Α2-adrenergic Agonist Research Articles

Role of Intraoperative Dexmedetomidine Infusion in Enhanced Recovery after Surgery Protocols for Reducing Postoperative Analgesic Requirements in Laparoscopic Bariatric Surgeries

Abstract Background The prevalence of obesity in modern societies leads to continuous growing of bariatric surgery throughout the world as it is an effective treatment for obesity. Dexmedetomidine (DEX), a selective α2-adrenergic agonist, is an opioid-sparing adjuvant sedative that avoids respiratory depression and has been shown to be beneficial in bariatric surgery patients Aim of the Work The aim of this study is to evaluate the analgesic profile of intraoperative Dexmedetomidine on postoperative analgesic requirements. Patients and Methods This study was carried out at bariatric surgery unit - Ain shams University Hospitals and included 06 patients of both sexes undergoing elective laparoscopic bariatric surgery. Results The main finding in this study was that nalbuphine consumption was less in group D compared to group C with p value < 0.001 with high significant difference between the two groups also it revealed a high significant difference between the two groups according to time for first use of rescue analgesia. There was a highly significant difference between the two groups according to hemodynamics including (MAP & HR) but with no clinically significant differences. While there was no significant difference as regard SO2 or respiratory rate Conclusion In patients undergoing bariatric surgeries using of intraoperative dexmedetomidine infusion with its opioid-sparing effect enhanced the recovery of this study population of morbidly obese patients with minimal side-effects.

Influence of rutin and its combination with metformin on vascular functions in type 1 diabetes

The present work examined the effect of oral administration of rutin and its combination with metformin, an antidiabetic drug on blood glucose, total cholesterol and triglycerides level and vascular function in streptozotocin (STZ) -induced diabetic rats. Male Sprague Dawley rats were rendered diabetic by a single intraperitoneal injection of STZ (50 mg/kg). Rutin and metformin were orally administered to diabetic rats at a dose of 100 mg/kg and 300 mg/kg body weight/day, respectively, for 4 weeks. Plasma analysis was conducted to determine changes in the plasma glucose and lipid levels. Rat aortic ring reactivity in response to endothelium-dependent (acetylcholine, ACh) and endothelium-independent (sodium nitroprusside, SNP) relaxants, and to the α1-adrenergic agonist phenylephrine (PE) were recorded. Histology of pancreas, liver and kidney were evaluated. In results, rutin and metformin alone and in combination has led to significant improvements in blood glucose, cholesterol and triglyceride levels compared to diabetic group. Diabetic aortic rings showed significantly greater contraction in response to PE, and less relaxation in response to ACh and SNP. Treatment with rutin and metformin in combination significantly reduced PE-induced contraction and increased ACh-induced and SNP-induced relaxation in diabetes when compared to rutin or metformin alone. Significant histological improvements were seen with combination therapy. In conclusion, rutin and metformin combination therapy has the most potentiality for restoring blood glucose and lipid level as well as vascular function.

Comparison of two pharmacological semen collection times with α2-adrenergic agonist in domestic cats.

The use of α2-adrenergic agonists in association with urethral catheterization has been used as a technique for pharmacological semen collection in cats. The mechanism of action of this drug is the stimulation of adrenoreceptors in the vas deferens, which results in ejaculation. While medetomidine is the α2-agonist most commonly used in studies, ejaculation with the use of dexmedetomidine associated with ketamine has been effective, but with variable results. Therefore, further studies regarding the methodology of use are required to obtain better seminal quality. This study aimed to compare two pharmacological semen collection times after the association of dexmedetomidine (30 μg/kg, IM; Dormitor®, Zoetis), ketamine (5 mg/kg, IM; ketamine, Vetnil) and urethral catheterization using a tomcat probe (0.8 mm × 1.00 mm × 11 cm). The collections were divided into two experimental groups: G10 (N = 8; urethral catheterization after 10 min of anaesthesia) and G15 (N = 8; urethral catheterization after 15 min of anaesthesia). The ejaculates were evaluated for ejaculate volume, sperm concentration, morphology and kinetics using the CASA system. To compare the groups, the t-test and the Mann-Whitney U-test were used with a significance level of 5%. It was identified that ejaculate volume (G10: 22.62 ± 2.13 vs. G15: 26.81 ± 1.55; p < .001) and sperm concentration (G10: 48.10 × 106 ± 17.84 vs. G15: 90.18 × 106 ± 19.35; p < .001) was higher in G15 than in G10 and had a lower percentage of minor defects than G10 (G10: 3.12 ± 2.41 vs. G15: 1.00 ± 1.19; p = .043). Regarding the kinetic parameters, the results of G15 were better for total motility-TM (G10: 67.00 ± 10.33 vs. G15: 81.87 ± 7.99; p = .006) and faster cells-RAPID: (G10: 55.00 ± 16.63 vs. G15: 74.25 ± 11.94; p = .019); whereas a higher proportion of cells with slow speed-SLOW were seen in G10 (G10: 31.00 ± 12.07 vs. 17.12 ± 7.53; p = .015). Based on these findings, we suggest that collection via urethral catheterization should be performed 15 min after the application of ketamine-associated dexmedetomidine to obtain a better-quality ejaculate.

