Dexmedetomidine Prolongs Lidocaine Intravenous Regional Anesthesia in Rats by Blocking the Hyperpolarization-Activated Cation Current.

Purpose: Intravenous regional anesthesia (IVRA) using lidocaine provides effective localized analgesia but its duration is limited. The mechanism by which dexmedetomidine enhances lidocaine IVRA is unclear but may involve modulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Materials and Methods: Lidocaine IVRA with varying dexmedetomidine concentrations was performed in the tails of Sprague-Dawley rats. Tail-flick and tail-clamping tests assessed IVRA analgesia and anesthesia efficacy and duration. Contributions of α2 adrenergic receptors and HCN channels were evaluated by incorporating an α adrenergic receptor antagonist, the HCN channel inhibitor ZD7288, and the HCN channel agonist forskolin. Furthermore, whole-cell patch clamp electrophysiology quantified the effects of dexmedetomidine on HCN channels mediating hyperpolarization-activated cation current (Ih) in isolated dorsal root ganglion neurons. Results: Dexmedetomidine dose-dependently extended lidocaine IVRA duration and analgesia, unaffected by α2 receptor blockade. The HCN channel inhibitor ZD7288 also prolonged lidocaine IVRA effects, while the HCN channel activator forskolin shortened effects. In dorsal root ganglion neurons, dexmedetomidine concentration-dependently inhibited Ih amplitude and shifted the voltage-dependence of HCN channel activation. Conclusion: Dexmedetomidine prolongs lidocaine IVRA duration by directly inhibiting HCN channel activity, independent of α2 adrenergic receptor activation. This HCN channel inhibition represents a novel mechanism underlying the anesthetic and analgesic adjuvant effects of dexmedetomidine in IVRA.

Dexmedetomidine protects the uterus against ischemia-reperfusion injury in rats.

OBJECTIVE: This study aimed to analyze the histopathological and biochemical effects of dexmedetomidine on the rat uteri exposed to experimental ischemia-reperfusion injury. MATERIALS AND METHODS: Twenty-four female rats were randomly divided into three groups. Group 1 was defined as the control group. An experimental uterine ischemia-reperfusion model was created in Group 2. Group 3 was assigned as the treatment group. Similar uterine ischemia-reperfusion models were created for the rats in Group 3, and then, unlike the other groups, 100 µg/kg of dexmedetomidine was administered intraperitoneally immediately after the onset of reperfusion. In blood biochemical analysis, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA), interleukin 1beta (IL-1ß), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels were measured. In the histopathological analyses, endometrial epithelial glandular changes (leukocytosis, cell degeneration) and endometrial stromal changes (congestion, edema) were analyzed using the tissue damage scoring system. RESULTS: It was observed that IL-1ß, IL-6, and TNF-α levels were significantly suppressed in Group 3 compared to Group 2 (p=0.001, p<0.001 and p=0.001, respectively). MDA level was noted as the highest in Group 2. The MDA value in Group 3 was measured at 5.37±0.82, which was significantly decreased compared to Group 2 (p<0.001). An increase in antioxidant enzyme activities (SOD and GSH-PX) was observed in Group 3 compared to Group 2 (p=0.001 and p=0.006, respectively). In our histopathological analysis, a significant improvement in endometrial epithelial glandular and endometrial stromal changes was revealed in Group 3 compared to Group 2 (p<0.001). CONCLUSIONS: In our study, it has been documented that dexmedetomidine protects the uterine tissue against ischemia-reperfusion injury.

Sedative and cardiorespiratory effects of dexmedetomidine alone or combined with acepromazine in healthy cats.

The purpose of this study was to assess sedation, emesis and cardiovascular effects of dexmedetomidine alone or combined with acepromazine in healthy cats. Fourteen male cats aged 0.9 ± 0.5 years and weighing 3.7 ± 0.7 kg were randomly assigned to one of two experimental groups: GD, dexmedetomidine 5 µg/kg; and GDA, dexmedetomidine 5 µg/kg with acepromazine 0.03 mg/kg, all intramuscularly. Measurements were recorded at baseline, at 20 minutes and then at 10-minute intervals following sedation and included heart rate (HR), respiratory rate (FR), systolic arterial pressure (SAP), rectal temperature (RT), number of episodes of emesis and sedation score (0-4). Data were compared using ANOVA for repeated measures followed by Sídák and Dunnet test. Sedation scores were compared between groups at T20 using Mann-Whitney test. Significance was considered when P <0.05. At T20, HR was significantly lower in GDA (99 ± 14 beats/min) compared with GD (133 ± 19 beats/min) and SAP was significantly lower in both groups compared with baseline (126 ± 14 vs. 148 ± 26 and 111 ± 13 vs. 144 ± 17 mmHg in GD and GDA, respectively). Duration of sedation was similar between groups, although sedation scores differed significantly at T20, with 1 (0-4) in GD and 4 (4-4) in GDA. More episodes of emesis were recorded in GD compared with GDA. The combination of dexmedetomidine and acepromazine produced more profound sedation with faster onset and lower incidence of emesis compared with dexmedetomidine alone in healthy cats.

