Hypidone hydrochloride (YL-0919) ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation.

JOURNAL/nrgr/04.03/01300535-202508000-00023/figure1/v/2024-09-30T120553Z/r/image-tiff Traumatic brain injury involves complex pathophysiological mechanisms, among which oxidative stress significantly contributes to the occurrence of secondary injury. In this study, we evaluated hypidone hydrochloride (YL-0919), a self-developed antidepressant with selective sigma-1 receptor agonist properties, and its associated mechanisms and targets in traumatic brain injury. Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema. Next, we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells. Finally, the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist (BD-1047). Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury, while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema. Furthermore, YL-0919 effectively combated oxidative stress both in vivo and in vitro. The protective effects of YL-0919 were partially inhibited by BD-1047. These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress, a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047. YL-0919 may have potential as a new treatment for traumatic brain injury.

Chronic Neuropathic Pain and Comorbid Depression Syndrome: From Neural Circuit Mechanisms to Treatment.

Chronic neuropathic pain and comorbid depression syndrome (CDS) is a major worldwide health problem that affects the quality of life of patients and imposes a tremendous socioeconomic burden. More than half of patients with chronic neuropathic pain also suffer from moderate or severe depression. Due to the complex pathogenesis of CDS, there are no effective therapeutic drugs available. The lack of research on the neural circuit mechanisms of CDS limits the development of treatments. The purpose of this article is to provide an overview of the various circuits involved in CDS. Notably, activating some neural circuits can alleviate pain and/or depression, while activating other circuits can exacerbate these conditions. Moreover, we discuss current and emerging pharmacotherapies for CDS, such as ketamine. Understanding the circuit mechanisms of CDS may provide clues for the development of novel drug treatments for improved CDS management.

Effect of Aggressive Warming versus Routine Thermal Management on the Incidence of Perioperative Hypothermia in Patients Undergoing Thyroid Surgery: A Prospective, Randomized, Double-Blind Controlled Trial.

Purpose: Despite the implementation of various insulation measures, the incidence of hypothermia during thyroid surgery remains high. This randomized controlled study aimed to evaluate the effects of aggressive thermal management combined with resistive heating mattresses to prevent perioperative hypothermia in patients undergoing thyroid surgery. Patients and Methods: 142 consecutive patients scheduled for elective thyroid surgery were enrolled in the study. They were randomly and equally allocated to the aggressive warming or routine care groups (n = 71). The patients' body temperature was monitored before the induction of anesthesia until they returned to the ward. The primary outcome was the incidence of perioperative hypothermia. Secondary outcomes included postoperative complications, such as mortality, cardiovascular complications, wound infection, shivering, postoperative nausea and vomiting (PONV), visual analog scale (VAS) pain scores, fever, headache and hospital length of stay (LOS). Results: In our study, the results showed that a significantly higher rate of hypothermia was observed in the routine care group compared with the aggressive warming group. The incidence of perioperative hypothermia was 19.72% (14/71) in the aggressive warming group and 35.21% (25/71) in the routine care group (P < 0.05). The incidence of shivering in the aggressive warming group (1.41%) was significantly lower than that in the routine care group (11.27%) (P < 0.05), and a one-day reduction in hospital length of stay was observed in the aggressive warming group (P < 0.05). There was no significant difference in mortality or other postoperative complications, such as cardiovascular complications, wound infection, PONV, pain, fever or headache, between the two groups (P > 0.05). Conclusion: Our results suggest that aggressive thermal management combined with resistive heating mattresses provided improved perioperative body temperature and reduced the incidence of perioperative hypothermia and shivering compared to routine thermal management.

●The incidence of perioperative hypothermia during thyroid surgery was high. ●The use of resistive heating mattresses during thyroid surgery can effectively reduce the occurrence of perioperative hypothermia. ●It is recommended to take aggressive thermal protection during the operation of minor and medium surgeries, and to continuously monitor the temperature.

Sevoflurane induces neurotoxic effects on developing neurons through the WNK1/NKCC1/Ca2+ /Drp-1 signalling pathway.