Dexmedetomidine Suppresses Glutamate-Stimulated Neuronal Injury Via MicroRNA-433/Janus Kinase 2/Signal Transducer and Activator of Transcription 3 Pathway.

Cerebral ischemia has been a hotpot in the prevention and treatment of cerebral ischemia. Dexmedetomidine (Dex) is a new type of highly selective α2 adrenergic receptor agonist with pharmacological properties. Quantitative studies have shown that Dex has a protective effect on glutamate (Glu)-induced neuronal damage. however, its mechanism has not been fully elucidated. The purpose of this study was to explore the underlying molecular mechanism by which Dex ameliorates Glu-induced neuronal injury by regulating miR-433/JAK2/STAT3 axis. A model of neuronal injury was constructed by Glu treatment and intervened with Dex. miRNA expression profiling assay was conducted to screen potential miRNAs affected by Dex. Cell viability, lactate dehydrogenase (LDH) release and apoptosis were detected by MTT assay, LDH kit, and TUNEL staining, respectively. Oxidative stress indicators were assessed by ELISA whereas mitochondrial membrane potential (MMP) was assessed by C11-BODIPY581/591 staining. The targeting relationship between the miR-433 and JAK2 was verified by dual-luciferase reporter assay and gene expression was analyzed by quantitative PCR and Western blot. Glu treatment decreased cell viability and MMP and promoted LDH release, apoptosis and oxidative damage. Glu-induced changes in neurons were reversed after Dex treatment through upregulating the miR-433 expression to block the activation of JAK2/STAT3 pathway. Dex protects against Glu-induced neuronal injury by regulating miR-433/JAK2/STAT3 pathway, which provides new insights into the treatment of neuronal injury.

Multiple-Factors-Induced Rheumatoid Arthritis Synoviocyte Activation Is Attenuated by the α2-Adrenergic Receptor Agonist Dexmedetomidine.

Dexmedetomidine (Dex) has analgesic and sedative properties and anti-inflammatory functions. Although the effects of Dex on arthritis have been revealed, the physiological mechanism underlying the interaction between Dex and rheumatoid arthritis (RA)-mediated inflammatory cytokines has not been fully studied. Inflamed and migrated fibroblast-like synoviocytes (FLSs) are involved in RA severity. Thus, we aimed to determine the effects of Dex on RA-FLSs treated with inflammatory cytokines and a growth factor as multiple stimulating inputs. TNF-α, IL-6, and EGF as multiple stimulating inputs increased the cAMP concentration of RA-FLSs, while Dex treatment reduced cAMP concentration. Dex reduced electroneutral sodium-bicarbonate cotransporter 1 (NBCn1) expression, NBC activity, and subsequent RA-FLS migration. The mRNA expression levels of RA-related factors, such as inflammatory cytokines and osteoclastogenesis factors, were enhanced by multiple-input treatment. Notably, Dex effectively reduced these expression levels in RA-FLSs. These results indicate that multiple inflammatory or stimulating inputs enhance RA-FLS migration, and treatment with Dex relieves activated RA-FLSs, suggesting that Dex is a potential therapeutic drug for RA.

