Narirutin Attenuates Cerebral Ischemia-Reperfusion Injury by Suppressing the TXNIP/NLRP3 Pathway.

Narirutin (Nar) is a flavonoid that is abundantly present in citrus fruits and has attracted considerable attention because of its diverse pharmacological activities and low toxicity. Here, we evaluated the preventive effects of Nar in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice and oxygen-glucose deprivation/reperfusion (OGD/R)-injured bEnd.3 cells. Pretreatment with Nar (150 mg/kg) for 7 days effectively reduced infarct volume, improved neurological deficits, and significantly inhibited neuronal death in the hippocampus and cortex in MCAO/R-injured mice. Moreover, anti-apoptotic effects of Nar (50 µM) were observed in OGD/R-injured bEnd.3 cells. In addition, Nar pre-administration regulated blood-brain barrier function by increasing tight junction-related protein expression after MCAO/R and OGD/R injury. Nar also inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation by reducing the expression of thioredoxin-interacting protein (TXNIP) in vivo and in vitro. Taken together, these results provide new evidence for the use of Nar in the prevention and treatment of ischemic stroke.

Safety and efficacy of a novel dexmedetomidine nasal spray for pre-anesthetic sedation in children: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Off-label intranasal administration of injectable dexmedetomidine has been widely applied in the pediatric sedation setting. However, the development of an improved drug delivery system that is easy to use is needed. We developed a novel dexmedetomidine nasal spray that can be administered directly without dilution or configuration for pediatric pre-anesthetic sedation. This nasal spray has a fixed dose and is stable during storage. To the best of our knowledge, this is the first licensed nasal spray preparation of dexmedetomidine worldwide. OBJECTIVE: To evaluate the pre-anesthetic sedation efficacy and safety of the novel dexmedetomidine nasal spray in children. METHODS: The study was conducted at 11 sites in China between 24 November 2021 and 20 May 2022 and was registered in ClinicalTrials.gov (NCT05111431, first registration date: 20/10/2021). Subjects (n = 159) between 2 and 6 years old who were to undergo elective surgery were randomized to the dexmedetomidine group (n = 107) or the placebo group (n = 52) in a 2:1 ratio. The dosage was 30 µg or 50 µg based on the stratified body weight. The primary outcome measure was the proportion of subjects who achieved the desired child-parent separation and Ramsay scale ≥ 3 within 45 min of administration. Safety was monitored via the assessments of adverse events, blood pressure, heart rate, respiratory rate and blood oxygen saturation. RESULTS: The proportion of subjects achieving desired parental separation and Ramsay scale ≥ 3 within 45 min was significantly higher in the dexmedetomidine group (94.4%) vs the placebo group (32.0%) (P < 0.0001). As compared with placebo, dexmedetomidine treatment led to more subjects achieving Ramsay scale ≥ 3 or UMSS ≥ 2, and shorter time to reach desired parental separation, Ramsay scale ≥ 3 and UMSS ≥ 2 (all P < 0.0001). Adverse events were reported in 90.7% and 84.0% of subjects in the dexmedetomidine and placebo groups, respectively, and all the events were mild or moderate in severity. CONCLUSIONS: This novel dexmedetomidine nasal spray presented effective pre-anesthetic sedation in children with a tolerable safety profile.

Efficacy and safety of 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1, 2-benzothiazin-3-carboxamide 1,1-dioxide, a rapid-acting meloxicam formulation, for analgesia after orthopaedic surgery under general anaesthesia: a randomized controlled trial.