Comparison between dexmedetomidine and a combination of medetomidine-vatinoxan on muscle tissue saturation in privately-owned adult dogs undergoing intradermal testing.

This double-blinded randomized cross-over study compared the muscle tissue oxygen saturation (StO2) measured at the sartorius muscle after intramuscular (IM) injection of dexmedetomidine hydrochloride (HCl) and co-administration of vatinoxan HCl, a peripheral α2-adrenoceptor antagonist, and medetomidine HCl in healthy privately-owned dogs undergoing intradermal testing (IDAT). After written owner consent, dogs received IM injections of either dexmedetomidine (0.5 mg/m2, DEX) or medetomidine (1 mg/m2) and vatinoxan (20 mg/m2) (MVX). Once sedated, intradermal injections were given on the lateral thorax of each dog, and the study was repeated with the alternative sedation on the opposite side one week later. At the end of the study, sedation was reversed with atipamezole (5 mg/m2). Depth of sedation, cardiopulmonary parameters, StO2, and rectal temperature were recorded and compared using mixed effect linear models (α ≤ 0.05). MVX achieved adequate sedation faster [median (interquartile range), 10 (8, 10) minutes] compared to DEX [18 (15, 22) minutes; hazard ratio = 7.44, p = 0.013), with higher scores at 10- and 15-min post-injection. StO2 was significantly reduced for 30 min after injection (p < 0.001), independently of the treatment (p = 0.68). Cardiopulmonary variables favored MVX. However, higher heart rate did not correlate with improved StO2. There was no difference in either subjective or objective assessment of the wheal size between sedations (p > 0.05). Both sedation protocols, MVX and DEX, were deemed suitable for IDAT in dogs, with mild reductions in StO2 measured at the sartorius muscle that were not significantly different between treatments.

Anti-inflammatory potential of remimazolam: A laboratory and clinical investigation.

BACKGROUND: Anesthetic agents, particularly intravenous anesthetics, may affect immune function and tumorigenic factors. We herein investigated whether the anti-inflammatory effects of anesthetic agents are attributed to their antioxidant properties. The antioxidant and anti-inflammatory effects of remimazolam, a new anesthetic, remain unclear. We hypothesized that remimazolam exerts anti-inflammatory effects due to its antioxidant properties, which may affect the postoperative inflammatory response. This retrospective clinical study examined this hypothesis using laboratory and clinical approaches. METHODS: The antioxidant effects of remimazolam and dexmedetomidine were assessed by electron spin resonance (ESR) spectroscopy, and postoperative inflammatory responses were compared in 143 patients who underwent transcatheter aortic valve replacement at Kindai University Hospital between April 2021 and December 2022. The primary endpoint was the presence or absence of the antioxidant effects of the anesthetics themselves using ESR. RESULTS: Remimazolam at clinical concentrations exerted antioxidant effects, whereas dexmedetomidine did not. Increases in C-reactive protein (CRP) levels on POD3 from preoperative values were significantly smaller in the remimazolam group than in the dexmedetomidine group (1.33 ± 1.29 vs. 2.17 ± 1.84, p = .014). CONCLUSIONS: Remimazolam exerted stronger anti-inflammatory effects than dexmedetomidine, and these effects were enhanced by its antioxidant properties, which may have affected postoperative CRP production.

Hypothermia Inhibits Dexmedetomidine-Induced Contractions in Isolated Rat Aortae.