Enteral administration of the protease inhibitor gabexate mesilate preserves vascular function in experimental trauma/hemorrhagic shock

Preserving vascular function is crucial for preventing multiorgan failure and death in ischemic and low-pressure states such as trauma/hemorrhagic shock (T/HS). It has recently been reported that inhibiting circulating proteases released from the bowel to the circulation during T/HS may preserve vascular function and improve outcomes following T/HS. This study aimed to evaluate the role of the serine protease inhibitor gabexate mesilate (GM) in preserving vascular function during T/HS when given enterally. We studied the vascular reactivity of mesenteric arteries from male Wistar rats treated with enteral GM (10 mg/kg) (GM-treated, n = 6) or control (Shock-control, n = 6) following (T/HS) using pressure myography. Concentration–response curves of endothelial-dependent and endothelial-independent agonists (e.g., acetylcholine, sodium nitroprusside) ranging from 10−10 to 10−5 M were performed. In a second set of experiments, ex-vivo arteries from healthy rats were perfused with plasma from shocked animals from both groups and vascular performance was similarly measured. Arteries from the GM-treated group demonstrated a preserved concentration–response curve to the α1 adrenergic agonist phenylephrine compared to arteries from Shock-control animals (− logEC50: − 5.73 ± 0.25 vs. − 6.48 ± 0.2, Shock-control vs. GM-treated, p = 0.04). When perfused with plasma from GM-treated rats, healthy arteries exhibited an even greater constriction and sensitivity to phenylephrine (− logEC50: − 6.62 ± 0.21 vs. − 7.13 ± 0.21, Shock-control vs. GM-treated, p = 0.02). Enteral GM also preserved the endothelium-dependent vascular response to agonists following T/HS and limited syndecan-1 shedding as a marker of glycocalyx compromise (41.84 ± 9 vs. 17.63 ± 3.97 ng/mL, Shock-control vs. GM-treated, p = 0.02). Syndecan-1 cleavage was correlated with plasma trypsin-like activity (r2 = 0.9611). Enteral gabexate mesilate was able to maintain vascular function in experimental T/HS, which was reflected by improved hemodynamics (mean arterial pressure 50.39 ± 7.91 vs. 64.95 ± 3.43 mmHg, Shock-control vs. GM treated, p = 0.0001). Enteral serine protease inhibition may be a potential therapeutic intervention in the treatment of T/HS.

Dexmedetomidine vs. fentanyl as adjuvants to hyperbaric bupivacaine for unilateral spinal anesthesia in lower limb orthopedic surgeries: a randomized trial

Background &amp; Objective: Opioids and α2 adrenergic receptor agonists are commonly used as adjuvants to intrathecal local anesthetics to improve the quality and duration of spinal anesthesia (SA). Fentanyl and dexmedetomidine (DEX) are the most commonly used opioid and α2 agonist respectively. We compared the efficacy of these two when used as adjuvants to hyperbaric bupivacaine for SA for lower limb surgeries.&#x0D; Methods: A total of 54 patients were randomly assigned to receive unilateral spinal anesthesia with bupivacaine 2.5 ml. Group F (n = 27) received 25 μg fentanyl, and Group D received 10 μg DEX added to the spinal bupivacaine. Time to first analgesic request was the primary outcome, while sensory and motor block characteristics, nalbuphine consumption as rescue analgesic, pain scores, side effects and sedation levels were the secondary outcomes.&#x0D; Results: Patients receiving dexmedetomidine as an adjuvant to hyperbaric bupivacaine for spinal anesthesia for lower limb surgeries had a significantly longer time to rescue analgesia than those receiving fentanyl. The mean time to rescue analgesia in Group D was 409.63 ± 74.60 min vs. 295.93 ± 36.72 min (P = 0.000) in the Group F. Also, patients in Group D had significantly longer sensory and motor blocks.&#x0D; Conclusion: Intrathecal dexmedetomidine 10 μg seems to be a good alternative to fentanyl 25 μg when used as an adjuvant in unilateral spinal anesthesia for lower limb orthopedic surgeries with better quality postoperative analgesia and with minimal side effects.&#x0D; Abbreviations: DEX - Dexmedetomidine; NYHA - New York Heart Association; BMI - Body mass index; MBP - Mean blood pressure; SBP- Systolic blood pressure; DBP- Diastolic blood pressure; VAS - Visual Analog Scale&#x0D; Key words: Dexmedetomidine; Fentanyl; Bupivacaine; Anesthesia, Spinal&#x0D; Citation: Ghaly SI, Shafik AM, AlTaher WAMM, Motawashleh MG, Alansary AM. Dexmedetomidine vs. fentanyl as adjuvants to hyperbaric bupivacaine for unilateral spinal anesthesia in lower limb orthopedic surgeries: a randomized trial. Anaesth. pain intensive care 2023;27(4):456−463. DOI: 10.35975/apic.v27i4.2191&#x0D; Received: March 30, 2023; Reviewed: April 22, 2023; Accepted: April 22, 2023

How should anti-hypertensive medications be adjusted before screening for primary aldosteronism?