BACKGROUND: Postoperative pain management is one of the most challenging treatments after orthopaedic surgery, and improved medical treatment options are urgently needed. This study aimed to evaluate the efficacy and safety of 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1, 2-benzothiazin-3-carboxamide 1,1-dioxide (QP001) for moderate to severe pain following orthopaedic surgery. METHODS: This randomized clinical trial enlisted patients experiencing moderate to severe pain following orthopaedic surgery in 20 hospitals in China. We allocated randomly 132 participants to receive 30 mg QP001 and 66 participants to receive 0.9% saline pre-surgery. The primary efficacy outcome was the total morphine consumption within 24 h. RESULTS: The total morphine consumption in the QP001 group, versus placebo group, was significantly lower over the following 24 h [12.53 (10.51) vs. 26.13 (13.98), P < 0.001]. The total morphine consumption in the QP001 group, versus placebo group, was also significantly decreased over the following 48 h (P < 0.001). The QP001 group, versus placebo, showed a significant decrease in the effective pressing times of the analgesic pump, morphine relief analgesia ratio over the 24 h and 48 h periods and the area under the curve for pain intensity-time as well as a significant prolonged in the time of first pressing the analgesic pump and the time of first morphine rescue analgesia (P < 0.001). The QP001 groups, versus placebo, show no significant difference in adverse events, but the incidence of adverse drug reactions decreased (59.4% vs. 75.8%, P = 0.023). CONCLUSION: QP001 provides analgesia and reduces opioid consumption in patients with moderate to severe pain after orthopaedic surgery, with a favorable safety profile.

Praeruptorin C alleviates cognitive impairment in type 2 diabetic mice through restoring PI3K/AKT/GSK3ß pathway.

Diabetic encephalopathy is a common consequence of diabetes mellitus that causes cognitive dysfunction and neuropsychiatric disorders. Praeruptorin C (Pra-C) from the traditional Chinese medicinal herb Peucedanum praeruptorum Dunn. is a potential antioxidant and neuroprotective agent. This study was conducted to investigate the molecular mechanisms underlying the effect of Pra-C on diabetic cognitive impairment. A novel object recognition test and the Morris water maze test were performed to assess the behavioral performance of mice. Electrophysiological recordings were made to monitor synaptic plasticity in the hippocampus. A protein-protein interaction network of putative Pra-C targets was constructed, and molecular docking simulations were performed to predict the potential mechanisms of the action of Pra-C. Protein expression levels were detected by western blotting. Pra-C administration significantly lowered body weight and fasting blood glucose levels and alleviated learning and memory deficits in type 2 diabetic mice. Network pharmacology and molecular docking results suggested that Pra-C affects the PI3K/AKT/GSK3ß signaling pathway. Western blot analysis confirmed significant increases in phosphorylated PI3K, AKT, and GSK3ß levels in vivo and in vitro upon Pra-C administration. Pra-C alleviated cognitive impairment in type 2 diabetic mice by activating PI3K/AKT/GSK3ß pathway.

Preemptive QP001, a fast-acting meloxicam formulation, provides analgesia and reduces opioid consumption following abdominal surgery: a randomized controlled trial.

BACKGROUND: QP001, a novel meloxicam formulation, has been developed to manage moderate to severe postoperative pain. This study aimed to evaluate the efficacy and safety of QP001 injections for moderate to severe pain following abdominal surgery. METHOD: This prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial enlisted patients experiencing moderate to severe pain following abdominal surgery. These patients were randomized to receive either QP001 injections (30 mg or 60 mg) or a placebo pre-surgery. The primary efficacy endpoint was the total morphine consumption within 24 h after the first administration. RESULTS: A total of 108 patients were enrolled, and 106 patients completed the study. The total morphine consumption in the QP001 30 mg group and 60 mg group, versus placebo group, were significantly lower over the following 24 h (5.11[5.46] vs 8.86[7.67], P = 0.011; 3.11[3.08] vs 8.86[7.67], P < 0.001), respectively. The total morphine consumption in the QP001 30 mg and 60 mg groups, versus placebo group, was also significantly decreased over the following 48 h, including the 24-48 h period (P ≤ 0.001). The QP001 30 mg and 60 mg groups, versus placebo, showed a significant decrease in the area under the curve for pain intensity-time as well as a significant decrease in the effective pressing times of the analgesic pump over the 24 h and 48 h periods (P < 0.05). The QP001 groups, versus placebo, show no significant different in Adverse Events or Adverse Drug Reactions (P > 0.05). CONCLUSION: Preoperative/preemptive QP001 provides analgesia and reduces opioid consumption in patients with moderate to severe pain following abdominal surgery, while maintaining a favorable safety profile.

