Sevoflurane acts as an antidepressant by suppression of GluN2D-containing NMDA receptors on interneurons.

BACKGROUND AND PURPOSE: Sevoflurane, a commonly used inhaled anaesthetic known for its favourable safety profile and rapid onset and offset, has not been thoroughly investigated as a potential treatment for depression. In this study, we reveal the mechanism through which sevoflurane delivers enduring antidepressant effects. EXPERIMENTAL APPROACH: To assess the antidepressant effects of sevoflurane, behavioural tests were conducted, along with in vitro and ex vivo whole-cell patch-clamp recordings, to examine the effects on GluN1-GluN2 incorporated N-methyl-d-aspartate (NMDA) receptors (NMDARs) and neuronal circuitry in the medial prefrontal cortex (mPFC). Multiple-channel electrophysiology in freely moving mice was performed to evaluate sevoflurane's effects on neuronal activity, and GluN2D knockout (grin2d-/-) mice were used to confirm the requirement of GluN2D for the antidepressant effects. KEY RESULTS: Repeated exposure to subanaesthetic doses of sevoflurane produced sustained antidepressant effects lasting up to 2 weeks. Sevoflurane preferentially inhibited GluN2C- and GluN2D-containing NMDARs, causing a reduction in interneuron activity. In contrast, sevoflurane increased action potentials (AP) firing and decreased spontaneous inhibitory postsynaptic current (sIPSC) in mPFC pyramidal neurons, demonstrating a disinhibitory effect. These effects were absent in grin2d-/- mice, and both pharmacological blockade and genetic knockout of GluN2D abolished sevoflurane's antidepressant actions, suggesting that GluN2D is essential for its antidepressant effect. CONCLUSION AND IMPLICATIONS: Sevoflurane directly targets GluN2D, leading to a specific decrease in interneuron activity and subsequent disinhibition of pyramidal neurons, which may underpin its antidepressant effects. Targeting the GluN2D subunit could hold promise as a potential therapeutic strategy for treating depression.

Increased risk of postpartum depression in women with lactational mastitis: a cross-sectional study.

Background: A high incidence of lactational mastitis mainly occurs during the first month of breastfeeding. It may cause severe pain, frustration, fatigue, stress, and breastfeeding concerns. However, few studies investigated the effects of lactational mastitis on postpartum depression. This study investigated the potential association between lactational mastitis and postpartum depression. Methods: We examined the associations of lactational mastitis with postpartum depression in 1,551 Chinese women. Lactational mastitis was diagnosed by breast specialists. The presence of depression symptoms was evaluated by the Edinburgh Postnatal Depression Scale (EPDS) and Patient Health Questionnaire 9 (PHQ9) at 6 weeks after delivery. Multiple linear regression analysis and multivariable log-binomial regression analysis were performed to estimate the association between lactational mastitis and postpartum depression. Results: Among the 1,551 mothers, 147 (9.5%) experienced lactational mastitis diagnosed by breast specialists during the postpartum period. Compared with women without lactational mastitis, the proportion of women with depression symptoms was significantly higher (38.1% vs. 27.4%, p = 0.008), and the risk of postpartum depression increased by 68% (RR = 1.68, 95% CI, 1.18, 2.40) in women who had experienced lactational mastitis. In addition, the risk of self-harm or suicidal ideation increased by 89% (RR = 1.89, 95% CI, 1.08, 3.29) in women who experienced lactational mastitis. In stratified analysis, the associations of lactational mastitis with postpartum depression appeared stronger among women aged ≥35 years, with maternal comorbidities, and who delivered a female neonate. Conclusion: The study results suggest that lactational mastitis is a risk factor for depression during the postpartum period. The impact of lactational mastitis on maternal mental health requires further attention. Clinical trial registration: chictr.org.cn, ChiCTR2000041519.

Subclavian vein ultrasound-guided fluid management to prevent post-spinal anesthetic hypotension during cesarean delivery: a randomized controlled trial.