Dexmedetomidine is widely used to induce sedation in the perioperative period. This study examined the effect of hypothermia (33 and 25 °C) on dexmedetomidine-induced contraction in an endothelium-intact aorta with or without the nitric oxide synthase inhibitor NW-nitro-L-arginine methyl ester (L-NAME). In addition, the effect of hypothermia on the contraction induced by dexmedetomidine in an endothelium-denuded aorta with or without a calcium-free Krebs solution was examined. The effects of hypothermia on the protein kinase C (PKC), myosin light chain (MLC20) phosphorylation, and Rho-kinase membrane translocation induced by dexmedetomidine were examined. Hypothermia inhibited dexmedetomidine-induced contraction in the endothelium-intact aorta with L-NAME or endothelium-denuded aorta. Hypothermia had almost no effect on the dexmedetomidine-induced contraction in the endothelium-denuded aorta with the calcium-free Krebs solution; however, the subsequent contraction induced by the addition of calcium was inhibited by hypothermia. Conversely, the transition from profound hypothermia back to normothermia reversed the hypothermia-induced inhibition of subsequent calcium-induced contractions. Hypothermia inhibited any contraction induced by KCl, PDBu, and NaF, as well as PKC and MLC20 phosphorylation and Rho-kinase membrane translocation induced by dexmedetomidine. These results suggest that hypothermia inhibits dexmedetomidine-induced contraction, which is mediated mainly by the impediment of calcium influx and partially by the attenuation of pathways involving PKC and Rho-kinase activation.

Effects of Dexmedetomidine on Cognitive Function, Oxidative Stress and Brain Protection in Patients Undergoing Craniocerebral Surgery.

BACKGROUND: The protective mechanism of dexmedetomidine on the brains of patients undergoing craniocerebral surgery remains unclear. The aim of this study was to examine the impact of dexmedetomidine on cognitive function, oxidative stress, and brain protection in such patients. METHODS: Fifty-four patients who underwent craniocerebral surgery at our hospital from January 2020 to June 2023 were retrospectively selected as study subjects. They were divided into two groups: the control group (n = 27) and the study group (n = 27), based on different auxiliary anesthesia protocols. Patients in the study group received dexmedetomidine before anesthesia induction, using a midline intravenous pump to assist anesthesia, while the control group received an equivalent amount of normal saline. The remaining anesthesia induction and maintenance protocols were consistent for both groups. Cognitive function was assessed using the Mini Mental State Examination (MMSE) before and 1 day after surgery for both groups. Oxidative stress indicators, including malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) levels in the serum of both groups, were measured using enzyme-linked immunosorbent assay (ELISA). Additionally, changes in postoperative brain injury indicators, namely neuron-specific enolase (NSE) and central nervous system-specific protein (S100ß), were detected and compared in the serum of both groups. Concurrently, postoperative adverse reactions were recorded for both groups. RESULTS: The MMSE scale scores of both groups of patients 24 hours after surgery were significantly lower than those before surgery. However, the MMSE scale scores of the study group patients were notably higher than those in the control group, with a statistically significant difference (p < 0.05). One hour after surgery, the serum levels of MDA, GSH-Px, and SOD in both groups of patients were significantly elevated compared to pre-surgery levels. Yet, the study group exhibited significantly lower levels of MDA, GSH-Px, and SOD in comparison to the control group, and these differences were statistically significant (p < 0.05). The serum levels of NSE and S100ß in both groups were markedly higher than preoperative levels 24 hours after surgery. However, the study group demonstrated significantly lower levels of serum NSE and S100ß compared to the control group, with a statistically significant difference (p < 0.05). The incidence of postoperative complications in the study group was 7.41% (2/27), indicating a decreasing trend compared to 18.52% (5/27) in the control group. However, this difference did not reach statistical significance (χ2 = 1.477, p = 0.224). CONCLUSION: Dexmedetomidine-assisted anesthesia in craniocerebral surgery can effectively enhance postoperative cognitive function, mitigate oxidative stress, and facilitate overall postoperative recovery for patients. The intervention exhibits a favorable safety profile with no reported serious adverse reactions, establishing it as a relatively safe and reliable approach.

Trial watch: dexmedetomidine in cancer therapy.

Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist that is widely used in intensive and anesthetic care for its sedative and anxiolytic properties. DEX has the capacity to alleviate inflammatory pain while limiting immunosuppressive glucocorticoid stress during major surgery, thus harboring therapeutic benefits for oncological procedures. Recently, the molecular mechanisms of DEX-mediated anticancer effects have been partially deciphered. Together with additional preclinical data, these mechanistic insights support the hypothesis that DEX-induced therapeutic benefits are mediated via the stimulation of adaptive anti-tumor immune responses. Similarly, published clinical trials including ancillary studies described an immunostimulatory role of DEX during the perioperative period of cancer surgery. The impact of DEX on long-term patient survival remains elusive. Nevertheless, DEX-mediated immunostimulation offers an interesting therapeutic option for onco-anesthesia. Our present review comprehensively summarizes data from preclinical and clinical studies as well as from ongoing trials with a distinct focus on the role of DEX in overcoming (tumor microenvironment (TME)-imposed) cancer therapy resistance. The objective of this update is to guide clinicians in their choice toward immunostimulatory onco-anesthetic agents that have the capacity to improve disease outcome.