Establishment and assessment of postoperative cognitive impairment in intermittent hypoxia rats. / é—´æ­‡æ€§ç¼ºæ°§å¤§é¼ æœ¯åŽè®¤çŸ¥åŠŸèƒ½æŸä¼¤æ¨¡åž‹çš„å»ºç«‹.

OBJECTIVES: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a chronic disease characterized by repeated episodes of apnea or hypopnea, accompanied by intermittent awakening and sleep disturbances. The incidence of OSAHS is increasing and has become a serious disease. In recent years, more and more evidence shows that OSAHS is closely related to postoperative neurocognitive disorders, and the preparation of models of postoperative cognitive impairment in intermittent hypoxia animals is an important way to study its pathogenesis and intervention targets. This study aims to explore the establishment and evaluation of the animal model of postoperative cognitive impairment in intermittent hypoxia rats. METHODS: A total of 108 male SD rats were randomly divided into 8 groups: a control group (C group, n=27), a surgery group (S group, n=27), an intermittent hypoxia 7 d group (H1 group, n=9), an intermittent hypoxia 14 d group (H2 group, n=9), an intermittent hypoxia 21 d group (H3 group, n=9), an intermittent hypoxia 7 d operation group (O1 group, n=9), an intermittent hypoxia 14 d operation group (O2 group, n=9), and an intermittent hypoxia 21 d operation group (O3 group, n=9). The rats in the H1, H2 and H3 group treated with intermittent hypoxia for 7, 14, and 21 d, respectively. The rats in the O1, O2 and O3 groups received left lateral hepatic lobectomy after 7, 14, and 21 d intermittent hypoxia, respectively. The rats in each group were subjected to open field test, new object recognition test, and Barnes Maze test. The expression of IL-1ß mRNA in hippocampus of rats was detected at the 1st day after the surgery. RESULTS: Compared with the C, S, and H2 groups, the discrimination index in novel object recognition test 6 h and 1 d after the surgery of the O2 group was significantly lower (P<0.05), the latency and errors in Barnes maze at the 1st day and 2nd day after the surgery were increased significantly (P<0.05) and the expression of IL-1ß mRNA in hippocampus was significantly increased at the 1st day after the operation (P<0.05). However, there was no difference in the preference index in NORT 6 h and 1 d after the surgery, the latency and errors in Barnes maze and the expression of IL-1ß mRNA in hippocampus between the O1 group and the H1 group, the H3 group and the O3 group (all P>0.05). CONCLUSIONS: The rate with intermittent hypoxia 14 d pretreatment with anesthesia and laparotomy could be established the animal model of postoperative cognitive impairment.

Pra-C exerts analgesic effect through inhibiting microglial activation in anterior cingulate cortex in complete Freund's adjuvant-induced mouse model.

Chronic pain is highly prevalent worldwide and severely affects daily lives of patients and family members. Praeruptorin C (Pra-C) is a main active ingredient derived from Peucedanum praeruptorum Dunn, traditionally used as antibechic, anti-bronchitis and anti-hypertension drug. Here, we evaluated the effects of Pra-C in a chronic inflammatory pain mouse model induced by complete Freund's adjuvant (CFA) injection. Pra-C (3 mg/kg) treatment for just 3 days after CFA challenge relieved CFA-induced mechanical allodynia and hindpaw edema in mice. In the anterior cingulate cortex (ACC), Pra-C treatment inhibited microglia activation and reduced levels of proinflammatory cytokines, TNF-α and IL-1ß, and suppressed upregulation of glutamate receptors caused by CFA injection. In addition, Pra-C attenuated neuronal hyperexcitability in ACC of CFA-injected mice. In vitro studies confirmed the analgesic effect of Pra-C was due to its inhibitory ability on microglial activation. In conclusion, Pra-C administration had a certain effect on relieving chronic pain by inhibiting microglial activation, attenuating proinflammatory cytokine releasing and regulating excitatory synaptic proteins in the ACC of the CFA-injected mice.

Association between well-characterized gene polymorphisms and the hypnosis response caused by sevoflurane-induced anaesthesia.