BACKGROUND: Hypotension frequently occurs after spinal anesthesia during cesarean delivery, and fluid loading is recommended for its prevention. We evaluated the efficacy of subclavian vein (SCV) ultrasound (US)-guided volume optimization in preventing hypotension after spinal anesthesia during cesarean delivery. METHODS: This randomized controlled study included 80 consecutive full-term parturients scheduled for cesarean delivery under spinal anesthesia. The women were randomly divided into the SCVUS group, with SCVUS analysis before spinal anesthesia with SCVUS-guided volume management, and the control group without SCVUS assessment. The SCVUS group received 3 mL/kg crystalloid fluid challenges repeatedly within 3 min with a 1-min interval based on the SCV collapsibility index (SCVCI), while the control group received a fixed dose (10 mL/kg). Incidence of post-spinal anesthetic hypotension was the primary outcome. Total fluid volume, vasopressor dosage, changes in hemodynamic parameters, maternal adverse effects, and neonatal status were secondary outcomes. RESULTS: The total fluid volume was significantly higher in the control group than in the SCVUS group (690 [650-757.5] vs. 160 [80-360] mL, p < 0.001), while the phenylephrine dose (0 [0-40] vs. 0 [0-30] µg, p = 0.276) and incidence of post-spinal anesthetic hypotension (65% vs. 60%, p = 0.950) were comparable between both the groups. The incidence of maternal adverse effects, including nausea/vomiting and bradycardia (12.5% vs. 17.5%, p = 0.531 and 7.5% vs. 5%, p = 1.00, respectively), and neonatal outcomes (Apgar scores) were comparable between the groups. SCVCI correlated with the amount of fluid administered (R = 0.885, p < 0.001). CONCLUSIONS: SCVUS-guided volume management did not ameliorate post-spinal anesthetic hypotension but reduced the volume of the preload required before spinal anesthesia. Reducing preload volume did not increase the incidence of maternal and neonatal adverse effects nor did it increase the total vasopressor dose. Moreover, reducing preload volume could relieve the heart burden of parturients, which has high clinical significance. CLINICAL TRIAL REGISTRATION: The trial was registered with the Chinese Clinical Trial Registry at chictr.org.cn (registration number, ChiCTR2100055050) on December 31, 2021.

Optimum programmed intermittent epidural bolus interval time between 8 mL boluses of Ropivacaine 0.1% with sufentanil 0.3 µg/mL with dural puncture epidural technique for labor analgesia: A biased-coin up-and-down sequential allocation trial.

OBJECTIVE: The combination of dural puncture epidural (DPE) technique and programmed intermittent epidural bolus (PIEB) is a novel alternative labor analgesia regimen providing rapid analgesia onset and improved analgesia quality. However, the optimum PIEB settings for using the DPE technique remain unclear. DESIGN: Biased-coin up-and-down sequential allocation design. SETTING: Labor analgesia. PATIENTS: Forty nulliparous women requesting labor analgesia. INTERVENTIONS: Dural was punctured using a 25-gauge Whitacre needle. 12 mL of 0.1% ropivacaine with 0.3 µg/mL of sufentanil was used for initiation. Labor analgesia was maintained using the same solution with a fixed 8 mL volume beginning 1 h after initiation. The interval for the first patient was 60 min and varied for subsequent patients according to the biased-coin design (groups 60, 50, 40, and 30; interval 60, 50, 40, and 30 min, respectively). MEASUREMENTS: The primary outcome was adequate analgesia, defined as no request of patient-controlled epidural analgesia or provider boluses for 6 h after the epidural analgesia initiation or until the maternal cervix was fully dilated, whichever came first. The secondary outcomes included sensory blockade level, motor strength, maternal hypotension, and pruritus. RESULTS: The estimated effective interval in 90% of participants was 41.5 min (95% CI 39.5-43.5 min) and 40.5 min (95% CI 33.7-47.5 min) by the truncated Dixon and Mood method and the isotonic regression method, respectively, for the 40 women included. The proportions of patients with the highest sensory block level achieving or above T6 were 60%, 26%, 27%, and 0% in groups 30, 40, 50, and 60, respectively. One patient presented a Bromage score of 1. There was a low incidence of hypotension in all the groups with no need for vasopressor treatment. CONCLUSIONS: The optimum PIEB interval time between 8 mL boluses of ropivacaine 0.1% and sufentanil 0.3 µg/mL when using the DPE technique was approximately 41 min.