Anti-hypertensive medications may affect plasma renin activity and/or plasma aldosterone concentration, misleading the interpretation of the aldosterone-to-renin ratio when screening for primary aldosteronism. The Task Force of Taiwan PA recommends that, when necessary, using α-adrenergic receptor blocking agents, centrally acting α-adrenergic agonists, and/or non-dihydropyridine calcium channel blockers should be considered to control blood pressure before screening for PA. We recommend temporarily holding β-adrenergic receptor blocking agents, mineralocorticoid receptor antagonists, dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and all diuretics before screening for PA. Further large-scale randomized controlled studies are required to confirm the recommendations.

Sublingual Dexmedetomidine for the Treatment of Agitation in Patients with Schizophrenia and Bipolar Disorder

Acute agitation is common amongst individuals with bipolar disorder and schizophrenia and represents a medical emergency. Commonly used medications for agitation, such as benzodiazepines and antipsychotics, are often delivered intramuscularly and may cause adverse effects. Non-invasive, effective, and safe alternative treatment options are needed. The purpose of this review article is to describe the efficacy and safety of sublingual formulation of dexmedetomidine (Igalmi), a selective α2-adrenergic receptor agonist, U.S. Food and Drug Administration approved for the treatment of acute agitation in adults with schizophrenia or bipolar I and II disorder. In two phase 3 trials, two dose strengths of sublingual dexmedetomidine 180 μg and 120 μg were safe and effective in managing acute agitation in patients with bipolar disorder or schizophrenia. Both doses significantly reduced Positive and Negative Syndrome Scale-Exited Component scores two hours after receiving a single dose as compared to placebo, indicating a substantial improvement in agitation. The beneficial effects of sublingual dexmedetomidine were achieved without serious adverse events with the most common side effect being mild somnolence. The clinical trial data suggest that sublingual dexmedetomidine represents a safe and effective treatment option in the armamentarium for acute agitation for people with schizophrenia or bipolar disorder.

Differential effects of dexmedetomidine on Gram-positive and Gram-negative bacterial killing and phagocytosis

Dexmedetomidine is a commonly used sedative in perioperative and intensive care settings with purported immunomodulatory properties. Since its effects on immune functions against infections have not been extensively studied, we tested the effects of dexmedetomidine on Gram-positive [Staphylococcus aureus and Enterococcus faecalis] and Gram-negative bacteria [Escherichia coli], and on effector functions of human monocytes THP-1 cells against them. We evaluated phagocytosis, reactive oxygen species (ROS) formation, and CD11b activation, and performed RNA sequencing analyses. Our study revealed that dexmedetomidine improved Gram-positive but mitigated Gram-negative bacterial phagocytosis and killing in THP-1 cells. The attenuation of Toll-like receptor 4 (TLR4) signaling by dexmedetomidine was previously reported. Thus, we tested TLR4 inhibitor TAK242. Similar to dexmedetomidine, TAK242 reduced E. coli phagocytosis but enhanced CD11b activation. The reduced TLR4 response potentially increases CD11b activation and ROS generation and subsequently enhances Gram-positive bacterial killing. Conversely, dexmedetomidine may inhibit the TLR4-signaling pathway and mitigate the alternative phagocytosis pathway induced by TLR4 activation through LPS-mediated Gram-negative bacteria, resulting in worsened bacterial loads. We also examined another α2 adrenergic agonist, xylazine. Because xylazine did not affect bacterial clearance, we proposed that dexmedetomidine may have an off-target effect on bacterial killing process, potentially involving crosstalk between CD11b and TLR4. Despite its potential to attenuate inflammation, we provide a novel insight into potential risks of dexmedetomidine use during Gram-negative infections, highlighting the differential effect of dexmedetomidine on Gram-positive and Gram-negative bacteria.

Dexmedetomidine as an Adjuvant in Peripheral Nerve Block.