Dexmedetomidine Alleviates Propofol Infusion Syndrome-Induced Myocardial Injury through Inhibiting Ferroptosis Associated with Accumulation of Reactive Oxygen Species.

OBJECTIVE: To observe the effect of dexmedetomidine (Dex) on propofol infusion syndrome (PRIS)-induced myocardial injury and explore the roles of ferroptosis and accumulation of reactive oxygen species (ROS). METHODS: Eighteen male Sprague-Dawley rats were evenly divided into the control group, model group and test group (n=6/group) based on a computer-generated random number table. The PRIS-induced myocardial injury model was prepared in the model group and test group through a 12 h-caudal vein infusion of 1% propofol medium and long chain fat emulsion injection at a rate of 20 mg·Kg-1·h-1 for the first 6 h and 40 mg·Kg-1·h--1 for the last 6 h, and meanwhile the test group was treated by Dex. The control group received the same amount of normal saline through the caudal vein. The following indicators were compared between the three groups including myocardial pathological results, enzymatic changes of myocardial injury, ferroptosis of myocardial cells and accumulation of ROS. RESULTS: Dex alleviated the myocardial pathological injury caused by propofol infusion. Propofol infusion caused time-dependent enzymatic changes of myocardial injury and Dex alleviated these enzymatic changes. Dex alleviated the ferroptosis of myocardial cells and accumulation of ROS caused by propofol infusion. CONCLUSIONS: Dex could alleviate PRIS-induced myocardial injury by inhibiting ferroptosis associated with accumulation of ROS. Combined sedation using propofol and Dex might be a potential strategy for the prevention and treatment of PRIS-induced cardiotoxicity.

COMPARISON OF SUBCUTANEOUS ALFAXALONE AND SUBCUTANEOUS ALFAXALONE-DEXMEDETOMIDINE FOR SEDATION IN THE HOUSTON TOAD (ANAXYRUS HOUSTONENSIS).

The Houston toad (Anaxyrus houstonensis), a primarily terrestrial amphibian of south-central Texas, has been listed as federally endangered since 1970. Sedation is an important tool for obtaining diagnostics and providing treatment in this species. This prospective, randomized, and blinded study compared the sedative effects of SC alfaxalone (Protocol A) at approximately 12 mg/kg (median [range] = 12.70 [12.09-13.95] mg/kg] to SC alfaxalone-dexmedetomidine (Protocol AD) at approximately 12 mg/kg (median [range] = 12.68 [12.16-13.56] mg/kg) and 0.1 mg/kg (median [range] = 0.1 [0.07-0.13] mg/kg), respectively, in adult Houston toads (n = 26). Toads from Protocol AD received atipamezole SC at approximately 1 mg/kg (median [range] = 0.96 [0.75-1.25] mg/kg) 45 min postinduction, whereas toads from Protocol A received the equivalent volume of SC sterile saline at the same time point. Heart rate, gular rate, and times to first effect, loss of righting reflex, ability to position for radiographs, loss of nociception, return of righting reflex, and full recovery were recorded. A significantly greater number of toads lost righting reflex, positioned for radiographs, and lost nociception with Protocol AD compared with Protocol A. Additionally, time to return of righting reflex and time to full recovery were significantly longer with Protocol AD than with Protocol A. The protocols did not differ significantly in time to first effect, time to radiographic positioning, or time to loss of nociception. Histologic examination of four toads euthanized during the study revealed acute injection site reactions from all administered drugs, including saline. No clinical adverse reactions were observed. This study demonstrates that the combination of SC alfaxalone and dexmedetomidine results in deeper sedation than SC alfaxalone alone, but also correlates with longer recovery times despite antagonist administration.

Activating astrocytic α2A adrenoceptors in hippocampus reduces glutamate toxicity to attenuate sepsis-associated encephalopathy in mice.

