The effect of norepinephrine on ovarian dysfunction by mediating ferroptosis in mice model.

Studies have shown that stress is associated with ovarian dysfunction. Norepinephrine (NE), a classic stress hormone involved in the stress response, is less recognized for its role in ovarian function. In this study, an NE-treated mouse model is induced by intraperitoneal injection of NE for 4 weeks. Compared with normal control mice, NE-treated mice show disturbances in the estrous cycle, decreased levels of anti-Mullerian hormone (AMH) and estradiol (E2), and increased level of follicle-stimulating hormone (FSH). Additionally, the numbers of primordial follicles, primary follicles, secondary follicles, and antral follicles are decreased, whereas the number of atretic follicles is increased in NE-treated mice, indicating NE-induced ovarian dysfunction. RNA sequencing further reveals that genes associated with ferroptosis are significantly enriched in NE-treated ovarian tissues. Concurrently, the levels of reactive oxygen species (ROS), ferrous ions, and malondialdehyde (MDA) are increased, whereas the expression level of glutathione peroxidase 4 (GPX4) is decreased. To elucidate the mechanism of NE-induced ferroptosis in ovaries and the potential reversal by Coenzyme Q10 (CoQ10), an antioxidant, we conduct both in vitro and in vivo experiments. In vitro, the granulosa cell line KGN, when treated with NE, shows decreased cell viability, reduced expression of GPX4, elevated levels of ferrous ion and ROS, and increased MDA level. However, these NE-induced changes are reversed by the addition of CoQ10. Compared with the NE group, the NE-treated mice supplemented with CoQ10 present increased GPX4 level and decreased iron, ROS, and MDA levels. Moreover, the differential expression of genes associated with ferroptosis induced by NE is ameliorated by CoQ10 in NE-treated mice. Additionally, CoQ10 improves ovarian function, as evidenced by increased ovarian weight, more regular estrous cycles, and an increase in follicles at various stages of growth in NE-treated mice. In conclusion, NE induces ovarian dysfunction by triggering ferroptosis in ovarian tissues, and CoQ10 represents a promising approach for protecting reproductive function by inhibiting ferroptosis.

Association between Drug Use and Perception of Mental Health in Women Diagnosed with Fibromyalgia: An Observational Study.

BACKGROUND/OBJECTIVES: Fibromyalgia (FM) is a chronic syndrome characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, and mental health issues. It affects approximately 1.78% of the general population; an estimated 4:1 ratio between women and men is observed. It significantly impacts quality of life and carries both clinical and social stigma. This study aims to evaluate the relationship between drug use and mental health in female patients with fibromyalgia. METHODS: This study is prospective, observational, and cross-sectional. A questionnaire was administered to 544 subjects, achieving a representative sample size from a population of 800,000 subjects by using an algorithm for proportion estimation with a known sampling frame. The selection was non-random, making the sampling non-probabilistic. Logistic regression models were applied to assess the effect of drug use on perception of mental health; presence of symptoms such as comprehension and memory problems, insomnia, depression, and anxiety; and severity of cognitive symptoms and non-restorative sleep. To quantify the impact, odds ratios and confidence intervals have been observed. RESULTS: The findings indicate the non-recommended use of medications and reveal the ineffectiveness and adverse effects of drug interactions on mental health. The use of benzodiazepines and sedative-hypnotics is significantly associated with a negative perception of mental health. Benzodiazepines do not improve symptoms or significantly reduce their severity. SSRI antidepressants do not enhance mental health perception; however, when used exclusively, they are effective in reducing the severity, but not the prevalence, of cognitive symptoms. CONCLUSIONS: The results highlight the complexity of pharmacological management in FM and raise concerns about the inappropriate use of ineffective or counterproductive drug interactions affecting patients' mental health. They underscore the need for multidisciplinary and personalized strategies that include close and careful monitoring, as well as the simultaneous use of non-pharmacological treatments that have demonstrated evidence in improving quality of life without negatively affecting mental health, such as patient education, psychological therapy, physiotherapy, and mindfulness.

Non-opioid psychiatric medications for chronic pain: systematic review and meta-analysis.

