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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

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‐3β 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‐3β 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‐3β 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‐3β‐dependent Nrf2 activation, which provides a novel mechanism for SPC‐induced neuroprotection., SPC promoted microglia/macrophages polarization toward to anti‐inflammatory phenotype in vitro and in vivo. Both SPC and TDZD administration enhanced Nrf2 nuclear translocation.SPC promoted microglia/macrophages toward to anti‐inflammatory phenotype shifting via GSK‐3β‐dependent Nrf2 activation.

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., General anesthesia decreases the activities of serotonergic neurons in the dorsal raphe. Activation of DRN 5‐HT neurons reduced the depth of anesthesia and accelerated the emergence from general anesthesia, partially through the 5‐HT 1A and 2C receptors.

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.

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-1β, 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-1β, 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.

The Bjerknes compensation (BJC) under global warming is studied using a simple box model and a coupled Earth system model. The BJC states the out-of-phase changes in the meridional atmosphere and ocean heat transports. Results suggest that the BJC can occur during the transient period of global warming. During the transient period, the sea ice melting in the high latitudes can cause a significant weakening of the Atlantic meridional overturning circulation (AMOC), resulting in a cooling in the North Atlantic. The meridional contrast of sea surface temperature would be enhanced, and this can eventually enhance the Hadley cell and storm-track activities in the Northern Hemisphere. Accompanied by changes in both ocean and atmosphere circulations, the northward ocean heat transport in the Atlantic is decreased while the northward atmosphere heat transport is increased, and the BJC occurs in the Northern Hemisphere. Once the freshwater influx into the North Atlantic Ocean stops, or the ocean even loses freshwater because of strong heating in the high latitudes, the AMOC would recover. Both the atmosphere and ocean heat transports would be enhanced, and they can eventually recover to the state of the control run, leading to the BJC to become invalid. The above processes are clearly demonstrated in the coupled model CO2 experiment. Since it is difficult to separate the freshwater effect from the heating effect in the coupled model, a simple box model is used to understand the BJC mechanism and freshwater’s role under global warming. In a warming climate, the freshwater flux into the ocean can cool the global surface temperature, mitigating the temperature rise. Box model experiments indicate clearly that it is the freshwater flux into the North Atlantic that causes out-of-phase changes in the atmosphere and ocean heat transports, which eventually plays a stabilizing role in global climate change.

Backgrounds Opinion remains controversial as to whether joint-saving surgery could be safely performed in patients with juxta-articular osteosarcoma. The aim of this study was to assess the validity of adjuvant cryosurgery in joint salvage surgery. Methods We evaluated the oncological and functional outcomes of patients who underwent joint-sparing surgery in which argon-based cryoablation was employed to aid partial epiphysis-preserved tumor resection for osteosarcoma around the knee (7 in proximal tibia, 5 in distal femur). Results The study included 12 patients (5 male, 7 female, mean age 15.8 years (11–24). At a mean follow-up of 48.4 months (38–61), lung metastasis occurred in three patients. Among these, one patient had died, one was alive with disease, and one had no evidence of disease after lobectomy. Histological examination of the resected specimens revealed no viable tumor at the osteotomy plane. There was no local recurrence in the residual epiphysis except one in soft tissue. The mean Musculoskeletal Tumor Society functional score was 92.7%. Conclusions Argon-based cryosurgery is a reliable method of sterilizing the tumor in the epiphysis thus allowing safe joint-saving tumor resection possible in patients with juxta-articular osteosarcoma.