WHAT IS KNOWN AND OBJECTIVE: Sevoflurane is the most widely used volatile anaesthetic in clinical practice. It exhibits a hypnotic (unconsciousness) effect and causes a loss of reaction to noxious stimuli (immobility). However, to date, the mechanism of action of sevoflurane is poorly understood. In this study, we explored the effects of genetic variations on sevoflurane-induced hypnosis. METHODS: Sixty-six SNPs in 18 candidate genes were genotyped using MALDI-TOF MassARRAY in a discovery cohort containing 161 patients administered sevoflurane. Significant polymorphisms were assessed in a validation cohort containing 265 patients. RESULTS AND DISCUSSION: Three polymorphisms (GRIN1 rs28681971, rs79901440 and CHRNA7 rs72713539) were significantly associated with the time to loss of consciousness in patients treated with sevoflurane in the discovery cohort; among them, GRIN1 rs28681971 showed a significant association even after false discovery rate (FDR) correction (pFDR  = 0.039). Following the validation analysis, GRIN1 rs28681971 and rs79901440 showed statistical efficacy (pFDR  = 0.027, 0.034). Combined assessments and meta-analysis of the results of the two cohorts indicated that the C carriers of rs28681971 and T carriers of rs79901440 in GRIN1 require a longer time to achieve unconsciousness. WHAT IS NEW AND CONCLUSION: These findings suggest that GRIN1 polymorphisms are associated with sevoflurane-induced unconsciousness. Thus, the genotypes of GRIN1 may serve as novel and meaningful biomarkers for sevoflurane-induced unconsciousness.

The IDO genetic polymorphisms and postpartum depressive symptoms: an association study in Chinese parturients who underwent cesarean section.

Postpartum depressive symptoms (PDS) are not an uncommon mood disorder in postpartum women. Our previous research indicated a role for increased tryptophan (TRP) metabolism along the kynurenine pathway (KP) in the pathogenesis of PDS. Accordingly, this study was going to investigate the association of indoleamine-2,3-dioxygenase (IDO, a key enzyme of KP) genetic polymorphisms with PDS. Seven hundred twenty-five women receiving cesarean section were enrolled in this study. PDS was determined by an Edinburgh Postnatal Depression Scale (EPDS) score ≥ 13. Subsequently, 48 parturients with PDS and 48 parturients without PDS were selected for investigation of perinatal serum concentrations of TRP, kynurenine (KYN), and KYN/TRP ratio, the latter is the representative of IDO activity. In addition, seven single nucleotide polymorphisms of the IDO gene were examined. Following this genotyping, 50 parturients carrying the IDO rs10108662 AA genotype and 50 parturients carrying the IDO rs10108662 AC + CC genotype were selected for comparisons of TRP, KYN, and KYN/TRP ratio levels. This study showed the PDS incidence of 6.9% in the Chinese population, with PDS characterized by increased IDO activity (p < 0.05), versus women without PDS. We also found that the variations of IDO1 gene rs10108662 were significantly related to PDS incidence (p < 0.05). Furthermore, there was a significant difference in IDO activity between the IDO rs10108662 CA + AA, versus CC, genotypes. Our findings indicate a role of the kynurenine pathway in the development of PDS, rs10108662 genetic polymorphism resulting in changes of IDO activity might contribute to PDS pathogenesis.

The role of tryptophan metabolism in postpartum depression.

The Postpartum depression (PPD) is the most common postpartum psychiatric disorder, afflicting approximately 10%-20% of new mothers. Clinical symptoms of the PPD include depressive disorder, agitation, insomnia, anxiety and confusion, resulting in an increase in suicidal tendencies, thereby having significant impacts on the puerpera, newborn and their family. A growing body of data indicate a role for alterations in tryptophan metabolism in the PPD. The metabolism of tryptophan produces an array of crucial factors that can differentially regulate key physiological processes linked to the PPD. Importantly, an increase in stress hormones and immune-inflammatory activity drives tryptophan to the production of neuroregulatory kynurenine pathway products and away from the serotonin and melatonin pathways. This links the PPD to other disorders of depressed mood, which are classically associated with decreased serotonin and melatonin, coupled to increases in kynurenine pathway products. Several kynurenine pathway products, such as kynurenic acid and quinolinic acid, can have neuroregulatory effects, with consequences pathological underpinnings of the PPD. The current article reviews the role of alterations in tryptophan metabolism in the PPD.