Background: The escalating number of deaths related to opioid usage has intensified the pursuit of non-opioid alternatives for managing chronic pain. It's often observed that psychiatric comorbidities coexist in patients suffering from chronic pain. There are a variety of psychotropic medications that have demonstrated effectiveness in treating both psychiatric symptoms and pain. This systematic review and meta-analysis aim to assess the effectiveness of various psychiatric drugs in managing specific types of chronic pain, including fibromyalgia, neuropathic pain, and chronic low back pain. Methods: A comprehensive search of five major databases was conducted through February 2023 to identify randomized controlled trials (RCTs) that met our inclusion criteria, focusing on outpatients Over 18 years of age with chronic pain. The study assessed the effectiveness of duloxetine, mirogabalin, pregabalin, gabapentin, and tricyclic antidepressants (TCAs), including serotonin-norepinephrine reuptake inhibitors (SNRIs), across various chronic pain conditions such as fibromyalgia, neuropathic pain, and chronic low back pain. The primary outcome measures included pain reduction, improvement in function, and quality of life. Of the 29 RCTs in the systematic review, 20 studies qualified for the meta-analysis. The analysis was stratified by pain type and treatment duration (short-term ≤14 weeks vs. long-term >14 weeks), using Hedge's g standardized mean differences and a random-effects model, along with sensitivity and subgroup analyses. Results: The overall short-term intervention effect across all studies was significant (SMD -1.45, 95% CI -2.15 to -0.75, p < 0.001), with considerable heterogeneity (I2 = 99%). For fibromyalgia, both duloxetine and mirogabalin demonstrated substantial efficacy with SMDs of -2.42 (95% CI -3.67 to -1.18, p < 0.0001) and -2.10 (95% CI -3.28 to -0.92, p = 0.0005), respectively. Conversely, treatments for neuropathic pain and chronic low back pain, including those with amitriptyline and desipramine, did not show significant benefits. The effectiveness of gabapentin could not be conclusively determined due to limited representation in the data. Additionally, no consistent long-term benefits were observed for any of the medications. Conclusions: While the results of this study underscore the importance of exploring non-opioid alternatives for chronic pain management, particularly in light of the opioid crisis, it is crucial to interpret the findings carefully. Our analysis suggests that certain psychiatric medications, such Duloxetine and mirogabalin demonstrated significant short-term efficacy in fibromyalgia patients. However, their effectiveness in treating neuropathic pain and chronic low back pain was not statistically significant. Additionally, the effectiveness of gabapentin and other medications, such as pregabalin for neuropathic pain, could not be conclusively determined due to limited data and high study heterogeneity. No consistent long-term benefits were observed for any of the drugs studied, raising questions about their sustained efficacy in chronic pain management. These findings highlight the need for further research to understand better the role of psychiatric medications in managing specific chronic pain conditions without prematurely concluding that they are ineffective or unsuitable for these purposes.

Evaluating the Economic Impact of the PedAMINES App in Reducing Medication Errors in Pediatric Emergency Care: Cost-Effectiveness Analysis.

BACKGROUND: The administration of drugs in pediatric emergency care is a time-consuming process and is associated with a higher occurrence of medication errors compared with adult care. This is attributed to the intricacies of administration, which involve calculating doses based on the child's weight or age. To mitigate the occurrence of adverse drug events (ADEs), the PedAMINES (Pediatric Accurate Medication in Emergency Situations; Geneva University Hospitals) mobile app has been developed. This app offers a step-by-step guide for preparing and administering pediatric drugs during emergency interventions by automating the dose calculation process. Although previous simulation-based randomized controlled trials conducted in emergency care have demonstrated the efficacy of the PedAMINES app in reducing drug administration errors, there is a lack of evidence regarding its economic implications. OBJECTIVE: This study aims to evaluate the cost-effectiveness of implementing the PedAMINES app for 4 emergency drugs: epinephrine, norepinephrine, dopamine, and midazolam. METHODS: The economic evaluation was conducted by combining hospital data from 2019, previous trial outcomes, information extracted from existing literature, and PedAMINES maintenance costs. The cost per avoided medication error was calculated, along with the number of administrations needed to achieve a positive return on investment. Subsequently, Monte Carlo simulations were used to identify the key parameters contributing to result uncertainty. RESULTS: The study revealed the number of preventable errors per administration for the 4 examined drugs: 0.513 for epinephrine, 0.484 for norepinephrine, 0.500 for dopamine, and 0.671 for midazolam. The cost-effectiveness ratios per ADE prevented were computed as follows: US $4808 for epinephrine, US $9705 for norepinephrine, US $6957 for dopamine, and US $2074 for midazolam. Accounting for the economic impact of ADEs, the analysis estimated that 16 administrations of epinephrine, 17 of norepinephrine and dopamine, and 13 of midazolam would be required to attain a positive return on investment. This corresponds to roughly one-third of the annual administrations at a major university hospital in Switzerland. The primary factors influencing the uncertainty in the estimated cost per ADE include the cost of maintenance of the app, the likelihood of an ADE resulting from an administration error, and the frequency of underdosing in the trial's control group. CONCLUSIONS: A dedicated mobile app presents an economically viable solution to alleviate the health and economic burden of drug administration errors in in-hospital pediatric emergency care. The widespread adoption of this app is advocated to pool costs and extend the benefits on a national scale in Switzerland.