The neuroprotective properties for certain medical gases have been observed for decades, leading to extensive research that has been widely reported and continues to garner interest. Common gases including oxygen, hydrogen, carbon dioxide and nitric oxide, volatile anesthetics such as isoflurane, sevoflurane, halothane, enflurane and desflurane, non-volatile anesthetics such as xenon and nitrous oxide, inert gases such as helium and argon, and even gases classically considered to be toxic (e.g., hydrogen sulfide and carbon monoxide) have all been supported by the evidence alluding to their use as potential neuroprotective agents. A wide range of neural injury types such as ischemic/hemorrhagic, stroke, subarachnoid hemorrhage, traumatic brain injury, perinatal hypoxic-ischemic brain injuries, neurodegenerative disease as well as spinal cord ischemia have been used as platforms for studying the neuroprotective effects of these gases, yet until now, none of the gases has been widely introduced into clinical use specifically for protection against neural injury. Insufficient clinical data together with contradictory paradigms and results further hinders the clinical trials. However, pre-clinical models suggest that despite the various classes of gases and the broad range of injuries to which medical gases confer, protection, several underlying mechanisms for their neuroprotective properties are similar. In this review, we summarize the literature concerning the neuroprotective effect of each gas and its underlying mechanisms, extract common targets reported for the neuroprotective effects of different gases, highlight the conflicting observations from clinical trials and further discuss the possible hindrances impeding clinical applications in order to propose future research perspectives and therapeutic exploitations.

Promoting neural stem/progenitor cell (NSC/NPC) survival in the pro-apoptotic environment is critical to stem cell replacement for neurodegenerative disease therapy. Paeoniflorin (PF), one of the principal bioactive components in Paeoniae Radix, has been used widely in central nervous system (CNS) diseases treatment and serves as an antioxidant to protect neurons against oxidative stress. The present study investigated the protective effects of PF on NPC injury induced by hydrogen peroxide (H₂O₂). After challenge with 200 μM H₂O₂ for 2h, loss of cell viability and excessive apoptotic cell death were observed in cultured NPC, PF treatment conferred protective effects against the loss of cellular viability in a concentration-dependent manner. PF pretreatment also inhibited NPC apoptosis induced by H₂O₂ by reversing the decreased level of Procaspase-3 and balancing Bcl-2 and Bax expression. Furthermore, PF-mediated NPC protection was associated with an increase in phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt-1) phosphorylation in a time- and concentration-dependent manner. Selective inhibition of PI3K using LY294002 abolished PF-mediated phosphorylation of Akt-1 and NPC protection upon oxidative stress. These data suggest that PF-mediated NPC protection on H₂O₂ injury is reliant on the activation of the PI3K/Akt-1 pathway, giving insight to an essential role of PF in NPC protection.

Our previous studies have shown that hyperbaric oxygen preconditioning (HBO-PC) induces tolerance to cerebral ischemia/reperfusion (I/R). This study aimed to investigate whether SirT1, a class III histone deacetylase, is involved in neuroprotection elicited by HBO-PC in animal and cell culture models of ischemia. Rats were subjected to middle cerebral artery occlusion for 120 minutes after HBO-PC (once a day for 5 days). Primary cultured cortical neurons were exposed to 2 hours of HBO-PC after 2 hours of oxygen–glucose deprivation (OGD). We showed that HBO-PC increased SirT1 protein and mRNA expression, promoted neurobehavioral score, reduced infarct volume, and improved morphology at 24 hours and 7 days after cerebral I/R. Neuroprotection of HBO-PC was attenuated by SirT1 inhibitor EX527 and SirT1 knockdown by short interfering RNA (siRNA), whereas it was mimicked by SirT1 activator resveratrol. Furthermore, HBO-PC enhanced SirT1 expression and cell viability and reduced lactate dehydrogenase release 24 hours after OGD/re-oxygenation. The neuroprotective effect of HBO-PC was emulated through upregulating SirT1 and, reversely, attenuated through downregulating SirT1. The modulation of SirT1 was made by adenovirus infection carrying SirT1 or SirT1 siRNA. Besides, SirT1 increased B-cell lymphoma 2 (Bcl-2) expression and decrease cleaved caspase 3. These results indicate that SirT1 mediates HBO-PC-induced tolerance to cerebral I/R through inhibition of apoptosis.