[Correlation between kynurenine metabolites and postpartum depression].

OBJECTIVE: To explore the correlation between kynurenine (KYN) metabolites and postpartum depression (PPD), and to provide new possible explanation for the pathogenesis of postpartum depression (PPD).
 Methods: A total of 726 Chinese women, who received cesarean section, were enrolled in this study. PPD was diagnosed with an Edinburgh Postnatal Depression Scale (EPDS) score ≥13. Twenty-four women with PPD and 48 matched women without PPD were randomly selected. The perinatal serum concentrations of KYN, quinolinic acid (QUIN) and kynurenic acid (KYNA) were measured. Subsequently, the puerperants were compared for the differences in the serum concentrations of KYN, QUIN and KYNA at the end of term, day 1 and day 3 after cesarean section, respectively.
 Results: The incidence of PPD was 7.99%. Of clinical characteristics, pressure during pregnancy was significantly different between subjects with or without PPD (P<0.01). Patients with PPD showed significantly increased serum KYN concentration (P<0.05) at the end of term, increased serum QUIN concentration (P<0.05) and decreased KYNA concentration (P<0.05) on the third day after cesarean section as compared with the control women. Furthermore, the KYNA/QUIN ratio was significantly higher in patients with PPD as compared to the control women on the third day after cesarean section (P<0.01).
 Conclusion: The contribution of alterations in plasma levels of KYN, QUIN and KYNA is closely related with the incidence of PPD, and correction of KYNA/QUIN ratio could be a new strategy for the prevention and treatment of postpartum depressive symptoms.

Population pharmacokinetics study of dexmedetomidine in Chinese adult patients during spinal anesthesia.

OBJECTIVES: The objectives of this study were to construct a population pharmacokinetics model for dexmedetomidine used in Chinese adult patients with spinal anesthesia and to identify the key factors affecting the pharmacokinetics of dexmedetomidine. METHODS: A total of 34 subjects (elderly group: n = 15; young group: n = 19) undergoing spinal anesthesia received dexmedetomidine with a loading dose of 0.5 µg×kg(-1) for 10 minutes, followed by a maintenance dose of 0.5 µg×kg-1×h(-1) for 50 minutes. Blood samples were collected until 10 hours after dosing. Laboratory and respiratory parameters, and dexmedetomidine concentrations were measured. A population pharmacokinetic model for dexmedetomidine was constructed using a nonlinear mixed effects model (NONMEM). RESULTS: Pharmacokinetics of dexmedetomidine can be described by a three-compartment model. The respective typical values for clearance (CL), V1, V2, Q2, Q3, and V3 were 0.883 L×min(-1), 17.6 L, 51.5 L, 2.37 L×min(-1), 0.517 L×min(-1), and 44.00 L. Alanine aminotransferase (ALT), age, and body weight were key factors affecting CL, V1, and V2, respectively. CONCLUSIONS: A three-compartment model can be used to describe the pharmacokinetics processing of dexmedetomidine for Chinese adult patients during spinal anesthesia. The population pharmacokinetic of dexmedetomidine was generally in line with results from previous studies.

Pharmacokinetic and pharmacodynamic study of dexmedetomidine in elderly patients during spinal anesthesia.