BACKGROUND: Glutamate metabolism disorder is an important mechanism of sepsis-associated encephalopathy (SAE). Astrocytes regulate glutamate metabolism. In septic mice, α2A adrenoceptor (α2A-AR) activation in the central nervous system provides neuroprotection. α2A-ARs are expressed abundantly in hippocampal astrocytes. This study was performed to determine whether hippocampal astrocytic α2A-AR activation confers neuroprotection against SAE and whether this protective effect is astrocyte specific and achieved by the modulation of glutamate metabolism. METHODS: Male C57BL/6 mice with and without α2A-AR knockdown were subjected to cecal ligation and puncture (CLP). They were treated with intrahippocampal guanfacine (an α2A-AR agonist) or intraperitoneal dexmedetomidine in the presence or absence of dihydrokainic acid [DHK; a glutamate transporter 1 (GLT-1) antagonist] and/or UCPH-101 [a glutamate/aspartate transporter (GLAST) antagonist]. Hippocampal tissue was collected for the measurement of astrocyte reactivity, GLT-1 and GLAST expression, and glutamate receptor subunit 2B (GluN2B) phosphorylation. In vivo real-time extracellular glutamate concentrations in the hippocampus were measured by ultra-performance liquid chromatography tandem mass spectrometry combined with microdialysis, and in vivo real-time hippocampal glutamatergic neuron excitability was assessed by calcium imaging. The mice were subjected to the Barnes maze and fear conditioning tests to assess their learning and memory. Golgi staining was performed to assess changes in the hippocampal synaptic structure. In vitro, primary astrocytes with and without α2A-AR knockdown were stimulated with lipopolysaccharide (LPS) and treated with guanfacine or dexmedetomidine in the presence or absence of 8-bromo- cyclic adenosine monophosphate (8-Br-cAMP, a cAMP analog). LPS-treated primary and BV2 microglia were also treated with guanfacine or dexmedetomidine. Astrocyte reactivity, PKA catalytic subunit, GLT-1 an GLAST expression were determined in primary astrocytes. Interleukin-1ß, interleukin-6 and tumor necrosis factor-alpha in the medium of microglia culture were measured. RESULTS: CLP induced synaptic injury, impaired neurocognitive function, increased astrocyte reactivity and reduced GLT-1 and GLAST expression in the hippocampus of mice. The extracellular glutamate concentration, phosphorylation of GluN2B at Tyr-1472 and glutamatergic neuron excitability in the hippocampus were increased in the hippocampus of septic mice. Intraperitoneal dexmedetomidine or intrahippocampal guanfacine administration attenuated these effects. Hippocampal astrocytes expressed abundant α2A-ARs; expression was also detected in neurons but not microglia. Specific knockdown of α2A-ARs in hippocampal astrocytes and simultaneous intrahippocampal DHK and UCPH-101 administration blocked the neuroprotective effects of dexmedetomidine and guanfacine. Intrahippocampal administration of DHK or UCPH-101 alone had no such effect. In vitro, guanfacine or dexmedetomidine inhibited astrocyte reactivity, reduced PKA catalytic subunit expression, and increased GLT-1 and GLAST expression in primary astrocytes but not in primary astrocytes that received α2A-AR knockdown or were treated with 8-Br-cAMP. Guanfacine or dexmedetomidine inhibited microglial reactivity in BV2 but not primary microglia. CONCLUSIONS: Our results suggest that neurocognitive protection against SAE after hippocampal α2A-AR activation is astrocyte specific. This protection may involve the inhibition of astrocyte reactivity and alleviation of glutamate neurotoxicity, thereby reducing synaptic injury. The cAMP/protein kinase A (PKA) signaling pathway is a potential cellular mechanism by which activating α2A-AR modulates astrocytic function.

Suppression of cerebral ischemia injury induced blood brain barrier breakdown by dexmedetomidine via promoting CCN1.

BACKGROUND: Blood-brain barrier (BBB) could aggravate cerebral ischemia injury. Dexmedetomidine (Dex) has been believed to play a protective role in cerebral ischemia injury-induced BBB injury. METHODS: Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD) models were established to simulate cerebral ischemia injury. Animal experiments included 4 groups, Sham, MCAO, MCAO+Dex, MCAO+Dex+sh-CCN1. Generally applicable gene set enrichment analysis was performed to analyze gene expression difference. Total collagen content and Evans blue staining were performed to measure infarct ratio and BBB breakdown, respectively. The cell apoptosis, mRNA and protein expression were measured through flow cytometry, PCR, and western blotting, respectively. The levels of IL-1ß, TNF-α, and IL-6 in serum were measured with commercial ELISA kits. RESULTS: Dex greatly promoted the expression level of CCN1. Dex suppressed cerebral ischemia injury, increased tight junction protein expression, improved the memory ability and neurological function of MCAO rats through targeting CCN1. The significant increase of inflammatory factors in the serum of MCAO rats were suppressed by Dex. Dex suppressed OGD induced increase of HRP permeability and promoting tight junction protein expression in vitro through regulating CCN1. The neurological function evaluation was performed with Neurological Severity Score (NSS) and Longa Score Scale. CONCLUSIONS: Dex could remarkably alleviate cerebral ischemia injury by inhibiting BBB breakdown, inflammatory response, and promoting neurological function and tight junction protein expression via up-regulating CCN1. This study might provide a novel therapeutic target for the prevention and treatment of cerebral ischemia injury-induced BBB.