We previously found that ginsenoside Rd (Rd), one of the main active ingredients in Panax ginseng , protects against ischemic brain damage induced by oxygen–glucose deprivation in vitro and middle cerebral artery occlusion (MCAO) in vivo . Considering stroke happens frequently in aged individuals, we herein sought to further define the protective effects of Rd in the aged mice. 16–18-month-old mice administered with Rd (0.1–200 mg/kg) or vehicle were subjected to transient MCAO. Rd at the doses of 10–50 mg/kg significantly reduced both cortical and striatal infarct volume. This protection was associated with an improvement in neurological function and was sustained for at least 2 weeks after the insult. Importantly, Rd was effective even when administered up to 4 h after recirculation. To evaluate the underlying mechanisms, oxidative DNA damage was identified by 8-hydroxy-deoxyguanosine immunostaining, oxidative protein damage was identified by the assessment of protein carbonyl, and lipid peroxidation was estimated by determining the malondialdehyde formation. Rd significantly suppressed the accumulations of DNA, protein and lipid peroxidation products at 24 h post-ischemia. Rd also protected mitochondria at 4 and 24 h after reperfusion as indicated by preserved respiratory chain complex activities and aconitase activity, lowered mitochondrial hydrogen peroxide production, and hyperpolarized mitochondrial membrane potential. Furthermore, Rd partly enhanced endogenous antioxidant activities following MCAO. Collectively, these findings demonstrated that Rd exerts neuroprotection against transient focal ischemia in the aged brain, which may be associated with the attenuation of redox imbalance.

Background Paraplegia is one of the most common complications following aortic aneurismal surgery. The present study examined the hypothesis that neuroprotection of sevoflurane postconditioning (PostC) against spinal cord reperfusion injury is associated with free radicals-mediated up-regulation of antioxidant enzymes in rabbits. Materials and Methods New Zealand White rabbits were subjected to sevoflurane PostC, oxygen (O2), or sham treatment at the onset of spinal cord reperfusion for 10min. Spinal cord ischemia was induced by clamping the aorta both below the left renal artery and above the aortic bifurcation. Forty-eight hours after reperfusion, the motor function of the lower limbs was evaluated and the lumbar spinal cord segment (L5-7) was harvested for histopathologic and biochemical analyses in the presence or absence of N-2-mercaptopropionylglycine, a potent oxygen free radical scavenger. Results Activities of superoxide dismutase and catalase in spinal cord tissue were increased in the sevoflurane PostC group 1h after reperfusion and retained a higher level 6 or 24h after reperfusion. Sevoflurane PostC produced a significant reduction of the malondialdehyde content at 6, 24, and 48h after reperfusion. A 20min continuous administration of N-2-mercaptopropionylglycine starting 10min before the beginning of PostC attenuated the neuroprotective effect against spinal cord ischemia, and reversed the increase of the two enzyme activities in spinal cord tissue induced by sevoflurane PostC. Conclusion An initial oxidative stress, as a trigger to up-regulate the antioxidant enzyme activities, plays an important role in the protection of sevoflurane PostC against spinal cord reperfusion injury.

This study investigates the effects of electroacupuncture (EA) preconditioning on blood-brain barrier (BBB) integrity and matrix metalloproteinase-9 (MMP-9) expression in subsequent ischemic hemisphere.Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in rats. Animals were randomly divided into four groups: normal, sham-operated, MCAO and EA groups. In EA group, rats received electroacupuncture stimuli at the Baihui acupoint (GV 20) 30 minutes/day for 5 days. Twenty-four hours after last treatment, the MCAO was performed. The brain water content and BBB permeability were measured 24 hours after MCAO. MMP-9 expression and activity were measured at 6, 12 and 24 hours after MCAO.The results showed that the brain water content of ischemic hemisphere was lower in EA group (81.45 +/- 1.09%) compared with MCAO group (83.98 +/- 1.30%; p0.05). Similarly, the Evans blue content in EA group (4.90 +/- 1.77 microg/g) was lower compared with MCAO group (9.41 +/- 2.87 microg/g; p0.05). The protein expression and enzyme activity of MMP-9 increased and reached maximum at 24 hours after reperfusion. However, the protein expression was lower in EA group at 12 and 24 hours after reperfusion (p0.01, versus MCAO group), and enzyme activity was lower in EA group only at 24 hours (p0.01, versus MCAO group).EA preconditioning could attenuate brain edema and BBB disruption caused by subsequent cerebral ischemia. EA preconditioning could decrease MMP-9 expression and activity, which may be an important mechanism of cerebral ischemic tolerance.