Effect of prophylactic infusion of norepinephrine on the prevention of hypotension during vertebroplasty: a randomized clinical trial.

BACKGROUND: Transient hypotension is a common occurrence during the implantation of bone cement. This placebo-controlled randomized clinical trial study investigated the effect of prophylactic infusion of norepinephrine on the incidence of hypotension in senior patients who underwent vertebroplasty. METHODS: The trial recruited patients who were greater than or equal to 65 years of age, had an American Society of Anesthesiologist physical status classification of I to III, and underwent vertebroplasty from August 2020 to August 2021 at the Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine in China. The patients were randomly grouped according to whether they received either a norepinephrine infusion of 0.05 µg/kg/min or an equivalent volume of saline 10 min before implantation of bone cement. Intraoperative hemodynamics were monitored continuously by the MostCare system at the following 7 time points: 10 min before implantation of bone cement and immediately, 30 s, 1, 3, 5, and 10 min after implantation of bone cement. We also recorded the number of hypotensive episodes and the total number of vasopressors after implantation of bone cement. Multivariable logistic regression was used to assess the risk factors associated with hypotension after implantation of bone cement. RESULTS: A total of 63 patients were randomized to the control group (n = 31; median [IQR] age, 74 [69-79] years) and the norepinephrine group (n = 32; median [IQR] age, 75 [71-79] years). The incidence of hypotension in the norepinephrine group was significantly lower than that in the control group after implantation of bone cement (12.5% vs. 45.2%; relative risk [RR], 3.61 [95% CI, 1.13-15.07]; P = 0.005). Moreover, the median (IQR) number of hypotensive episodes (0 [0-0] vs. 0 [0-2]; P = 0.005) and the total number of vasopressors (0 [0-0] vs. 0 [0-1]; P = 0.004) in the norepinephrine group were significantly lower than those in the control group. Furthermore, compared with the baseline, the MAP significantly decreased at 1 min (P = 0.007) and 3 min (P < 0.001) after bone cement implantation in the control group. However, the MAP at 3 min in the norepinephrine group was significantly higher than that in the control group (P < 0.001). The incidence of complications was not different between the groups. In multivariable logistic regression, the FRAIL score (OR, 2.29; 95% CI, 1.21-4.31) was identified as a risk factor associated with hypotension. CONCLUSION: Prophylactic infusion of norepinephrine before bone cement implantation can stabilize hemodynamics and reduce the incidence of hypotension after implantation of bone cement.

Effect of low-dose norepinephrine combined with goal-directed fluid therapy on postoperative pulmonary complications in lung surgery: A prospective randomized controlled trial.

