemokine CX3CL1 and its receptor CX3CR1 in the lumbar spinal cord play crucial roles in pain processing. Electroacupuncture (EA) is recognized as an alternative therapy in pain treatment due to its efficacy and safety. However, the analgesic mechanism of EA remains unclear. The aim of this study was to investigate whether EA suppressed complete Freund's adjuvant (CFA)-induced pain via modulating CX3CL1-CX3CR1 pathway. MATERIALS AND METHODS: Inflammatory pain was induced by intraplantar injection of CFA to the left hind paw of Sprague-Dawley rats. EA with 2 Hz for 30 mins was given to bilateral Zusanli acupoints (ST36) on the first and third day after CFA injection. Mechanical allodynia and thermal hyperalgesia were tested with von Frey tests and Hargreaves tests, respectively. The expressions of CX3CL1, CX3CR1 and p38 mitogen-activated protein kinase (MAPK) were quantified with Western blots. The release of IL-1ß, IL-6 and TNF-α were evaluated with ELISA. Recombinant CX3CL1 or control IgG were then injected through intrathecal catheters in the EA-treated CFA model rats. The behavioral tests, p38 MAPK activation and cytokine release were then evaluated. RESULTS: EA significantly inhibited inflammatory pain induced by CFA for 3 days. Meanwhile, EA downregulated the expression of CX3CL1 but not CX3CR1 in the lumbar spinal cord of the CFA rats. Besides, activation of p38 MAPK and the release of pain-related cytokines (IL-1ß, IL-6 and TNF-α) were inhibited by EA. Intrathecal injection of CX3CL1 largely reversed the analgesic effect of EA treatment and re-activated p38 MAPK signaling, and resulted in pro-inflammatory cytokines increase in acupuncture-treated rats. CONCLUSION: Our findings indicate that EA alleviates inflammatory pain via modulating CX3CL1 signaling in lumbar spinal cord, revealing a potential mechanism of anti-nociception of EA in inflammatory pain.