The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis.

Neutrophils play a vital role in the formation of arterial, venous and cancer-related thrombosis. Recent studies have shown that in a process known as NETosis, neutrophils release proteins and enzymes complexed to DNA fibers, collectively called neutrophil extracellular traps (NETs). Although NETs were originally described as a way for the host to capture and kill bacteria, current knowledge indicates that NETs also play an important role in thrombosis. According to recent studies, the destruction of vascular microenvironmental homeostasis and excessive NET formation lead to pathological thrombosis. In vitro experiments have found that NETs provide skeletal support for platelets, red blood cells and procoagulant molecules to promote thrombosis. The protein components contained in NETs activate the endogenous coagulation pathway to promote thrombosis. Therefore, NETs play an important role in the formation of arterial thrombosis, venous thrombosis and cancer-related thrombosis. This review will systematically summarize and explain the study of NETs in thrombosis in animal models and in vivo experiments to provide new targets for thrombosis prevention and treatment.

WS635 Attenuates the Anesthesia/Surgery-Induced Cognitive Impairment in Mice.

Anesthesia/surgery has been reported to be associated with perioperative neurocognitive disorder (PND) in patients and induces cognitive impairment in mice. Previous studies demonstrate cyclosporine A (CsA) attenuates the anesthesia/surgery-induced cognitive impairment in mice. However, CsA has immunosuppressive effects and may not be routinely used to prevent or treat PND in patients. WS635 is a nonimmunosuppressive CsA analog. We, therefore, set out to determine whether WS635 could mitigate the anesthesia/surgery-induced cognitive impairment in mice. We performed abdominal surgery under 1.4% isoflurane anesthesia (anesthesia/surgery) for 2 h in 9 month-old wild-type (WT) mice. We treated the mice with CsA (10 mg/kg) or different doses (13.2 mg/kg, 26.4 mg/kg and 52.8 mg/kg) of WS635 before and after the anesthesia/surgery. Barnes maze and fear conditioning system (FCS) were employed to evaluate the cognitive function in mice. We measured the amounts of postsynaptic density (PSD)-95, synaptophysin, and ATP in the hippocampus and cortex of the mice using western blot and ATP Colorimetric/Fluorometric Assay, respectively. We found that the treatment with 52.8 mg/kg, but not 13.2 mg/kg or 26.4 mg/kg, of WS635 attenuated the anesthesia/surgery-induced cognitive impairment in mice and the reductions in the amounts of PSD-95, synaptophysin, and ATP in the mice brain tissues. These results have established a system to study WS635 further and suggest that we need to perform more experiments to determine whether WS635 can ultimately be used as one of the interventions for PND in patients.

Ketamine activated glutamatergic neurotransmission by GABAergic disinhibition in the medial prefrontal cortex.

The fast-onset antidepressant actions of ketamine at subanaesthetic doses have attracted enormous interest in psychiatric disease treatment. However, the severe psychotomimetic side effects foster an urgent need to deeply understand the fast-onset antidepressant mechanism of ketamine. Ketamine, as a non-competitive NMDAR antagonist, increases the overall excitability of the mPFC, which is presumed to be essential for the antidepressant action of ketamine. However, the underlying mechanism is still elusive. Here, our results showed that low concentration of ketamine increased the activity and the excitatory/inhibitory ratio of pyramidal neurons; these changes were accompanied by diminished interneurons activity in the mPFC. Moreover, ketamine induced increases in excitatory transmission and antidepressant-like effects, which might rely on the functional intact of GABAergic system in the mPFC. These results suggest a critical role of the mPFC GABAergic system in the fast antidepressant effects of a subanaesthetic dose ketamine.

Repeated Nitrous Oxide Exposure Exerts Antidepressant-Like Effects Through Neuronal Nitric Oxide Synthase Activation in the Medial Prefrontal Cortex.