OBJECTIVE: The application of dexmedetomidine in patient sedation is generally accepted, though its clinical application is limited because of the lack of information detailing the specific properties among diverse populations of patients. The aim of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of dexmedetomidine between elderly and young patients during spinal anesthesia. METHODS: 34 subjects (elderly group: n = 15; young group: n = 19) with spinal anesthesia were enrolled in the present study following the inclusion/exclusion criteria detailed below. All subjects received intravenous infusion of dexmedetomidine with a loading dose of 0.5 µg x kg⁻¹ for 10 minutes and a maintenance dose of 0.5 µg x kg⁻¹ x h⁻¹ for 50 minutes. Plasma concentrations of dexmedetomidine were detected by the HPLC-MS/MS method and pharmacokinetic parameters were calculated using WinNolin software. RESULTS: There was no significant difference between the elderly and young subjects in major pharmacokinetic parameters. There was a marked gender difference in the Cmax (peak plasma concentration) and tmax (time to reach Cmax) between genders in elderly subjects, though in this cohort the other pharmacokinetic parameters were not significantly different. In the young subjects there were no noteworthy variations between genders in pharmacokinetic parameters. There was no significant difference between the two groups in BISAUC(0-t) (the area under the bispectral index-time curve from time 0 to t hours), BISmin (the minimum value of the bispectral index after drug delivery), and or tmin-BIS (bispectral index for the minimum value of time). SBP (systolic blood pressure), DBP (diastolic blood pressure), HR (heart rate), and SpO2(pulse oxygen saturation) developed substantive differences in a time-dependent manner, but there were no statistically significant differences in these four indicators in the time*group at three time points (1 hour, 2 hours, and 3 hours after drug administration); while SBP was significantly different between the groups, this differential declined in a time-dependent manner, and there were no significant attendant differences in the D-value. The observed values and D-values of DBP and HR were similar in the groups, but the observed value and D-value of SpO2did differ. There were 14 drug-related adverse events in the young group, and 26 drug-related adverse events in the elderly group, a 46% differential. The percentage of patients who requiring intervention during surgery was 68.75% (11/16) in the elderly group and 36.84% (7/19) in the young group, with no significant difference between the two groups once age was factored in (p = 0.06). None of the pharmacodynamic indices, however, correlated with the key pharmacokinetic parameters (Cmax, AUC(0→t), AUC(0→∞)) of dexmedetomidine. CONCLUSIONS: The clearance of dexmedetomidine in elderly patients showed a declining trend compared to young patients. Interventions in the elderly group were more frequent than in the young group, and the elderly group showed significant adverse effects. It is suggested that elderly patients who use dexmedetomidine may benefit from a different dose. However, further research with a larger population size is required to confirm these findings.

Perioperative intravenous infusion of dexmedetomidine for alleviating postpartum depression after cesarean section: A meta-analysis and systematic review.

The efficacy of perioperative dexmedetomidine (DEX) infusion as a precaution against postpartum depression (PPD) in women undergoing cesarean section has not been substantiated systematically. A literature search for RCTs on DEX against PPD was retrieved in the following databases from inception to January 3, 2024: PubMed, Embase, Web of Science, the Cochrane Library, CNKI, Wanfang, CBM, VIP, etc. A total of 13 RCTs with 1711 participants were included. Meta-analysis was performed by RevMan5.3 and Stata16 using a random-effects model. EPDS scores were significantly decreased in the DEX group within one week or over one week postpartum compared to the control group (SMD = -1.25, 95 %CI: -1.73 to -0.77; SMD = -1.08, 95 %CI: -1.43 to -0.73). The prevalence of PPD was significantly inferior to the control at both time points (RR = 0.36, 95 %CI: 0.24 to 0.54; RR = 0.39, 95 %CI: 0.26 to 0.57). Univariate meta-regression suggested that age influenced the heterogeneity of the EPDS scores (P = 0.039), and DEX infusion dose was a potential moderator (P = 0.074). The subgroup analysis results of PPD scores at both time points were consistent, showing that: ① Mothers younger than 30 years old had better sensitivity to DEX for treating PPD. ② The anti-PPD efficacy of continuous infusion of DEX by PCIA was superior to both single infusion and combined infusion. ③ DEX showed a better anti-PPD effect when the total infusion dose was ≤ 2 µg/kg. Moreover, DEX improved analgesia and sleep quality, provided appropriate sedation, and reduced the incidence of nausea, vomiting, and chills. The current evidence confirmed the prophylaxis and superiority of DEX for PPD. More high-quality, large-scale RCTs are required for verifying the reliability and formulating administration methods.

Effect of Dexmedetomidine on Postpartum Depression in Women With Prenatal Depression: A Randomized Clinical Trial.