Peripheral nerve block technology is important to balanced anesthesia technology. It can effectively reduce opioid usage. It is the key to enhance clinical rehabilitation as an important part of the multimodal analgesia scheme. The emergence of ultrasound technology has accelerated peripheral nerve block technology development. It can directly observe the nerve shape, surrounding tissue, and diffusion path of drugs. It can also reduce the dosage of local anesthetics by improving positioning accuracy while enhancing the block's efficacy. Dexmedetomidine is a highly selective drug α2-adrenergic receptor agonist. Dexmedetomidine has the characteristics of sedation, analgesia, anti-anxiety, inhibition of sympathetic activity, mild respiratory inhibition, and stable hemodynamics. Numerous studies have revealed that dexmedetomidine in peripheral nerve blocks can shorten the onset time of anesthesia and prolong the time of sensory and motor nerve blocks. Although dexmedetomidine was approved by the European Drug Administration for sedation and analgesia in 2017, it has not yet been approved by the US Food and Drug Administration (FDA). It is used as a non-label drug as an adjuvant. Therefore, the risk-benefit ratio must be evaluated when using thesedrugs as adjuvants. This review explains the pharmacology and mechanism of dexmedetomidine, the effect of dexmedetomidine on various peripheral nerve block as an adjuvant, and compare it with other types of adjuvants. We summarized and reviewed the application progress of dexmedetomidine as an adjuvant in nerve block and look forward to its future research direction.

Cardiac Na/K-ATPase alpha1 isoform-specific role in hypertrophic response: role of metabolic and oxidative signaling

Cardiac Na/K-ATPase (NKA) inhibition by cardiotonic steroids (CTS) modulates intracellular Na + and Ca 2+ , leading to increased force of contraction. In contrast, hypertrophy of cardiomyocytes (CM) is triggered by CTS through stimulation of reactive oxygen species (ROS) and fetal gene re-expression independently of changes in intracellular Na + or Ca 2+ . Based on recent evidence that NKAα1 serves an isoform-specific function in the regulation of oxidative metabolism and ROS generation, we used a genetic approach in the mouse and in human cardiac cells (AC16) to test the hypothesis that NKAα1 is required for cardiac hypertrophy. Cardio α1 -/- mice, a conditional KO of NKAα1 in the heart, were viable without overt abnormality of cardiac structure or function. NKAα1 was undetectable in heart lysates or isolated CM of adult cardio α1 -/- mice. Despite a compensatory upregulation of NKAα2, Na/K-ATPase activity in crude heart homogenates and NKA currents in CM were reduced by about 60%. Decreased ROS (assessed by total protein carbonylation) and reduced fatty acid oxidation (FAO) and oxidative phosphorylation pathways (revealed by RNA-seq analysis) were noted at baseline. RT-qPCR revealed downregulated genes involved with FAO and the electron transport chain (such as, Acadl and Ndufa9, about 20% decrease, n=6) in cardio α1 -/- hearts. The activity of the electron transport chain complex I was decreased in cardio α1 -/- hearts (0.3354 vs 0.2732 mOD/min/mg of protein, p&lt;0.05). When 3-month-old male mice were challenged with angiotensin II (1.5 mg.kg -1 .day -1 for 1 week, n=6-15), cardio α1 -/- mice did not develop cardiac hypertrophy, as assessed by heart weight to tibia length ratio, but displayed exacerbated cardiac fibrosis, revealed by Trichrome staining, consistent with the postulated role of CM NKAα1 isoform-specific function in cardiac hypertrophy in vivo. In vitro, CRISPR-Cas9-mediated KO of NKAα1 in AC16 cells led to a drastic downregulation of NKAα1 compared to WT AC16 cells. In contrast to WT AC16 cells, NKAα1 KO cells did not respond to the α-adrenergic agonist phenylephrine (50 μM for 24h) with the expected increase in cell area (2243 vs 3520 μm 2 for WT, p&lt;0.05; 2454 vs 2563 μm 2 for KO, p&gt;0.05). These data suggest that NKAα1 isoform-specific function is required for cardiac hypertrophy. Mechanistically, our data support an isoform-specific regulatory function of NKAα1 in normal FAO, electron transport chain activity, and ROS generation, which are critical for CM hypertrophy. Supported by NIH Grant R15 HL145666 and American Heart Association Grant 22POST917776 (Marco T. Pessoa) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Vascular Effects of Perinatal Hypoxia in the Early Postnatal Period in Rats