Clinical studies have demonstrated that exposure to the inhalational general anesthetic nitrous oxide (N2O) produces antidepressant effects in depressed patients. However, the mechanisms underlying the antidepressant effects of N2O remain largely unknown. Neuronal nitric oxide synthase (nNOS)-mediated nitric oxide (NO) synthesis is essential for brain function and underlies the molecular mechanisms of many neuromodulators. We hypothesized that activation of the nNOS/NO pathway in the medial prefrontal cortex (mPFC) might mediate the antidepressant effects of N2O. In this study, we revealed that repeated N2O exposure produced antidepressant-like responses in mice. Our mechanistic exploration showed that repeated N2O exposure increased burst firing activity and that the expression levels of BDNF with nNOS activation were dependent in the mPFC. In particular, the antidepressant-like effects of N2O were also antagonized by local nNOS inhibition in the mPFC. In summary, our results indicated that N2O exposure enhances BDNF expression levels and burst firing rates in an nNOS activation dependent manner, which might underlie the pharmacological mechanism of the antidepressant-like effects of N2O exposure. The present study appears to provide further mechanistic evidence supporting the antidepressant effects of N2O.

Propofol Protects Against TNF-α-induced Blood-brain Barrier Disruption via the PIM-1/eNOS/NO Pathway.

BACKGROUND: The Inflammatory cytokine, tumor necrosis factor-α (TNF-α), disrupts blood-brain barrier (BBB). Propofol reportedly exerts an anti-inflammatory effect in the central nervous system. OBJECTIVE: We hypothesized that propofol could provide a protective effect against TNF-α-induced disruption in human cerebral microvascular endothelial cells (hCMEC/D3 cells) and explored the underlying mechanisms. METHODS: The hCMEC/D3 cell monolayers were pretreated with propofol, followed by TNF-α treatment. The integrity of BBB was reflected by assessing the trans-endothelial electrical resistance (TEER) and determining the expression of proteins within tight junctions (TJs). The effect of propofol on TNF-α-modulated nitric oxide production was measured by a nitrate reductase assay kit. The expression of ZO-1, claudin-5, occludin, TNF receptor 1 (TNFR1), TNF receptor 2 (TNFR2), proviral-integration site for Moloney murine leukaemia virus (PIM)-1kinase, the phosphorylation of endothelial nitric oxide synthase at ser633 (peNOS-ser633) were detected by western blot. RESULTS: In hCMEC/D3 cells, TNF-α treatment markedly disrupted the integrity of BBB. Further, we found TNF-α treatment could increase the expression of PIM-1, then activate the phosphorylation of eNOS and induce the release of nitric oxide (NO). More importantly, we found that TNF- α-impaired BBB integrity could be reversed by propofol. CONCLUSION: These results suggest that the PIM-1/eNOS/NO pathway plays a vital role, in which Propofol protects against TNF-α-induced blood-brain barrier disruption.

Oxytocin Exerts Antidepressant-like effect by potentiating dopaminergic synaptic transmission in the mPFC.

Oxytocin (OT) and dopamine (DA) are two important elements that are closely related to mental and reward processes in the brain. OT controlled DA functional regulation contributes to various behaviours such as social reward, social cognition and emotion-related behaviours. Previous studies indicated that diminished dopaminergic transmission in the medial prefrontal cortex (mPFC) is correlated with the pathophysiology of depression. However, the interaction of OT and DA and their roles in antidepressant effects still require further exploration. Here, we investigated the antidepressant effect of OT through local mPFC administration, and further explored the underlying mechanisms that indicated that OT could strengthen dopaminergic synaptic transmission with OT receptor (OTR) activation dependent in the mPFC. Our results showed that local administration of OT in the mPFC exerts antidepressant (-like) effects in both naïve and social defeat stress (SDS) depressive animal model. Mechanism study suggested that OT enhances DA level with OTR activation dependent, and elevated mPFC DA levels might further enhance excitatory synaptic transmission by activating the D1/PKA/DARPP32 intracellular signalling pathway in the mPFC. Hence, our study revealed that the activation of OTR strengthens excitatory synaptic transmission via the potentiation of dopaminergic synaptic transmission, especially via D1R activation dependent, in the mPFC, which may be the underlying mechanism of antidepressant (-like) effects mediated by OT. With specifically activation of the D1/PKA/DAPRR32 signalling pathway, our results may augment the important role of OT in reward circuits in the central nervous system.