STUDY OBJECTIVE: Postoperative pulmonary complications (PPCs), the predominant complications following lung surgery, are closely associated with intraoperative fluid therapy. This study investigates whether continuous low-dose norepinephrine infusion combined with goal-directed fluid therapy (GDFT) reduced the risk of PPCs after lung surgery relative to either GDFT alone or standard fluid treatment. DESIGN: A prospective, randomized controlled trial. SETTING: The First Affiliated Hospital of Anhui Medical University, Anhui, China. PATIENTS: The study included 184 patients undergoing elective thoracoscopic lung resection surgery. INTERVENTIONS: Patients were randomized into three groups based on different fluid treatment regimens: Group C received standard fluid treatment, Group G received GDFT, and Group N received continuous low-dose norepinephrine infusion combined with GDFT. MEASUREMENTS: The primary outcome was the incidence of PPCs, including respiratory infection, atelectasis, pneumothorax, pleural empyema, respiratory failure, pulmonary embolism and bronchopleural fistula, during the postoperative hospital stay. Secondary outcomes were hemodynamic variables and arterial blood gases. Additional recorded parameters included other postoperative complications such as bleeding, postoperative re-intubation, re-hospitalization within 30 days, and the length of hospital stay. MAIN RESULTS: Group N showed a significantly lower PPCs incidence during hospitalization compared to Group C (11.5 % vs 27.9 %; odds ratio, 2.98; 95 % confidence interval, 1.17-8.31; P = 0.023). No significant difference in PPCs was found between Group N and Group G (11.5 % vs 14.5 %; odds ratio, 1.31; 95 % confidence interval, 0.46-3.91; P = 0.616). Additionally, there were no significant differences among the three groups in the components of PPCs. Group N showed higher mean arterial pressure and stroke volume index intraoperatively compared to Group C. CONCLUSIONS: Continuous low-dose norepinephrine infusion combined with GDFT reduced PPCs incidence in elective lung surgery patients compared with standard fluid management, but showed no difference compared to GDFT alone. CLINICAL TRIAL REGISTRATION: ChiCTR2200064081.

Incidence of Hematoma Following Breast Reduction in Patients Taking Selective Serotonin Reuptake Inhibitor or Serotonin-Norepinephrine Reuptake Inhibitor: A Retrospective Review.

Background Selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) use is more common in the plastic surgery population compared to the general population. This study was designed to assess the theoretical effect of SSRIs and SNRIs on platelet function and the potential for increased bleeding risk. This study sought to establish the incidence of postoperative bleeding following routine bilateral breast reduction for patients on SSRIs or SNRIs. The outcomes of this study contribute to the discussion of whether these medications should be discontinued before elective surgery. Methodology A retrospective chart review of all patients who received bilateral breast reduction surgery over a 10-year period was performed. Patient charts were reviewed for postoperative hematoma formation as well as medications being used around the time of surgery. The rate of hematoma formation in patients actively taking SSRIs or SNRIs at the time of surgery was compared with the rest of the study population. Results A total of 1,022 patients met the inclusion criteria for the study. The overall incidence of postoperative hematoma was 7.7%. Of these, 1.9% of patients had clinically significant hematomas that required operative evacuation, and the remaining were treated conservatively. The only variable associated with a significantly higher risk of hematoma formation was advanced age (p = 0.005). Conclusions There was no significant difference in hematoma incidence after breast reduction in patients taking SNRIs or SSRIs compared with the general population. This contradicts some of the previously published literature and can hopefully guide clinicians in counseling their patients preoperatively.

[Acupuncture at stellate ganglion combined with western medication for orthostatic hypotension in Parkinson's disease: a randomized controlled trial].

OBJECTIVE: To observe the effect of acupuncture at stellate ganglion on orthostatic hypotension (OH) in Parkinson's disease (PD), and explore its action mechanism. METHODS: A total of 68 patients with OH in PD were randomly divided into a combination group (34 cases, 2 cases dropped out, 1 case was eliminated) and a western medication group (34 cases, 1 case was eliminated). Both groups received stable dose anti-PD western medication, the western medication group received oral midodrine hydrochloride tablets, 2.5 mg each time, 2 times a day. The combination group was treated with acupuncture at bilateral stellate ganglion on the basis of the western medication group, without retaining needles, once a day, 5 times a week. Both groups were treated for 2 weeks. Supine and orthostatic blood pressure, orthostatic hypotension questionnaire (OHQ) score, TCM syndrome score, unified Parkinson's disease rating scale (UPDRS) score before and after treatment in the two groups were observed, the level of serum norepinephrine (NE) was detected, and the clinical effect was evaluated. RESULTS: After treatment, orthostatic systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the combination group were increased compared with those before treatment (P<0.01), OHQ score, TCM syndrome score, UPDRS score were decreased compared with those before treatment (P<0.01); supine SBP in the western medication group was increased compared with that before treatment (P<0.05), OHQ score was decreased compared with that before treatment (P<0.05); the levels of serum NE in both groups were increased compared with those before treatment (P<0.01). After treatment, orthostatic SBP, orthostatic DBP and the level of serum NE in the combination group were higher than those in the western medication group (P<0.01, P<0.05), the OHQ score, TCM syndrome score, UPDRS score were lower than those in the western medication group (P<0.05, P<0.01). The total effective rate was 87.1% (27/31) in the combination group, which was higher than 63.6% (21/32) in the western medication group (P<0.05). CONCLUSION: Acupuncture at stellate ganglion can increase the orthostatic blood pressure in patients with OH in PD , improve clinical symptoms, and the mechanism may be related to the up-regulation of NE.