Children repeatedly exposed to anaesthesia have a high risk of cognitive impairment, but the mechanism of its regulation in this context is unknown. The objective of this study was to investigate the possible toxic mechanism of sevoflurane through the WNK1/NKCC1/Ca2+ /Drp-1 signalling pathway. The hippocampal neuronal HT22 cell line was used in this study. The intervention group was treated with the WNK1 inhibitor WNK-463, CaN inhibitor FK506 and Drp-1 inhibitor Mdivi-1 respectively in the medium for 30 min before sevoflurane anaesthesia. The sevofluane group and all intervention group treated with 4.1% sevoflurane for 6 h. Compared with the control group, sevoflurane treatment decreased cell viability and increased cellular apoptosis. Our study found that WNK-463, FK506 and Mdivi-1 can all alleviate the sevoflurane-induced reduction in cell viability, decrease the cell apoptosis. In addition, WNK-463 pretreatment could inhibit the increase of WNK1 kinase and NKCC1 protein concentration caused by sevoflurane. Further, sevoflurane anaesthesia causes intracellular calcium overload, increases the expression of CaN and induces the dephosphorylation of Drp-1 protein at ser637, while CaN inhibitor FK506 pretreatment could reduce the dephosphorylation of Drp-1. Therefore, the WNK1/NKCC1/Ca2+ /Drp-1 signalling pathway plays an important role in sevoflurane-related neurotoxicity. Reducing intracellular calcium influx may be one of the important mechanism to ameliorate sevoflurane toxicity.

Auts2 regulated autism-like behavior, glucose metabolism and oxidative stress in mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by abnormal social behavior and communication. The autism susceptibility candidate 2 (AUTS2) gene has been associated with multiple neurological diseases, including ASD. Glucose metabolism plays an important role in social behaviors associated with ASD, but the potential role of AUTS2 in glucose metabolism has not been studied. Here, we generated Auts2flox/flox; Emx1Cre+ conditional knockout mice with Auts2 deletion specifically in Exm1-positive neurons in the brain (Auts2-cKO mice) to evaluate the effects of Auts2 knockdown on social behaviors and metabolic pathways. Auts2-cKO mice exhibited ASD-like behaviors, including impaired social interactions and repetitive grooming behaviors. At the molecular level, we found that Auts2 knockdown reduced brain glucose uptake and inhibited the pentose phosphate pathway. Auts2 knockdown also resulted in signs of oxidative stress, and we documented increased levels of reactive oxygen species and malondialdehyde as well as decreased levels of antioxidant molecules, including glutathione and superoxide dismutases in Auts2-cKO mouse brains compared to controls. Finally, Auts2 knockdown significantly disrupted mitochondrial homeostasis and inhibited activity of the SIRT1-SIRT3 axis. Taken together, our findings indicate that loss of AUTS2 expression in Emx1-expressing cells induces multiple changes in metabolic pathways that have been linked to the pathology of ASD. Further characterization of the role of AUTS2 in Emx1-expressing cells in regulating the metabolism of brain neurons may identify opportunities to treat ASD and AUTS2-deficiency disorders with metabolism-targeted therapies.

Combined spinal-epidural analgesia and epidural analgesia induced maternal fever with a similar timing during labor-A randomized controlled clinical trial.

Background: Both epidural and combined spinal-epidural (EA and CSEA) analgesia can induce intrapartum maternal fever. CSEA has a more rapid onset and wider nerve block than EA. Therefore, CSEA might have a different profile of intrapartum maternal fever, including higher temperatures or earlier occurrence. This randomized clinical trial was to determine whether CSEA could cause maternal fever earlier than EA. Methods: A randomized, double-blind, controlled clinical trial was performed on 233 nulliparous full-term pregnant women during vaginal delivery. The pregnant women were randomly allocated into the EA group (n = 113) and the CSEA group (n = 120). The fever latent period, from analgesia start to fever occurrence, was the primary endpoint in this study. The temperature was measured every 30 min using an eardrum thermometer during labor analgesia. The fever was defined as an eardrum temperature of ≥38 °C. Results: No difference was found in the maternal fever rate between the EA and the CSEA groups (10/113 vs. 7/120, P = 0.356). There was no significant difference in the fever latent period between the two groups (4.75 ± 0.86 h vs. 3.79 ± 2.2 h, p = 0.305). The temperatures at all points had no differences between EA and CSEA. Conclusion: CSEA had a similar latent fever period as EA. A further study is warranted to confirm the similar characteristic between CSEA and EA in the development of intrapartum maternal fever. Clinical trial registration: www.chictr.org.cn, identifier ChiCTR2000038793.