In Vivo Evaluation of Brain [18F]F-FDG Uptake Pattern Under Different Anaesthesia Protocols.

BACKGROUND/AIM: Since the use of anaesthetics has the drawback of altering radiotracer distribution, preclinical positron emission tomography (PET) imaging findings of anaesthetised animals must be carefully handled. This study aimed at assessing the cerebral [18F]F-FDG uptake pattern in healthy Wistar rats under four different anaesthesia protocols using microPET/magnetic resonance imaging (MRI) examinations. MATERIALS AND METHODS: Post-injection of 15±1.2 MBq of [18F]F-FDG, either while awake or during the isoflurane-induced incubation phase was applied. Prior to microPET/MRI imaging, one group of the rats was subjected to forane-only anaesthesia while the other group was anaesthetised with the co-administration of forane and dexmedetomidine/Dexdor® Results: While as for the whole brain it was the addition of dexmedetomidine/Dexdor® to the anaesthesia protocol that generated the differences between the radiotracer concentrations of the investigated groups, regarding the cortex, the [18F]F-FDG accumulation was rather affected by the way of incubation. To ensure the most consistent and highest uptake, forane-induced anaesthesia coupled with an awake uptake condition seemed to be most suitable method of anaesthetisation for cerebral metabolic assessment. Diminished whole brain and cortical tracer accumulation detected upon dexmedetomidine/Dexdor® administration highlights the significance of the mechanism of action of different anaesthetics on radiotracer pharmacokinetics. CONCLUSION: Overall, the standardization of PET protocols is of utmost importance to avoid the confounding factors derived from anaesthesia.

Mapping cerebral perfusion in mice under various anesthesia levels using highly sensitive BOLD MRI with transient hypoxia.

Cerebral perfusion is critical for the early detection of neurological diseases and for effectively monitoring disease progression and treatment responses. Mouse models are widely used in brain research, often under anesthesia, which can affect vascular physiology. However, the impact of anesthesia on regional cerebral blood volume and flow in mice has not been thoroughly investigated. In this study, we have developed a whole-brain perfusion MRI approach by using a 5-second nitrogen gas stimulus under inhalational anesthetics to induce transient BOLD dynamic susceptibility contrast (DSC). This method proved to be highly sensitive, repeatable within each imaging session, and across four weekly sessions. Relative cerebral blood volumes measured by BOLD DSC agree well with those by contrast agents. Quantitative cerebral blood volume and flow metrics were successfully measured in mice under dexmedetomidine and various isoflurane doses using both total vasculature-sensitive gradient-echo and microvasculature-sensitive spin-echo BOLD MRI. Dexmedetomidine reduces cerebral perfusion, while isoflurane increases cerebral perfusion in a dose-dependent manner.

Possible Involvement of Protein Binding Inhibition in Changes in Dexmedetomidine Concentration in Extracorporeal Circuits during Midazolam Use.

It was recently reported that the dexmedetomidine concentration within the extracorporeal circuit decreases with co-administration of midazolam. In this study, we investigated whether displacement of dexmedetomidine by midazolam from the binding site of major plasma proteins, human serum albumin (HSA) and α1-acid glycoprotein (AAG), would increase levels of free dexmedetomidine that could be adsorbed to the circuit. Equilibrium dialysis experiments indicated that dexmedetomidine binds to a single site on both HSA and AAG with four times greater affinity than midazolam. Midazolam-mediated inhibition of the binding of dexmedetomidine to HSA and AAG was also examined. The binding of dexmedetomidine to these proteins decreased in the presence of midazolam. Competitive binding experiments suggested that the inhibition of binding by midazolam was due to competitive displacement at site II of HSA and due to non-competitive displacement at the site of AAG. Thus, our present data indicate that free dexmedetomidine displaced by midazolam from site II of HSA or from AAG is adsorbed onto extracorporeal circuits, resulting in a change in the dexmedetomidine concentration within the circuit.

The influencer effect of Dexmedetomidine on radioiodine relevant to lacrimal gland impairment.