Examining resilience to Alzheimer's disease through the lens of monoaminergic neuromodulator systems.

The monoaminergic nuclei are thought to be some of the earliest sites of Alzheimer's disease (AD) pathology in the brain, with tau-containing pretangles appearing in these nuclei decades before the onset of clinical impairments. It has increasingly been recognized that monoamine systems represent a critical target of investigation towards understanding the progression of AD and designing early detection and treatment approaches. This review synthesizes evidence across animal studies, human neuropathology, and state-of-the-art neuroimaging and daily life assessment methods in humans, which demonstrate robust relationships between monoamine systems and AD pathophysiology and behavior. Further, the review highlights the promise of multimethod, multisystem approaches to studying monoaminergic mechanisms of resilience to AD pathology.

Safety of Peripherally Infused Sympathomimetic Vasopressors in the Intensive Care Unit and Emergency Department.

BACKGROUND: Sympathomimetic vasopressors may be administered through a peripheral catheter, but there are limited data available on the safety of peripheral use. OBJECTIVE: The purpose of this study was to analyze the safety of peripherally infused sympathomimetic vasopressors. METHODS: A multicenter, retrospective observational study was conducted to evaluate patients who received peripheral vasopressors. The study's primary outcome was to assess the incidence of extravasation during the administration of peripheral vasopressors. Secondary outcomes include avoidance of central venous catheter (CVC) placement and institution protocol deviations. RESULTS: There were 198 patients included in the study, of which 142 patients received norepinephrine, 48 patients received phenylephrine, and 8 patients received epinephrine peripherally. Extravasation events occurred in 11 (5.6%) patients. Seven patients required a pharmacologic antidote and 10 patients required a warm compress. No significant differences were seen in characteristics of patients who extravasated compared with those who did not. Protocol deviations identified during the study included 24 (12.1%) patients receiving doses above the protocol maximum, 19 (9.6%) with a body mass index above the protocol maximum, and 45 (22.7%) patients receiving peripheral vasopressor over 24 hours. The majority of patients were able to avoid CVC placement (59.1%). CONCLUSION AND RELEVANCE: Peripherally infused sympathomimetic vasopressors are safe to administer up to 24 hours with a low incidence of extravasation events while avoiding CVC placement in the majority of patients.

The sympathetic nervous system drives hyperinflammatory responses to Clostridioides difficile infection.

Clostridioides difficile infection (CDI) is a leading cause of hospital-acquired infections in the United States, known for triggering severe disease by hyperactivation of the host response. In this study, we determine the impact of the sympathetic nervous system (SNS) on CDI disease severity. Mouse models of CDI are administered inhibitors of SNS activity prior to CDI. Chemical sympathectomy or pharmacological inhibition of norepinephrine synthesis greatly reduces mortality and disease severity in the CDI model. Pharmacological blockade or genetic ablation of the alpha 2 adrenergic receptor ameliorates intestinal inflammation, disease severity, and mortality rate. These results underscore the role of the SNS and the alpha 2 adrenergic receptor in CDI pathogenesis and suggest that targeting neural systems could be a promising approach to therapy in severe disease.

Efficacy and safety of norepinephrine versus phenylephrine for post-spinal hypotension in preeclamptic patients: A systematic review and meta-analysis.

OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the fetomaternal outcomes after the administration of norepinephrine or phenylephrine for the treatment of post spinal hypotension in preeclamptic women undergoing a cesarean section. DATA SOURCES: We searched on PubMed, Embase, Scopus, Cochrane CENTRAL, and clinicaltrials.gov from inception till June 2024. STUDY SELECTION: Randomized controlled trials of preeclamptic women receiving norepinephrine or phenylephrine for post spinal hypotension were included. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted data onto an Excel spreadsheet. R version 4.4 was used for statistical analysis. Risk ratios (RR) and their 95% confidence intervals (CIs) were calculated and pooled using the random effects model. Cochrane's risk of bias (RoB 2) tool was used for quality assessment. This review has been registered with PROSPERO (CRD42024532740). RESULTS: A total of 4 trials, comprising 413 participants, were included in this review. 206 patients received norepinephrine, while 207 received phenylephrine. The incidence of maternal bradycardia was significantly lower in the norepinephrine group compared with the phenylephrine group (RR = 0.25, 95 % CI = 0.16 to 0.39, p < 0.01). There were no statistical differences in other maternal outcomes or in the umbilical artery and umbilical vein blood gas analysis values. We also analyzed adverse events such as nausea (RR = 1.00, 95 % CI: 0.62 to 1.60, p = 1.00) and vomiting (RR = 0.99, 95 % CI: 0.89 to 1.11, p = 0.61), but they did not show a significant association with any group. All the trials had a moderate or low risk of bias. CONCLUSION: Bolus doses of NE and PE for the treatment of post-spinal hypotension in preeclamptic women undergoing cesarean sections were found to exhibit comparable neonatal outcomes. However, NE provided superior maternal safety due to a lower incidence of bradycardia compared to PE.

Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity.

The mechanisms underlying obesity-induced insulin resistance remain incompletely understood, as impaired cellular insulin signaling, traditionally considered the primary driver of insulin resistance, does not always accompany impaired insulin action. Overnutrition rapidly increases plasma norepinephrine (NE), suggesting overactivation of the sympathetic nervous system (SNS). However, the role of the SNS in obesity is controversial, as both increased and decreased SNS activity (SNA) have been reported. Here, we show that reducing catecholamine (CA) release from the SNS protects against overnutrition-induced insulin resistance as well as hyperglucagonemia, adipose tissue dysfunction, and fatty liver disease, as we demonstrate utilizing a mouse model of inducible and peripherally restricted deletion of tyrosine hydroxylase (th; THΔper). A key mechanism through which heightened SNA induces insulin resistance is by triggering adipose tissue lipolysis. Increased SNA emerges as a critical driver in the pathogenesis of overnutrition-induced insulin resistance and metabolic disease independent of cellular insulin signaling.

An overview of the pathophysiology of agitation in Alzheimer's dementia with a focus on neurotransmitters and circuits.

Alzheimer's dementia (AD) is a progressive, neurodegenerative disease often accompanied by neuropsychiatric symptoms that profoundly impact both patients and caregivers. Agitation is among the most prevalent and distressing of these symptoms and often requires treatment. Appropriate therapeutic interventions depend on understanding the biological basis of agitation and how it may be affected by treatment. This narrative review discusses a proposed pathophysiology of agitation in Alzheimer's dementia based on convergent evidence across research approaches. Available data indicate that agitation in Alzheimer's dementia is associated with an imbalance of activity between key prefrontal and subcortical brain regions. The monoamine neurotransmitter systems serve as key modulators of activity within these brain regions and circuits and are rendered abnormal in AD. Patients with AD who exhibited agitation symptoms during life have alterations in neurotransmitter nuclei and related systems when the brain is examined at autopsy. The authors present a model of agitation in Alzheimer's dementia in which noradrenergic hyperactivity along with serotonergic deficits and dysregulated striatal dopamine release contribute to agitated and aggressive behaviors.

Adenosine 2A Receptors Link Astrocytic Alpha-1 Adrenergic Signaling to Wake-Promoting Dopamine Neurons.

BACKGROUND: Sleep and arousal disorders are common, but the underlying physiology of wakefulness is not fully understood. The locus coeruleus promotes arousal via alpha-1 adrenergic receptor (α1AR) driven recruitment of wake-promoting dopamine (DA) neurons in the ventral periaqueductal gray (vPAGDA neurons). α1AR expression is enriched on vPAG astrocytes, and chemogenetic activation of astrocytic Gq signaling promotes wakefulness. Astrocytes can release extracellular "gliotransmitters," such as ATP and adenosine, but the mechanism underlying how vPAG astrocytic α1ARs influence sleep/wake behavior and vPAGDA neuron physiology is unknown. METHODS: In this study, we utilized genetic manipulations with ex vivo calcium imaging in vPAGDA neurons and astrocytes, patch-clamp electrophysiology, and behavioral experiments in mice to probe our hypothesis that astrocytic α1ARs mediate noradrenergic modulation of wake-promoting vPAGDA neurons via adenosine signaling. RESULTS: Activation of α1ARs with phenylephrine increased calcium transients in vPAGDA neurons and vPAG astrocytes, and increased vPAGDA neuron excitability ex vivo. Chemogenetic Gq-DREADD activation of vPAG astrocytes similarly increased vPAGDA neuron calcium activity and intrinsic excitability. Conversely, shRNA knockdown of vPAG astrocytic α1ARs reduced the excitatory effect of phenylephrine on vPAGDA neurons and blunted arousal during the wake phase. Pharmacological blockade of adenosine 2A (A2A) receptors precludes the α1AR-induced increase in vPAGDA calcium activity and excitability in brain slices, as well as the wake-promoting effects of vPAG α1AR activation in vivo. CONCLUSIONS: We have identified a crucial role for vPAG astrocytic α1AR receptors in sustaining arousal through heightened excitability and activity of vPAGDA neurons mediated by local A2A receptors.

