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.

Evaluating the efficacy and safety of perianal injection of liposomal ropivacaine HR18034 for postoperative analgesia following hemorrhoidectomy: A multicenter, randomized, double-blind, controlled phase II clinical trial.

STUDY OBJECTIVE: HR18034, composed of the ropivacaine encapsulated in multi-lamellar, concentric circular structure liposomes as the major component and a small amount of free ropivacaine, has performed well in animal experiments and phase I clinical trials. This trial was to investigate the efficacy, safety, pharmacokinetic profile and the minimum effective dose of HR18034 for postoperative analgesia after hemorrhoidectomy compared with ropivacaine. DESIGN: A multicenter, randomized, double-blind trial. SETTING: 19 medical centers in China. PATIENTS: 85 patients undergoing hemorrhoidectomy between October 2022 to November 2022. INTERVENTIONS: Patients were randomly divided into HR 18034 190 mg group, 285 mg group, 380 mg group and ropivacaine 75 mg group, receiving single local anesthetic perianal injection for postoperative analgesia. MEASUREMENTS: The primary outcome was the area under the resting state NRS score -time curve within 72 h after injection. The second outcomes included the proportion of patients without pain, the proportion of patients not requiring rescue analgesia, cumulative morphine consumption for rescue analgesia, etc. Safety was evaluated by adverse events incidence and plasma ropivacaine concentrations were measured to explore the pharmacokinetic characteristics of HR18034. MAIN RESULTS: The areas under the NRS score (at rest and moving states)-time curve were significantly lower in HR 18034 380 mg group than ropivacaine 75 mg at 24 h, 48 h, and 72 h after administration. However, this superiority was not observed in HR18034 190 mg group and 285 mg group. There was no difference in cumulative morphine consumption for rescue analgesia between HR 18034 groups and ropivacaine group. CONCLUSIONS: HR 18034 380 mg showed superior analgesic efficacy and equivalent safety compared to ropivacaine 75 mg after hemorrhoidectomy, thus preliminarily determined as minimum effective dose.

Psilocybin promotes neuroplasticity and induces rapid and sustained antidepressant-like effects in mice.

BACKGROUND: Psilocybin offers new hope for treating mood disorders due to its rapid and sustained antidepressant effects, as standard medications require weeks or months to exert their effects. However, the mechanisms underlying this action of psilocybin have not been identified. AIMS: To investigate whether psilocybin has rapid and sustained antidepressant-like effects in mice and investigate whether its potential mechanisms of action are related to promoted neuroplasticity. METHODS: We first examined the antidepressant-like effects of psilocybin in normal mice by the forced swimming test and in chronic corticosterone (CORT)-exposed mice by the sucrose preference test and novelty-suppressed feeding test. Furthermore, to explore the role of neuroplasticity in mediating the antidepressant-like effects of psilocybin, we measured structural neuroplasticity and neuroplasticity-associated protein levels in the prefrontal cortex (PFC) and hippocampus. RESULTS: We observed that a single dose of psilocybin had rapid and sustained antidepressant-like effects in both healthy mice and chronic CORT-exposed mice. Moreover, psilocybin ameliorated chronic CORT exposure-induced inhibition of neuroplasticity in the PFC and hippocampus, including by increasing neuroplasticity (total number of dendritic branches and dendritic spine density), synaptic protein (p-GluA1, PSD95 and synapsin-1) levels, BDNF-mTOR signalling pathway activation (BDNF, TrkB and mTOR levels), and promoting neurogenesis (number of DCX-positive cells). CONCLUSIONS: Our results demonstrate that psilocybin elicits robust, rapid and sustained antidepressant-like effects which is accompanied by the promotion of neuroplasticity in the PFC and hippocampus.

Intravenous injection of dexamethasone is non-inferior to perineural administration for popliteal sciatic nerve and saphenous nerve blocks: A randomized, controlled, triple-blind study.