Ultrasound-Assisted Technology Versus the Conventional Landmark Location Method in Spinal Anesthesia for Cesarean Delivery in Obese Parturients: A Randomized Controlled Trial.

BACKGROUND: Spinal anesthesia, which is commonly used in cesarean deliveries, is often difficult to perform in obese parturients because of poorly palpable surface landmarks and positioning challenges. This study aimed to evaluate the benefits of ultrasound-assisted technology for performing spinal anesthesia in obese parturients. METHODS: Parturients with a body mass index (BMI) ≥30 kg/m scheduled for elective cesarean delivery were randomized to undergo spinal anesthesia using the conventional landmark location technique (landmark group, n = 40) or prepuncture ultrasound examination (ultrasound group, n = 40). All participants underwent spinal anesthesia in the lateral position. The primary outcome was the first-attempt success rate. Secondary outcomes were the number of skin punctures and needle passes, procedure times, patient satisfaction, changes in the intended interspace, and incidence of complications. RESULTS: The ultrasound group had a significantly higher first-attempt success rate (87.5% vs 52.5%; P = .001), fewer cases requiring >10 needle passes (1 vs 17; P < .001), and fewer skin punctures and needle passes (P < .001 for both). There was no statistically significant difference in the time taken to identify the needle insertion site between the 2 groups (202.5 vs 272.0 seconds; P = .580). Both the spinal injection time and total procedure time were significantly longer in the landmark group (P < .001). Patient satisfaction scores were significantly higher in the ultrasound group (P = .001). Among patients with BMI between 30 and 34.9 kg/m, there was no statistically significant difference in the first-attempt success rate (P = .407), number of cases with >10 needle passes (P = .231), spinal injection time (P = .081), or total procedure time (P = .729); however, more time was required to identify the needle insertion site in the ultrasound group (P < .001). For patients with BMI between 35 and 43 kg/m, the ultrasound group had a significantly higher first-attempt success rate (P ≤ .041), fewer cases with >10 needle passes (P ≤ .01), and shorter procedure times, including the time required to identify the needle insertion site (P < .001). CONCLUSIONS: Prepuncture ultrasound examination can facilitate spinal anesthesia in the lateral position in obese parturients (35 kg/m ≤ BMI ≤ 43 kg/m) by improving the first-attempt success rate, reducing the number of needle passes and puncture attempts, shortening the total procedure time, and improving patient satisfaction.

Cognitive Impairment and Endoplasmic Reticulum Stress Induced by Repeated Short-Term Sevoflurane Exposure in Early Life of Rats.

Sevoflurane is one of the most commonly used volatile anaesthetics for children, but the safety of prolonged or repeated clinical use of sevoflurane in infants or children is controversial. Here, we investigated the effects of sevoflurane on rats in early life and the time scale of those effects. Our behavioral results indicated that repeated short-term exposure of new-born rats to sevoflurane caused learning and memory impairment, while a single exposure of rats to sevoflurane was relatively safe. Further mechanistic investigation revealed that repeated sevoflurane exposure impaired long-term potentiation (LTP), downregulated the expression of certain synaptogenesis-related proteins (GluR1, PSD95) and upregulated proteins related to endoplasmic reticulum (ER) stress in the hippocampus. An ER stress inhibitor, tauroursodeoxycholic acid (TUDCA), reversed the changes in the levels of synaptic plasticity proteins. Our results provide new evidence for the clinical concerns regarding repeated sevoflurane anesthesia.

Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD.