The normal functioning of the vascular system in early ontogenesis can be altered by adverse effects affecting the organism of the fetus / newborn during pregnancy, during or after childbirth. However, at the moment there is not enough data on the “acute” (immediately after exposure) and “delayed” (after several days) effects of short-term (within several hours) perinatal normobaric hypoxia on the functioning of the peripheral vascular system of the systemic circulation in early ontogenesis in mammals. The aim of this work was to study the “acute” and “delayed” effects of a single normobaric hypoxia on the functioning of the arteries of the systemic circulation in early postnatal ontogenesis. The contractile responses of the saphenous artery of rats aged 10–14 days were studied in isometric myograph. Acute normobaric hypoxia (8% O2) was simulated for 2 hours in 10-day-old rat pups. The selected hypoxia regimen did not lead to changes in arterial contractile responses to the α1-adrenergic agonist methoxamine either immediately after exposure or several days later. Endothelium-dependent relaxation of arteries to acetylcholine also did not differ between groups. Hypoxia did not change the contribution of anticontractile pathways associated with nitric oxide and Kv7 channels, as well as the pro contractile role of Rho-kinase. Thus, according to the presented results, short-term normobaric hypoxia on the 10th day of life in rat pups does not lead to either “acute” or “delayed” changes in the regulation of the tone of the peripheral arteries of the systemic circulation in the early postnatal period.

Orally administered sodium nitrite prevents the increased α-1 adrenergic vasoconstriction induced by hypertension and promotes the S-nitrosylation of calcium/calmodulin-dependent protein kinase II

The unsatisfactory rates of adequate blood pressure control among patients receiving antihypertensive treatment calls for new therapeutic strategies to treat hypertension. Several studies have shown that oral sodium nitrite exerts significant antihypertensive effects, but the mechanisms underlying these effects remain unclear. While these mechanisms may involve nitrite-derived S-nitrosothiols, their implication in important alterations associated with hypertension, such as aberrant α1-adrenergic vasoconstriction, has not yet been investigated. Here, we examined the effects of oral nitrite treatment on vascular responses to the α1-adrenergic agonist phenylephrine in two-kidney, one clip (2K1C) hypertensive rats and investigated the potential underlying mechanisms. Our results show that treatment with oral sodium nitrite decreases blood pressure and prevents the increased α1-adrenergic vasoconstriction in 2K1C hypertensive rats. Interestingly, we found that these effects require vascular protein S-nitrosylation, and to investigate the specific S-nitrosylated proteins we performed an unbiased nitrosoproteomic analysis of vascular smooth muscle cells (VSMCs) treated with the nitrosylating compound S-nitrosoglutathione (GSNO). This analysis revealed that GSNO markedly increases the nitrosylation of calcium/calmodulin-dependent protein kinase II γ (CaMKIIγ), a multifunctional protein that mediates the α1-adrenergic receptor signaling. This result was associated with reduced α1-adrenergic receptor-mediated CaMKIIγ activity in VSMCs. We further tested the relevance of these findings in vivo and found that treatment with oral nitrite increases CaMKIIγ S-nitrosylation and blunts the increased CaMKIIγ activity induced by phenylephrine in rat aortas. Collectively, these results are consistent with the idea that oral sodium nitrite treatment increases vascular protein S-nitrosylation, including CaMKIIγ as a target, which may ultimately prevent the increased α1-adrenergic vasoconstriction induced by hypertension. These mechanisms may help to explain the antihypertensive effects of oral nitrite and hold potential implications in the therapy of hypertension and other cardiovascular diseases associated with abnormal α1-adrenergic vasoconstriction.

Analgesics can affect the sensitivity of temozolomide to glioma chemotherapy through gap junction.

This study investigated the effect of frequently used analgesics in cancer pain management (flurbiprofen (FLU), tramadol (TRA), and morphine (MOR)) and a novel α2-adrenergic agonist (dexmedetomidine, DEX) on temozolomide (TMZ) sensitivity in glioma cells. Cell counting kit-8 and colony-formation assays were performed to analyze the viability of U87 and SHG-44 cell lines. A high and low cell density of colony method, pharmacological methods, and connexin43 mimetic peptide GAP27 were used to manipulate the function of gap junctions; "Parachute" dye coupling and western blot were employed to determine junctional channel transfer ability and connexin expression. The results showed that DEX (in the concentration range of 0.1 to 5.0ng/ml) and TRA (in the concentration range of 1.0 to 10.0µg/ml) reduced the TMZ cytotoxicity in a concentration-dependent manner but was only observed with high cell density (having formed gap junction). The cell viability percentage was 71.3 to 86.8% when DEX was applied at 5.0ng/ml, while tramadol showed 69.6 to 83.7% viability at 5.0μg/ml in U87 cells. Similarly, 5.0ng/ml of DEX resulted in 62.6 to 80.5%, and 5.0μg/ml TRA showed 63.5 to 77.3% viability in SHG-44 cells. Further investigating the impact of analgesics on gap junctions, only DEX and TRA were found to decrease channel dye transfer through connexin phosphorylation and ERK pathway, while no such effect was observed for FLU and MOR. Analgesics that can affect junctional communication may compromise the effectiveness of TMZ when used simultaneously.