Midazolam Attenuates Esketamine-Induced Overactive Behaviors in Mice Before the Sedation, but Not During the Recovery.

Esketamine showed more potency, more rapid recovery from anesthesia, and less psychotomimetic side effects when compared with ketamine. However, the patients still experience psychotomimetic side effects of esketamine. In order to investigate whether midazolam can attenuate the esketamine-induced overactive behaviors and neuronal hyperactivities, midazolam 0, 40, 80, and 120 mg/kg combined with esketamine 50 mg/kg were administrated on Kunming mice to assess the behaviors changes during anesthesia. The indicators, including action time, duration of agitation before the sedation, duration of sedation, duration of loss of pedal withdrawal reaction (PWR), duration of loss of righting reaction (RR), duration of agitation during the recovery, and recovery time, were monitored for up to 3-4 h after intraperitoneal administration. The results demonstrated that midazolam 40, 80, and 120 mg/kg efficiently decreased the esketamine-induced overactive behaviors including ataxia, excitation, and catalepsy before sedation. Midazolam and esketamine synergically improved the anesthesia quality assessed by PWR and RR. However, even high doses of midazolam were not able to suppress the esketamine-induced psychotomimetic effects during the recovery.

A Single Low Dose of Dexmedetomidine Efficiently Attenuates Esketamine-Induced Overactive Behaviors and Neuronal Hyperactivities in Mice.

Introduction: Esketamine (Esk) (S(+)-ketamine) is now used as an alternative to its racemic mixture, i. e., ketamine in anesthesia. Esk demonstrated more powerful potency and rapid recovery in anesthesia and less psychotomimetic side effects comparing with ketamine, but Esk could still induce psychological side effects in patients. This study was to investigate whether dexmedetomidine (Dex) can attenuate the Esk-induced neuronal hyperactivities in Kunming mice. Methods: Dexmedetomidine 0.25, 0.5, and 1 mg/kg accompanied with Esk 50 mg/kg were administrated on Kunming mice to assess the anesthesia quality for 1 h. The indicators, such as time to action, duration of agitation, duration of ataxia, duration of loss pedal withdrawal reaction (PWR), duration of catalepsy, duration of righting reflex (RR) loss, duration of sedation, were recorded for 1 h after intraperitoneal administration. The c-Fos expression in the brain was detected by immunohistochemistry and Western Blot after 1 h of administration. Considering the length of recovery time for more than 1 h in Dex and Dex with Esk groups, other mice were repeatedly used to evaluate recovery time from the administration to emerge from anesthesia. Results: Dexmedetomidine dose-dependently increased recovery time when administrated with Esk or alone. Dex combined with Esk efficiently attenuated the duration of agitation, ataxia, and catalepsy. Dex synergically improved the anesthesia of Esk by increasing the duration of sedation, loss of RR, and loss of PWR. Esk induced the high expression of c-Fos in the cerebral cortex, hippocampus, thalamus, amygdala, hypothalamus, and cerebellum 1 h after administration. Western Blot results indicated that Dex at doses of 0.25, 0.5, and 1 mg/kg could significantly alleviate the Esk-induced c-Fos expression in the mice brain. Conclusion: Dexmedetomidine ranged from 0.25 to 1 mg/kg could improve the anesthesia quality and decreased the neuronal hyperactivities and the overactive behaviors when combined with Esk. However, Dex dose-dependently increased the recovery time from anesthesia. It demonstrated that a small dose of Dex 0.25 mg/kg could be sufficient to attenuate Esk-induced psychotomimetic side effects without extension of recovery time in Kunming mice.

Transcutaneous electrical acupuncture stimulation (TEAS) for gastrointestinal dysfunction in adults undergoing abdominal surgery: study protocol for a prospective randomized controlled trial.