Major depressive disorder (MDD) is a common neuropsychiatric disorder characterized by diverse symptoms. Although several antidepressants can influence dopamine system in the medial prefrontal cortex (mPFC), but the role of D1R or D2R subtypes of dopamine receptor during anti-depression process is still vague in PFC region. To address this question, we investigate the antidepressant effect of levo-stepholidine (l-SPD), an antipsychotic medication with unique pharmacological profile of D1R agonism and D2R antagonism, and clarified its molecular mechanisms in the mPFC. Our results showed that l-SPD exerted antidepressant-like effects on the Sprague-Dawley rat CMS model of depression. Mechanism studies revealed that l-SPD worked as a specific D1R agonist, rather than D2 antagonist, to activate downstream signaling of PKA/mTOR pathway, which resulted in increasing synaptogenesis-related proteins, such as PSD 95 and synapsin I. In addition, l-SPD triggered long-term synaptic potentiation (LTP) in the mPFC, which was blocked by the inhibition of D1R, PKA, and mTOR, supporting that selective activation of D1R enhanced excitatory synaptic transduction in PFC. Our findings suggest a critical role of D1R/PKA/mTOR signaling cascade in the mPFC during the l-SPD mediated antidepressant process, which may also provide new insights into the role of mesocortical dopaminergic system in antidepressant effects.

Combined spinal-epidural anesthesia with hypobaric ropivacaine in sitting position significantly increases the incidence of hypotension in parturients undergoing cesarean section.

AIM: Maternal position during induction of combined spinal-epidural anesthesia (CSEA) may affect hemodynamics and block characteristics. This study aimed to assess whether the sitting position is more likely to induce hypotension and higher block level than the lateral position in CSEA with hypobaric ropivacaine. METHODS: Ninety American Society of Anesthesiologists physical status I and II parturients undergoing elective cesarean section were randomized into three groups: the sitting, left-lateral, and right-lateral position groups. The L3-4 interspace was selected as the puncture site, and subarachnoid injection of 2.5 mL 0.5% hypobaric ropivacaine was administered. After the epidural catheter was inserted and fixed, the patient's position was changed to the left-leaning supine position. The blood pressure was measured once every 1 min followed by once every 3 min after the delivery. The sensory block level was regularly measured. RESULTS: A total of 88 parturients were included in this study. The incidences of hypotension in the sitting, left-lateral, and right-lateral position groups were 72%, 38%, and 40%, respectively, P = 0.012. Incidence and total dose of the phenylephrine supplement in the sitting position group were significantly higher than in the other two groups. The sitting position group showed a significantly higher block level (T4 [T3, T4]) as compared to the left-lateral (T6 [T5, T6]) and right-lateral position groups (T6 [T4, T6]), P < 0.01. The Apgar scores of neonates at 1 min and 5 min, and the pH values of the umbilical arterial and venous blood were similar among the three groups. CONCLUSION: As compared to the lateral positions, CSEA with hypobaric ropivacaine in the sitting position is more likely to cause hypotension and excessively high block level.

The rapid antidepressant and anxiolytic-like effects of YY-21 involve enhancement of excitatory synaptic transmission via activation of mTOR signaling in the mPFC.

Although antidepressants have been widely prescribed to treat patients with major depressive disease (MDD), there is little disagreement over the need for improved antidepressant therapeutics as the typical treatments have a slow therapeutic onset and moderate efficacy. In the present study, we assessed a novel compound, YY-21, from timosaponin B-III derived from sarsasapogenin of Anemarrhenae Rhizoma. From the initial results, we found that YY-21 obviously increased presynaptic glutamate release and enhanced long-term synaptic activity within 10min as determined by excitatory postsynaptic current (EPSC) and field excitatory postsynaptic potential (fEPSP) in medial prefrontal cortex (mPFC) slices, respectively. YY-21 demonstrated anxiolytic-like effects following acute administration in naïve animals and reversed the depressive-like and anxiety phenotypes induced by chronic unpredictable mild stress (CMS) with a relatively fast therapeutic onset. Furthermore, analysis of intracellular signaling pathways showed that YY-21 normalized the CMS-induced low protein levels of GluN2B, p-mTOR, synaptic-related proteins, such as BDNF, PSD-95 and GluA1. Pre-application of the mTOR-selective inhibitor rapamycin blocked YY-21-induced long-term synaptic enhancement. These findings suggest that the activation of BDNF-dependent mTOR signaling, which produces a rapid increase in the postsynaptic protein PSD-95 and GluA1 and further triggers the long-term enhancement of synaptic neurotransmission, may be the mechanism underlying the rapid antidepressant and anxiolytic effects induced by YY-21.