Importance: Postpartum depression (PPD) is emerging as a major public health problem worldwide. Although the particular period and context in which PPD occurs provides an opportunity for preventive interventions, there is still a lack of pharmacologic prevention strategies for PPD. Objective: To assess the efficacy and safety of dexmedetomidine for prevention of PPD among women with prenatal depression undergoing cesarean delivery. Design, Setting, and Participants: This randomized clinical trial enrolled 338 women who screened positive for prenatal depression at 2 hospitals in Hunan, China from March 28, 2022, to April 16, 2023. Women with an Edinburgh Postnatal Depression Scale score of more than 9 who were 18 years of age or older and were scheduled for elective cesarean delivery were eligible. Interventions: Eligible participants were randomly assigned in a 1:1 ratio to either the dexmedetomidine group or the control group via centrally computer-generated group randomization. Dexmedetomidine, 0.5 µg/kg and 0.9% saline were intravenously infused for 10 minutes after delivery in the dexmedetomidine and control groups, respectively. After infusion, sufentanil or dexmedetomidine plus sufentanil was administered via patient-controlled intravenous analgesia for 48 hours in the control group and dexmedetomidine group, respectively. Main Outcomes and Measures: The primary outcome was positive PPD screening results at 7 and 42 days post partum, defined as a postpartum Edinburgh Postnatal Depression Scale score of more than 9. Analysis was on an intention-to-treat basis. Results: All 338 participants were female, with a mean (SD) age of 31.5 (4.1) years. Positive PPD screening incidence at 7 and 42 days post partum in the dexmedetomidine group vs the control group was significantly decreased (day 7, 21 of 167 [12.6%] vs 53 of 165 [32.1%]; risk ratio, 0.39 [95% CI, 0.25-0.62]; P < .001; day 42, 19 of 167 [11.4%] vs 50 of 165 [30.3%]; risk ratio, 0.38 [95% CI, 0.23-0.61]; P < .001). The dexmedetomidine group showed no significant difference in adverse events vs the control group (46 of 169 [27.2%] vs 33 of 169 [19.5%]; P = .10), but the incidence of hypotension increased (31 of 169 [18.3%] vs 16 of 169 [9.5%]; risk ratio, 2.15 [95% CI, 1.13-4.10]; P = .02). Conclusions and Relevance: Dexmedetomidine administration in the early postpartum period significantly reduced the incidence of a positive PPD screening and maintained a favorable safety profile. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200057213.

miR-29a-5p rescues depressive-like behaviors in a CUMS-induced mouse model by facilitating microglia M2-polarization in the prefrontal cortex via TMEM33 suppression.

BACKGROUND: Depression accounts for a high proportion of neuropsychiatric disorders and is associated with abnormal states of neurons in specific brain regions. Microglia play a pivotal role in the inflammatory state during depression development; however, the exact mechanism underlying chronic mood states remains unknown. Thus, the present study aimed to determine whether microRNAs (miRNAs) alleviate stress-induced depression-like behavior in mice by regulating the expression levels of their target genes, explore the role of neuroinflammation induced by microglial activation in the pathogenesis and progression of depression, and determine whether the role of the miR-29a-5p/transmembrane protein 33 (TMEM33) axis. METHODS: In this study, chronic unpredictable mild stress (CUMS) mouse depression model, various behavioral tests, western blotting, dual-luciferase reporter assay, enzyme-linked immunosorbent assay, real-time quantitative reverse transcription PCR, immunofluorescence and lentivirus-mediated gene transfer were used. RESULTS: After exposure to the CUMS paradigm, miR-29a-5p was significantly down-regulated. This downregulation subsequently promoted the polarization of microglia M1 by upregulating the expression of TMEM33, resulting in enhanced inflammatory chemokines affecting neurons. Conversely, the upregulation of miR-29a-5p within the prefrontal cortex (PFC) suppressed TMEM33 expression, facilitated microglia M2-polarization, and ameliorated depressive-like behavior. LIMITATIONS: Only rodent models of depression were used, and human samples were not included. CONCLUSIONS: The results of this study suggest that miR-29a-5p deficits within the PFC mediate microglial anomalies and contribute to depressive-like behaviors. miR-29a-5p and TMEM33 may, therefore, serve as potential therapeutic targets for the treatment of depression.

Influenza A Virus PB1-F2 Induces Affective Disorder by Interfering Synaptic Plasticity in Hippocampal Dentate Gyrus.