BACKGROUND: Postoperative gastrointestinal (GI) dysfunction (PGD) is a common problem after abdominal surgery. PGD can increase the length of hospital stay and may lead to serious complications. Acupuncture and moxibustion are alternative therapies for PGD that have been used in some settings. However, the effect of preventive application of acupuncture or transcutaneous electrical acupuncture stimulation (TEAS) is still uncertain. The purpose of this study is to investigate the efficacy of the continuous application of TEAS on GI function recovery in adults undergoing abdominal surgery. At the same time, we will try to confirm the mechanism of TEAS through the brain-gut axis. METHODS/DESIGN: This study is a prospective, single-center, two-arm, randomized controlled trial that will be performed in a general hospital. In total, 280 patients undergoing abdominal surgery were stratified by type of surgery (i.e. gastric or colorectal procedure) and randomized into two treatment groups. The experimental group will receive TEAS stimulation at L14 and PC6, ST36 and ST37. The sham group will receive pseudo-TEAS at sham acupoints. The primary outcome will be the time to the first bowel motion by auscultation. The recovery time of flatus, defecation, the changes in perioperative brain-intestinal peptides, postoperative pain, perioperative complications, and hospitalization duration will be the secondary outcomes. DISCUSSION: The results of this study will demonstrate that continuous preventive application of TEAS can improve the GI function recovery in patients undergoing abdominal surgery and that this effect may act through brain-gut peptides. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900023263 . Registered on 11 May 2019.

Effects of intraoperative individualized PEEP on postoperative atelectasis in obese patients: study protocol for a prospective randomized controlled trial.

BACKGROUND: Obese patients undergoing general anesthesia and mechanical ventilation during laparoscopic abdominal surgery commonly have a higher incidence of postoperative pulmonary complications (PPCs), due to factors such as decreasing oxygen reserve, declining functional residual capacity, and reducing lung compliance. Pulmonary atelectasis caused by pneumoperitoneum and mechanical ventilation is further aggravated in obese patients. Recent studies demonstrated that individualized positive end-expiratory pressure (iPEEP) was one of effective lung-protective ventilation strategies. However, there is still no exact method to determine the best iPEEP, especially for obese patients. Here, we will use the best static lung compliance (Cstat) method to determine iPEEP, compared with regular PEEP, by observing the atelectasis area measured by electrical impedance tomography (EIT), and try to prove a better iPEEP setting method for obese patients. METHODS: This study is a single-center, two-arm, prospective, randomized control trial. A total number of 80 obese patients with body mass index ≥ 32.5 kg/m2 scheduled for laparoscopic gastric volume reduction and at medium to high risk for PPCs will be enrolled. They will be randomly assigned to control group (PEEP5 group) and iPEEP group. A PEEP of 5 cmH2O will be used in PEEP5 group, whereas an individualized PEEP value determined by a Cstat-directed PEEP titration procedure will be applied in the iPEEP group. Standard lung-protective ventilation methods such as low tidal volumes (7 ml/kg, predicted body weight, PBW), a fraction of inspired oxygen ≥ 0.5, and recruitment maneuvers (RM) will be applied during and after operation in both groups. Primary endpoints will be postoperative atelectasis measured by chest electrical impedance tomography (EIT) and intraoperative oxygen index. Secondary endpoints will be serum IL-6, TNF-α, procalcitonin (PCT) kinetics during and after surgery, incidence of PPCs, organ dysfunction, length of in-hospital stay, and hospital expense. DISCUSSION: Although there are several studies about the effect of iPEEP titration on perioperative PPCs in obese patients recently, the iPEEP setting method they used was complex and was not always feasible in routine clinical practice. This trial will assess a possible simple method to determine individualized optimal PEEP in obese patients and try to demonstrate that individualized PEEP with lung-protective ventilation methods is necessary for obese patients undergoing general surgery. The results of this trial will support anesthesiologist a feasible Cstat-directed PEEP titration method during anesthesia for obese patients in attempt to prevent PPCs. TRIAL REGISTRATION: www.chictr.org.cn ChiCTR1900026466. Registered on 11 October 2019.