PURPOSE: To assess the potential influencing effects of Dexmedetomidine on impaired lacrimal glands after high-dose radioiodine treatment (RAI). METHODS: Thirty-six rats were arbitrarily separated into 3 groups: Sham, RAI, and Dexmedetomidine. Dexmedetomidine group was given Dexmedetomidine and RAI, the Sham group was given the same millimeters of saline, and the RAI group was given RAI only. All forms of lacrimal glands, including harderian glands (HG), extraorbital (EG), and intraorbital (IG) lacrimal glands, were evaluated for immunohistochemical, histopathologic assessments and also for tissue cytokines, oxidant and antioxidant levels. RESULTS: Dexmedetomidine significantly ameliorated histopathologic changes such as periacinar fibrosis, acinar atrophy, lymphocytic infiltration, ductal proliferation, lipofuscin-like accumulation, and nucleus changes caused by RAI in all lacrimal gland forms (p < 0.05 for all of the parameters). However, periductal fibrosis was improved significantly only in EG (p = 0.049), and mast cell infiltration was improved significantly only in IG (p = 0.038) in Dexmedetomidine groups. There was a significant decrease in the elevated caspase-3 and TUNEL levels after RAI administration in the Dexmedetomidine group in all lacrimal gland forms (p < 0.05 for all parameters). Dexmedetomidine attenuated NF-kb, TNF-α, and IL-6 levels significantly diminished total oxidant status and raised total antioxidant status levels (p < 0.05 for all parameters). CONCLUSIONS: The results of this study demonstrated that following RAI, Dexmedetomidine diminished inflammation, tissue cytokine levels, and apoptosis and ameliorated impaired histopathologic patterns of the lacrimal glands.

Dexmedetomidine activates the PKA/CREB pathway and inhibits proinflammatory factor expression through ß2 adrenergic receptors.

INTRODUCTION: Dexmedetomidine (DEX) is primarily utilized for sedation in the context of general anesthesia or intensive care. However, the exact regulatory mechanism by which DEX affects cytokines remains unclear. This study aims to investigate the underlying mechanism by which DEX inhibits proinflammatory factors through activation of the ß2 adrenergic receptor (ß2 AR). METHODS: The inflammatory cell model of human mononuclear macrophage (THP-1) cells induced by lipopolysaccharide (LPS) was established to study the effect of DEX on the expression of cell-related inflammatory factors. ADRA2A gene knockout THP-1 cells (THP-1KO ) were constructed by CRISPR technology, and the effect of DEX on the expression of inflammatory factors of THP-1KO cells was detected. The target sites of DEX on ß2 AR were screened by molecular docking. Reversion experiments were performed using ADRB2-siRNA. Western blot was used to detect the activation of ß2 AR/PKA/CREB pathway and NF-κB, and ELISA was used to detect the release level of inflammatory factors. RESULTS: The results demonstrated a significant reduction in the expression levels of MCP-1, interleukin-06, and IL-8 in both THP-1 and THP-1KO cells when induced by LPS following treatment with DEX. Additionally, DEX treatment led to an increase in IL-10 expression. Immunofluorescence analysis revealed an upregulation of ß2 AR expression after DEX treatment. Western blot results indicated that DEX notably enhanced the activation of the ß2 AR and PKA/CREB pathways, while concurrently suppressing the activation of NF-κB. Notably, the use of ADRB2 siRNA reversed the effects of DEX treatment and promoted the release of inflammatory cytokines. CONCLUSION: DEX initiates the activation of the PKA/CREB pathway through the activation of ß2 AR. Simultaneously, it exerts an inhibitory effect on the activation of NF-κB, consequently reducing the transcription of proinflammatory factors while increasing the transcription of anti-inflammatory factors.

Prevention of post-operative delirium using an overnight infusion of dexmedetomidine in patients undergoing cardiac surgery: a pragmatic, randomized, double-blind, placebo-controlled trial.

BACKGROUND: After cardiac surgery, post-operative delirium (PoD) is acknowledged to have a significant negative impact on patient outcome. To date, there is no valuable and specific treatment for PoD. Critically ill patients often suffer from poor sleep condition. There is an association between delirium and sleep quality after cardiac surgery. This study aimed to establish whether promoting sleep using an overnight infusion of dexmedetomidine reduces the incidence of delirium after cardiac surgery. METHODS: Randomized, pragmatic, multicentre, double-blind, placebo controlled trial from January 2019 to July 2021. All adult patients aged 65 years or older requiring elective cardiac surgery were randomly assigned 1:1 either to the dexmedetomidine group or the placebo group on the day of surgery. Dexmedetomidine or matched placebo infusion was started the night after surgery from 8 pm to 8 am and administered every night while the patient remained in ICU, or for a maximum of 7 days. Primary outcome was the occurrence of postoperative delirium (PoD) within the 7 days after surgery. RESULTS: A total of 348 patients provided informed consent, of whom 333 were randomized: 331 patients underwent surgery and were analysed (165 assigned to dexmedetomidine and 166 assigned to placebo). The incidence of PoD was not significantly different between the two groups (12.6% vs. 12.4%, p = 0.97). Patients treated with dexmedetomidine had significantly more hypotensive events (7.3% vs 0.6%; p < 0.01). At 3 months, functional outcomes (Short-form 36, Cognitive failure questionnaire, PCL-5) were comparable between the two groups. CONCLUSION: In patients recovering from an elective cardiac surgery, an overnight infusion of dexmedetomidine did not decrease postoperative delirium. Trial registration This trial was registered on ClinicalTrials.gov (number: NCT03477344; date: 26th March 2018).