Recent studies indicate that adiponectin can attenuate cerebral ischemic lesions via its functional area located in the C-terminal globular domain, which is called globular adiponectin (gAD). However, the mechanisms underlying this action remain unclear. In this study, we investigated the antioxidant properties of gAD during cerebral ischemia. Adult male C57BL/6 mice received an intracerebral injection of gAD with or without tetrabromocinnamic acid (TBCA, a NADPH oxidase activator). Mice were subjected to middle cerebral artery occlusion (MCAO) after gAD injection. Infarct volume, neurological function, the activity of antioxidant enzymes (superoxide dismutase [SOD], catalase), the content of malondialdehyde (MDA), and the expression of Bax, Bcl-2, cleaved caspase-3 and NADPH oxidase 2 (NOX2) were examined at 24h after MCAO. Infarct volume was attenuated in gAD-transduced mice when compared with mice in the MCAO group, with significant improvement in neurological function. In addition, neuronal apoptosis was attenuated, along with the expression of Bax/Bcl-2 and cleaved caspase 3. Furthermore, the activities of SOD and catalase increased, and the content of MDA reduced. However, TBCA blocked the effect of gAD on cerebral protection and its antioxidant abilities. Taken together, these results demonstrate that the neuroprotective action of gAD may result from the promotion of antioxidant capacity by inhibiting the NOX2 signaling system.

Background We have previously reported that electroacupuncture (EA) pretreatment induced tolerance against cerebral ischemic injury, but the mechanisms underlying this effect of EA are unknown. In this study, we assessed the effect of EA pretreatment on the expression of α7 nicotinic acetylcholine receptors (α7nAChR), using the ischemia-reperfusion model of focal cerebral ischemia in rats. Further, we investigated the role of high mobility group box 1 (HMGB1) in neuroprotection mediated by the α7nAChR and EA. Methods Rats were treated with EA at the acupoint "Baihui (GV 20)" 24 h before focal cerebral ischemia which was induced for 120 min by middle cerebral artery occlusion. Neurobehavioral scores, infarction volumes, neuronal apoptosis, and HMGB1 levels were evaluated after reperfusion. The α7nAChR agonist PHA-543613 and the antagonist α-bungarotoxin (α-BGT) were used to investigate the role of the α7nAChR in mediating neuroprotective effects. The roles of the α7nAChR and HMGB1 release in neuroprotection were further tested in neuronal cultures exposed to oxygen and glucose deprivation (OGD). Results Our results showed that the expression of α7nAChR was significantly decreased after reperfusion. EA pretreatment prevented the reduction in neuronal expression of α7nAChR after reperfusion in the ischemic penumbra. Pretreatment with PHA-543613 afforded neuroprotective effects against ischemic damage. Moreover, EA pretreatment reduced infarct volume, improved neurological outcome, inhibited neuronal apoptosis and HMGB1 release following reperfusion, and the beneficial effects were attenuated by α-BGT. The HMGB1 levels in plasma and the penumbral brain tissue were correlated with the number of apoptotic neurons in the ischemic penumbra. Furthermore, OGD in cultured neurons triggered HMGB1 release into the culture medium, and this effect was efficiently suppressed by PHA-543,613. Pretreatment with α-BGT reversed the inhibitory effect of PHA-543,613 on HMGB1 release. Conclusion These data demonstrate that EA pretreatment strongly protects the brain against transient cerebral ischemic injury, and inhibits HMGB1 release through α7nAChR activation in rats. These findings suggest the novel potential for stroke interventions harnessing the anti-inflammatory effects of α7nAChR activation, through acupuncture or pharmacological strategies.