Exploring the Molecular and Genetic Mechanisms of Action of the α2-Adrenergic Agonist Mafedine in Experimental Traumatic Brain Injury in Rats

Neurological impairments due to traumatic, vascular, or neurodegenerative brain diseases have a high prevalence worldwide. Among them are motor, cognitive, and mental disorders, which have a serious negative impact on the working and social activities of the patients. This calls for the search and development of novel effective neuroprotective agents. Previous studies have shown the pyrimidine-derived α2-adrenergic agonist mafedine to be highly effective for the amelioration of neurological deficits in experimental traumatic brain injury (TBI) in rats. Despite the results of the previous works favouring the major role of the α2 adrenergic receptor activation in the mechanism of action of mafedine, the search for additional molecular targets is an important part of the development of any drug to be used in clinical practice. In this work, we evaluated the effects of 7 day-long course administration of mafedine (2.5 mg/kg b.w.) on the expression of brain-derived neurotrophic factor (BDNF), the proinflammatory cytokines interleukin (IL)-1β, -6, tumour necrosis factor (TNF)-α, and the α2A, α2B, and α2C α2-adrenergic receptor subtypes in the brain cortex of rats subjected to TBI, using the reverse-transcription real-time polymerase chain reaction method. TBI was modelled by the controlled cortical impact technique in an open area of sensorimotor cortex of the left brain hemisphere. Behavioural alterations in the injured animals were assessed in the Open field test, and the fore- and hindlimb motor function, in the Limb placing, Cylinder, and Beam walking tests. Our experiments show that TBI causes severe motor impairments as well as decreases exploration in rats. Besides, at post-TBI day 7, a reduction in the expression of all analyzed genes is seen, which is the most pronounced in the contralateral (uninjured) hemisphere. Course administration of mafedine (2.5 mg/kg b.w.) resulted in moderate stimulation of the injured rats’ behaviour, increased exploratory activity compared to controls, and improved sensorimotor deficit as assessed by the Beam walking test. Gene expression analysis results indicated that mafedine decreased α2B-adrenergic receptor, TNF-α, and IL-6 expression in the injured hemisphere. At the same time, compared to rats with TBI having received no treatment, mafedine-treated animals exhibited higher α2B-adrenergic receptor and IL-1β expression in the injured rather than the intact hemisphere. These results confirm the previously observed neuroprotective activity of mafedine and imply that it may exert its effects via suppression of α2B-adrenergic receptor and proinflammatory cytokine expression in the injured brain hemisphere, at the same time increasing their expression in the intact one.

Efficacy of dexmedetomidine in attenuating pressor response to laryngoscopy and endotracheal intubation under bispectral index controlled anesthesia: a prospective randomized double-blinded study

BackgroundLaryngoscopy and endotracheal intubation may lead to a remarkable hemodynamic pressor response. Dexmedetomidine, an α2-adrenergic receptor agonist, can be effectively used to attenuate this pressor effect. This study was aimed to compare the efficacy of two different doses of dexmedetomidine (0.5 µg/kg and 1.0 µg/kg) in attenuation of hemodynamic pressor response to largyngoscopy and endotracheal intubation under bispectral index (BIS) monitoring. One hundred twenty adult patients with American Society of Anesthesiologists (ASA) physical status I or II posted for various elective surgeries under general anesthesia were enrolled to receive an intravenous (IV) infusion of dexmedetomidine 0.5 μg/kg (group D1; n = 40), 1.0 μg/kg (group D2; n = 40) or normal saline over 15 min (group C; n = 40). The primary outcome measure was to assess the hemodynamic changes while the secondary outcome measures were to assess sedation, dose of propofol required for induction and side effects.ResultsThe mean HR, SBP, DBP, and MAP remained significantly lower in both dexmedetomidine groups as compared to control group after study drug infusion, after induction, at and after intubation (P < 0.05). Group D2 also had significantly lower mean HR, SBP, DBP, and MAP in comparison to group D1 (P < 0.05). The induction dose of propofol was significantly less in dexmedetomidine groups as compared to control group (P < 0.05). Ramsay sedation scale (RSS) score was found to be significantly more in both groups D1 and D2 after study drug infusion (P<0.001). No significant difference was noted in incidence of side effects (P = 0.907).ConclusionsDexmedetomidine (0.5 µg/kg and 1.0 µg/kg) was found to be effective in attenuating the hemodynamic pressor response to laryngoscopy and endotracheal intubation with BIS monitoring.Trial registrationCTRI, CTRI/2020/03/024088. Registered 19 March 2020.