Impact of Dexmedetomidine on Hemodynamics, Plasma Catecholamine Levels, and Delirium Incidence Among Intubated Patients in the ICU--A Randomized Controlled Trial.

Objective: To investigate the impact of various sedative medications on hemodynamics and plasma levels of epinephrine (E) and norepinephrine (NE) in mechanically ventilated patients postoperatively in the intensive care unit (ICU). Methods: Ninety-seven patients admitted to the ICU undergoing postoperative mechanical ventilation with tracheal intubation and continuous analgesic sedation following general anesthesia were randomly assigned to either the observation group (dexmedetomidine) (n = 49) or the control group (propofol) (n = 48) in this randomized controlled trial. Upon transfer to the ICU, vital signs (heart rate [HR], respiratory rate [RR], mean arterial pressure [MAP]) were recorded prior to the initiation of the sedation treatment (T0), at one-hour post sedation (T1) and two hours following tracheal extubation (T2), plasma levels of epinephrine (E) and norepinephrine (NE) were measured at these time points. The incidence of delirium was recorded in both groups. Results: MAP between the two groups at both T0 and T1 At T2 plasma NE and HR were found to be lower in the observation group compared to the control group (P < 0.001). Among the patients receiving antihypertensive medication in the ICU, NE levels were significantly lower in the observation group compared to the control group (P = 0.019) Among the patients not receiving antihypertensive medication, both NE (P < 0.001) and MAP (P = 0.001) levels were lower in the observation group compared to the control group. The incidence of delirium in the observation group (dexmedetomidine) was not significantly different from that in the control group (propofol). Conclusion: With dexmedetomidine sedation, blood pressure fluctuated less, plasma catecholamine levels were lower, and sympathetic inhibition was stronger in patients before and after extubation. However, it did not significantly reduce the incidence of postoperative delirium.

DiDBiT-TMT: A Novel Method to Quantify Changes in the Proteomic Landscape Induced by Neural Plasticity.

Direct detection of biotinylated proteins (DiDBiT) is a proteomic method that can enrich and detect newly synthesized proteins (NSPs) labeled with bio-orthogonal amino acids with 20-fold improved detectability compared to conventional methods. However, DiDBiT has currently been used to compare only two conditions per experiment. Here, we present DiDBiT-TMT, a method that can be used to quantify NSPs across many conditions and replicates in the same experiment by combining isobaric tandem mass tagging (TMT) with DiDBiT. We applied DiDBiT-TMT to brain slices to determine changes in the de novo proteome that occur after inducing chemical long-term potentiation (cLTP) or treatment with the neuromodulator norepinephrine. We successfully demonstrated DiDBiT-TMT's capacity to quantitatively compare up to 9 samples in parallel. We showed that there is a minimal overlap among NSPs that are differentially expressed in cLTP-treated organotypic brain slices, norepinephrine-treated organotypic brain slices, and organotypic slices undergoing combinatorial treatment with norepinephrine and cLTP. Our results point to the possible divergence of the molecular mechanisms underlying these treatments and showcase the applicability of DiDBiT-TMT for studying neurobiology.

Minimum effective dose of intrathecal hyperbaric bupivacaine for cesarean section with and without prophylactic norepinephrine infusion: Randomized triple-blinded trial.