Background: The aim of this study was to assess whether intravenous dexamethasone was noninferior to perineural dexamethasone as an adjuvant to ropivacaine for a combination of saphenous and sciatic nerve blocks in patients undergoing foot and ankle surgery. Methods: This was a prospective, blinded, randomized noninferiority study. Seventy-five patients, aged 18-75 years, with an American Society of Anesthesiologists (ASA) physical status I-III who underwent foot and ankle surgery were involved. Patients scheduled for ultrasound-guided popliteal sciatic nerve block and saphenous nerve block were randomized to receive 0.375% ropivacaine with 7.5 mg of dexamethasone perineurally (Dex-PN), 10 mg of dexamethasone intravenously (Dex-IV) or neither (Placebo). The primary outcome was the duration of analgesia. The major secondary outcomes were the composite pain intensity and opioid consumption score at 0-48 h intervals after anesthesia. Results: The mean analgesic duration was 26.2 h in the Dex-IV group and 27.9 h in the Dex-PN group (duration difference, -1.7; 95% CI, -3.8 to 0.43; P = 0.117), and both durations were significantly longer than that in the placebo group (17.6 h, P < 0.001). Conditions for establishing non-inferiority were met. Conclusions: Our findings indicate that a single 10-mg intravenous dose of dexamethasone was noninferior to the combined dose of ropivacaine plus deaxmethasone in terms of duration of analgesia for foot and ankle surgery.

The protective effect of vitamin A palmitate eye gel on the ocular surface during general anaesthesia surgery: a randomized controlled trial.

PURPOSE: To investigate the change in tear production associated with general anesthesia and the protective effect of vitamin A palmitate eye gel on the ocular surface during general anesthesia. METHODS: This double-blind, randomized clinical trial included patients undergoing non-ophthalmic surgery under general anesthesia who randomly received vitamin A palmitate eye gel and taping for one eye (Group A, n = 60) or taping alone for the other eye (Group B, n = 60). Symptom assessment in dry eye (SANDE) score, tear film break-up time (TBUT), corneal fluorescein staining (CFS) score, and Schirmer tear test I (STT-1) were analyzed under a hand-held slit lamp before anesthesia (T0), 0.5 h postoperatively (T1), and 24 h postoperatively (T2). RESULTS: At 0.5 h postoperatively, an increase in CFS score was observed in both groups (P < 0.05 in Group A and P < 0.01 in Group B), and the participants in Group A had less corneal abrasions than those in Group B. STT-1 significantly increased in Group A (P < 0.05), while it significantly decreased in Group B (P < 0.001). The changes between the two groups were statistically significant (P < 0.001). At 24 h postoperatively, both CFS score and STT-1 almost returned to baseline levels in the two groups. In both groups, the SANDE score and TBUT showed little change at 0.5 h and 24 h postoperatively (all P > 0.05). CONCLUSION: Vitamin A palmitate eye gel effectively protected the ocular surface and aqueous supplementation during general anesthesia. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (ChiCTR2100052140) on 20/10/2021.

Comparison of diffusion ranges at different local anesthetic volumes during superior laryngeal nerve block.

OBJECTIVES: Ultrasound-guided superior laryngeal nerve (SLN) block is a practical and painless approach to avoid the hemodynamic stress response during endotracheal intubation and relieve sore throat after laryngeal surgery. The main purpose of this study was to establish an optimal dosage of local anesthetic when performing SLN block to help anesthetists balance analgesia and side effects. METHODS: Twenty fresh larynx specimens were obtained immediately after resection and then injected with 2-, 3-, 4-, or 5- mL of a lidocaine-blue dye mixture at bilateral SLN puncture sites. Superficial areas of deposited blue dye were measured. Dye leakage and surrounding dyed tissue were recorded. Another 40 patients were included in the ultrasound investigation. Distances between the internal branch of the SLN (iSLN) and adjacent structures were calculated. RESULTS: The dye spread area was greater with the administration of larger doses, especially to the visceral space. A 2- or 3-mL injection of local anesthetic was sufficient to infiltrate the SLN gap. A higher incidence of dye leaking out of the thyrohyoid membrane and anterior epiglottis space was observed; furthermore, there was substantially more dyed hyoid/thyroid cartilage with 4 and 5 mL of injected dye mixture than 2 mL. There was no significant difference between the specimen and ultrasound measurements of for length of iSLN-adjacent structures. CONCLUSIONS: In the Chinese population, 2- or 3- mL of local anesthetic is a safe dose during SLN block. A larger volume could overflow from the cavity to cause complications. The thyrohyoid membrane combined with the superior laryngeal artery is a reliable target for positioning the iSLN during ultrasound-guided regional anesthesia.