Dexmedetomidine alleviates host ADHD-like behaviors by reshaping the gut microbiota and reducing gut-brain inflammation

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders that affects children and even continues into adulthood. Dexmedetomidine (DEX), a short-term sedative, can selectively activate the α2-adrenoceptor. Treatment with α2-adrenergic agonists in patients with ADHD is becoming increasingly common. However, the therapeutic potential of DEX for the treatment of ADHD is unknown. Here, we evaluated the effect of DEX on ADHD-like behavior in spontaneously hypertensive rats (SHRs), a widely used animal model of ADHD. DEX treatment ameliorated hyperactivity and spatial working memory deficits and normalized θ electroencephalogram (EEG) rhythms in SHRs. We also found that DEX treatment altered the gut microbiota composition and promoted the enrichment of beneficial gut bacterial genera associated with anti-inflammatory effects in SHRs. The gut pathological scores and permeability and the level of inflammation observed in the gut and brain were remarkably improved after DEX administration. Moreover, transplantation of fecal microbiota from DEX-treated SHRs produced effects that mimicked the therapeutic effects of DEX administration. Therefore, DEX is a promising treatment for ADHD that functions by reshaping the composition of the gut microbiota and reducing inflammation in the gut and brain.

Duloxetine and Amitriptyline Reduce Neuropathic Pain by Inhibiting Primary Sensory Input to Spinal Dorsal Horn Neurons via α1- and α2-Adrenergic Receptors.

Antidepressants, such as duloxetine and amitriptyline, are effective for treating patients with chronic neuropathic pain. Inhibiting norepinephrine and serotonin transporters at presynaptic terminals raises extracellular concentrations of norepinephrine. The α1- and α2-adrenergic receptor agonists inhibit glutamatergic input from primary afferent nerves to the spinal dorsal horn. However, the contribution of spinal α1- and α2-adrenergic receptors to the analgesic effect of antidepressants and associated synaptic plasticity remains uncertain. In this study, we showed that systemic administration of duloxetine or amitriptyline acutely reduced tactile allodynia and mechanical and thermal hyperalgesia caused by spinal nerve ligation in rats. In contrast, duloxetine or amitriptyline had no effect on nociception in sham rats. Blocking α1-adrenergic receptors with WB-4101 or α2-adrenergic receptors with yohimbine at the spinal level diminished the analgesic effect of systemically administered duloxetine and amitriptyline. Furthermore, intrathecal injection of duloxetine or amitriptyline similarly attenuated pain hypersensitivity in nerve-injured rats; the analgesic effect was abolished by intrathecal pretreatment with both WB-4101 and yohimbine. In addition, whole-cell patch-clamp recordings in spinal cord slices showed that duloxetine or amitriptyline rapidly inhibited dorsal root-evoked excitatory postsynaptic currents in dorsal horn neurons in nerve-injured rats but had no such effect in sham rats. The inhibitory effect of duloxetine and amitriptyline was abolished by the WB-4101 and yohimbine combination. Therefore, antidepressants attenuate neuropathic pain predominantly by inhibiting primary afferent input to the spinal cord via activating both α1- and α2-adrenergic receptors. This information helps the design of new strategies to improve the treatment of neuropathic pain.

Radioprotective effects of α2-adrenergic receptor agonist dexmedetomidine on X-ray irradiation-induced pancreatic islet cell damage.

Comprehensive epidemiological analyses conducted in the last 30years have revealed a link between radiation and DM. We aimed to determine the effects of dexmedetomidine pretreatment on radiation-induced pancreatic islet cell damage. Twenty-four rats were divided into three groups: group 1 (control group), group 2 (only X-ray irradiation group), and group 3 (X-ray irradiation + dexmedetomidine). We observed necrotic cells with vacuoles accompanying loss of cytoplasm in the islets of Langerhans, extensive edematous areas, and vascular congestions in group 2. In group 3, we observed a decrease in necrotic cells in the islets of Langerhans, and edematous areas and vascular congestion was also reduced. We determined a decrease in β-cells, α-cells, and D-cells in the islets of Langerhans in group 2 compared to the control group. In group 3, β-cells, α-cells, and D-cells were elevated compared to group 2. Ionizing radiation may induce DM. Dexmedetomidine appears to exert a radioprotective effect.