Background and Aims: Vasopressor usage can affect the rostral spread of intrathecal drug and, hence, its requirement during cesarean delivery. Although a decreased spread is evidenced with phenylephrine, there is no data for norepinephrine usage. The present study aimed to evaluate the minimum effective dose of intrathecal hyperbaric bupivacaine for cesarean section with and without prophylactic norepinephrine infusion. Material and Methods: Patients scheduled for elective cesarean section under combined spinal-epidural block were randomized to receive intravenous infusion of norepinephrine (0.05 µg/kg/min) or normal saline (placebo), initiated immediately after intrathecal injection. Postspinal hypotension in either group (systolic arterial pressure ≤0.8 baseline) was treated with norepinephrine 4 µg rescue. Dose of intrathecal hyperbaric bupivacaine (0.5%) was decided for individual patients using up-and-down sequential allocation method. Primary outcome measure was the minimum effective dose of intrathecal hyperbaric bupivacaine (0.5%) defined as ED50, while secondary observations included spinal block characteristics and neonatal outcomes. Results: Demographic parameters were statistically similar between both groups (P > 0.05). ED50 of intrathecal hyperbaric bupivacaine was 7.8 mg (95% confidence interval [CI]: 6.7-8.8) and 7.4 mg (95% CI: 6.1-8.7) for normal saline and norepinephrine group respectively (P = 0.810). Block characteristics were similar between both groups as was neonatal APGAR score, but umbilical artery base excess was greater for norepinephrine versus normal saline group (-4.4 ± 3.6 vs. -6.5 ± 2.4, P = 0.038). Conclusion: Use of prophylactic norepinephrine (0.05 µg/kg/min) during cesarean delivery does not require adjustment of intrathecal hyperbaric bupivacaine.

Palmitoylation regulates norepinephrine transporter uptake, surface localization, and total expression with pathogenic implications in postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is an adrenergic signaling disorder characterized by excessive plasma norepinephrine, postural tachycardia, and syncope. The norepinephrine transporter (NET) modulates adrenergic homeostasis via the reuptake of extracellular catecholamines and is implicated in the pathogenesis of adrenergic and neurological disorders. In this study, we reveal NET is palmitoylated in male Sprague-Dawley rats and Lilly Laboratory Cell Porcine Kidney (LLC-PK1) cells. S-palmitoylation, or the addition of a 16-carbon saturated fatty acid, is a reversible post-translational modification responsible for the regulation of numerous biological mechanisms. We found that LLC-PK1 NET is dynamically palmitoylated, and that inhibition with the palmitoyl acyltransferase (DHHC) inhibitor, 2-bromopalmitate (2BP) results in decreased NET palmitoylation within 90 min of treatment. This result was followed closely by a reduction in transport capacity, cell surface, and total cellular NET expression after 120 min of treatment. Increasing 2BP concentrations and treatment time revealed a nearly complete loss of total NET protein. Co-expression with individual DHHCs revealed a single DHHC enzyme, DHHC1, promoted wild-type (WT) hNET palmitoylation and elevated NET protein levels. The POTS-associated NET mutant, A457P, exhibits dramatically decreased transport capacity and cell surface levels which we have confirmed in the current study. In an attempt to recover A457P NET expression, we co-expressed the A457P variant with DHHC1 to drive expression as seen with the WT protein but instead saw an increase in NET N-terminal immuno-detectable forms and fragments. Elimination of a potential palmitoylation site at cysteine 44 in the N-terminal tail of hNET resulted in a low expression phenotype mimicking the A457P hNET variant. Further investigation of A457P NET palmitoylation and surface expression is necessary, but our preliminary novel findings reveal palmitoylation as a mechanism of NET regulation and suggest that dysregulation of this process may contribute to the pathogenesis of adrenergic disorders like POTS.

Social isolation promotes tumor immune evasion via ß2-adrenergic receptor.

Social isolation is a recognized risk factor for tumor initiation and mortality, but the role and mechanisms responsible for social isolation on tumor progression are poorly understood. In this study, we found that social isolation contributed to accelerated tumor growth and induced a remodeling of the tumor immune microenvironment, resulting in immunosuppression. Mechanistically, social isolation triggered the activation of the sympathetic nervous system, leading to impaired CD8+ T cell antitumor immune responses by activating ß-adrenergic receptor 2 (ß2-AR), which highly expressed on tumor-infiltrating CD8+ T cells. Pharmacological inhibition of ß2-AR signaling effectively enhanced CD8+ T cell anti-tumor immune responses and improved the efficacy of anti-PD-1 immunotherapy in the context of social isolation. Thus, our study uncovers a mechanism through which social isolation induces tumor immune evasion and offers potential directions for cancer immunotherapy in socially isolated patients.