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.

The Use of Preoperative Video Distraction on Emergence Delirium in Preschool Children Undergoing Strabismus Surgery Under Anesthesia with Sevoflurane: A Randomized Controlled Trial.

Purpose: The aim of this study was to determine whether preoperative video distraction reduces the incidence of emergence delirium in preschool children under general anesthesia with sevoflurane. Patients and Methods: In this prospective randomized controlled study, children aged 3-6 years were randomized to receive either video distraction (Group V) or common clinical practice (Group C) from arrival at the holding area to induction of anesthesia. The primary outcome was the incidence of emergence delirium. Preoperative anxiety scores, assessed by the simple modified Yale Perioperative Anxiety Scale, were also collected. Results: A total of 160 patients were included in our study. The children in Group V (n=80) exhibited a significantly lower incidence of emergence delirium than did those in Group C (n=80) (12.5% vs 35.0%; RR 0.36, 95% CI 0.19, 0.69; P =0.0008). The maximum Pediatric Anesthesia Emergence Delirium score in Group V was significantly lower than that in Group C (3.0 vs 5.0; mean difference -2.64, 95% CI: -4.12, -1.16; P=0.0003). The simple modified Yale Perioperative Anxiety Scale scores at separation from parents and the onset of inhalation induction in Group V were significantly lower than those in Group C (36.4 ± 9.9 vs 48.2 ± 16.7; mean difference 11.92, 95% CI 7.25, 16.59; P<0.0001 and 41.5 ± 15.9 vs 59.7 ± 21.5; mean difference 18.11, 95% CI 11.76, 24.47; P<0.0001). Conclusion: Preoperative video distraction reduces the incidence of emergence delirium in preschool children who undergo strabismus surgery under general anesthesia with sevoflurane.

Protection of Ndrg2 deficiency on renal ischemia-reperfusion injury via activating PINK1/Parkin-mediated mitophagy.

BACKGROUND: Renal ischemia-reperfusion (R-I/R) injury is the most prevalent cause of acute kidney injury, with high mortality and poor prognosis. However, the underlying pathological mechanisms are not yet fully understood. Therefore, this study aimed to investigate the role of N-myc downstream-regulated gene 2 (Ndrg2) in R-I/R injury. METHODS: We examined the expression of Ndrg2 in the kidney under normal physiological conditions and after R-I/R injury by immunofluorescence staining, real-time polymerase chain reaction, and western blotting. We then detected R-I/R injury in Ndrg2-deficient (Ndrg2-/-) mice and wild type (Ndrg2+/+) littermates in vivo, and detected oxygen and glucose deprivation and reperfusion injury (OGD-R) in HK-2 cells. We further conducted transcriptomic sequencing to investigate the role of Ndrg2 in R-I/R injury and detected levels of oxidative stress and mitochondrial damage by dihydroethidium staining, biochemical assays, and western blot. Finally, we measured the levels of mitophagy in Ndrg2+/+ and Ndrg2-/- mice after R-I/R injury or HK-2 cells in OGD-R injury. RESULTS: We found that Ndrg2 was primarily expressed in renal proximal tubules and significantly decreased its expression 24 h after R-I/R injury. Ndrg2-/- mice exhibited significantly attenuated R-I/R injury compared to Ndrg2+/+ mice. Transcriptomics profiling showed that Ndrg2 deficiency induced perturbations of multiple signaling pathways, downregulated inflammatory responses and oxidative stress, and increased autophagy following R-I/R injury. Further studies revealed that Ndrg2 deficiency reduced oxidative stress and mitochondrial damage. Notably, Ndrg2 deficiency significantly activated phosphatase and tensin homologue on chromosome ten-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy. The downregulation of NDRG2 expression significantly increased cell viability after OGD-R injury, increased the expression of heme oxygenase-1, decreased the expression of nicotinamide adenine dinucleotide phosphate oxidase 4, and increased the expression of the PINK1/Parkin pathway. CONCLUSION: Ndrg2 deficiency might become a therapy target for R-I/R injury by decreasing oxidative stress, maintaining mitochondrial homeostasis, and activating PINK1/Parkin-mediated mitophagy.