Influenza A virus (IAV) infection, which leads to millions of new cases annually, affects many tissues and organs of the human body, including the central nervous system (CNS). The incidence of affective disorders has increased after the flu pandemic; however, the potential mechanism has not been elucidated. PB1-F2, a key virulence molecule of various influenza virus strains, has been shown to inhibit cell proliferation and induce host inflammation; however, its role in the CNS has not been studied. In this study, we constructed and injected PB1-F2 into the hippocampal dentate gyrus (DG), a region closely associated with newborn neurons and neural development, to evaluate its influence on negative affective behaviors and learning performance in mice. We observed anxiety- and depression-like behaviors, but not learning impairment, in mice injected with PB1-F2. Furthermore, pull-down and mass spectrometry analyses identified several potential PB1-F2 binding proteins, and enrichment analysis suggested that the most affected function was neural development. Morphological and western blot studies revealed that PB1-F2 inhibited cell proliferation and oligodendrocyte development, impaired myelin formation, and interfered with synaptic plasticity in DG. Taken together, our results demonstrated that PB1-F2 induces affective disorders by inhibiting oligodendrocyte development and regulating synaptic plasticity in the DG after IAV infection, which lays the foundation for developing future cures of affective disorders after IAV infection.

Santacruzamate A Alleviates Pain and Pain-Related Adverse Emotions through the Inhibition of Microglial Activation in the Anterior Cingulate Cortex.

Chronic pain is a complex disease. It seriously affects patients' quality of life and imposes a significant economic burden on society. Santacruzamate A (SCA) is a natural product isolated from marine cyanobacteria in Panama. In this study, we first demonstrated that SCA could alleviate chronic inflammatory pain, pain-related anxiety, and depression emotions induced by complete Freund's adjuvant in mice while inhibiting microglial activation in the anterior cingulate cortex. Moreover, SCA treatment attenuated lipopolysaccharide (LPS)-induced inflammatory response by downregulating interleukin 1ß and 6 (IL-1ß and IL-6) and tumor necrosis factor-α (TNF-α) levels in BV2 cells. Furthermore, we found that SCA could bind to soluble epoxide hydrolase (sEH) through molecular docking technology, and the thermal stability of sEH was enhanced after binding of SCA to the sEH protein. Meanwhile, we identified that SCA could reduce the sEH enzyme activity and inhibit sEH protein overexpression in the LPS stimulation model. The results indicated that SCA could alleviate the development of inflammation by inhibiting the enzyme activity and expression of sEH to further reduce chronic inflammatory pain. Our study suggested that SCA could be a potential drug for treating chronic inflammatory pain.

Linderane Attenuates Complete Freund's Adjuvant-Induced Pain and Anxiety in Mice by Restoring Anterior Cingulate Cortex Microglia M2 Polarization through Activating Cannabinoid 2 Receptor.

Chronic pain is a common condition that causes negative emotions as the disease progresses. The anterior cingulate cortex (ACC) is a key region in the integration of nociceptive perception and emotional response in chronic pain. Linderane (LDR) is an active ingredient from Linderae radix, a traditional Chinese medicine with anti-inflammatory, analgesic, and antibacterial properties. In this study, the analgesic and antianxiety effects of LDR were evaluated using a complete Freund's adjuvant (CFA)-induced inflammatory pain model in C57BL/6 male mice. Mechanical and thermal pain sensitivity were measured through plantar mechanical analgesia and hot plate apparatus, and anxiety-like behavior was evaluated by open field and elevated plus maze tests. The results showed that LDR-alleviated CFA-induced pain and anxiety, reduced the release of inflammatory cytokines, and inhibited ACC microglial activation. Target prediction, molecular docking, and cellular thermal shift assay demonstrated that LDR could bind to the cannabinoid 2 receptor (CB2R), a key component of the endocannabinoid system with an important role in regulating pain and related emotions. Moreover, both the analgesic effect of LDR and its regulation of microglia polarization were reversed by a CB2R antagonist (SR144528) treatment. Therefore, our results suggested that LDR exerted analgesic effects by regulating microglial polarization in ACC via CB2R activation.

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.