THE PROTECTIVE EFFECT OF DEXMEDETOMIDINE ON THE LIVER INJURY IN SEPSIS THROUGH INHIBITION OF NECROPTOSIS.

ABSTRACT: Background: Sepsis-induced liver injury leads to extensive necroptosis in hepatocytes, which is the main factor of liver dysfunction. This study aims to investigate the protective effect of dexmedetomidine (DEX) on septic liver and to explore whether its molecular mechanism is related to the modulation of necroptosis. Methods: The model of septic liver injury was induced by cecal ligation and puncture (CLP) in rats. DEX and necrostatin-1(Nec-1), a specific antagonist of necroptosis, were administered 1 h before CLP. The levels of arterial blood gas, serum aspartate aminotransferase, and alanine aminotransferase were measured at 6, 12 and 24 h after CLP. The survival rate was observed 24 h after CLP. Liver pathological changes and apoptosis, the contents of IL-6 and TNF-α in liver tissue homogenates, the ROS content in liver tissue, and the expression levels of RIP1, RIP3, MLKL, and HMGB1 were detected. Results: At 6, 12, and 24 h after CLP, the levels of aspartate aminotransferase, and alanine aminotransferase levels increased, and liver enzyme levels gradually increased with the progression of sepsis. In arterial blood gas analysis, P a O 2 gradually decreased and lactic acid concentration gradually increased during these three periods. The morphological impairment of liver tissues, increased apoptosis, elevated inflammatory factors (IL-6 and TNF-α), increased ROS level, and necroptosis components (RIP1, RIP3, MLKL, and HMGB1) were all observed in sepsis rats. However, these injuries can be ameliorated by pretreatment with DEX. Meanwhile, Nec-1 pretreatment also reduced the expression of RIP1, RIP3, MLKL, HMGB1, and ROS level. Conclusion: Our study suggests that DEX alleviates septic liver injury, and the mechanism is associated with the inhibition of necroptosis.

Microglial Nrf2/HO-1 signaling gates remifentanil-induced hyperalgesia via suppressing TRPV4-mediated M1 polarization.

Remifentanil-induced hyperalgesia (RIH) represents a significant clinical challenge due to the widespread use of opioids in pain management. However, the molecular and cellular mechanisms underlying RIH remain elusive. This study aimed to unravel the role of spinal cord microglia, focusing on the Nrf2/HO-1 signaling pathway and TRPV4 channels in the development of RIH. We used both in vivo and in vitro models to investigate the activation state of spinal cord microglia, the expression of TRPV4 channels, and the modulation of the Nrf2/HO-1 pathway under remifentanil exposure. In addition, we evaluated the potential therapeutic effects of dexmedetomidine, a perioperative α2-adrenergic agonist, on RIH and its related molecular pathways. Our results revealed a prominent role of spinal cord microglia in RIH, demonstrating an apparent microglial M1 polarization and increased TRPV4 channel expression. A notable observation was the downregulation of the Nrf2/HO-1 pathway, which was associated with increased neuroinflammation and mechanical allodynia. By upregulating or overexpressing Nrf2, we confirmed its ability to inhibit TRPV4 and thereby attenuate RIH-associated mechanical allodynia, M1 polarization, and neuroinflammation. Encouragingly, dexmedetomidine demonstrated therapeutic potential by positively modulating the Nrf2-TRPV4 nexus, attenuating mechanical allodynia, and reducing microglial inflammation. Our research highlights the critical role of spinal cord microglia in RIH mediated by the Nrf2-TRPV4 axis. The ability of dexmedetomidine to modulate this axis suggests its potential as an adjunctive therapy to remifentanil in mitigating RIH. Further studies are imperative to explore the broader implications and practical applicability of our findings.