Α2-adrenergic Receptor Antagonist Research Articles

Genome-Wide RNAi Screening Identifies Novel Pathways/Genes Involved in Oxidative Stress and Repurposable Drugs to Preserve Cystic Fibrosis Airway Epithelial Cell Integrity.

Recurrent infection-inflammation cycles in cystic fibrosis (CF) patients generate a highly oxidative environment, leading to progressive destruction of the airway epithelia. The identification of novel modifier genes involved in oxidative stress susceptibility in the CF airways might contribute to devise new therapeutic approaches. We performed an unbiased genome-wide RNAi screen using a randomized siRNA library to identify oxidative stress modulators in CF airway epithelial cells. We monitored changes in cell viability after a lethal dose of hydrogen peroxide. Local similarity and protein-protein interaction network analyses uncovered siRNA target genes/pathways involved in oxidative stress. Further mining against public drug databases allowed identifying and validating commercially available drugs conferring oxidative stress resistance. Accordingly, a catalog of 167 siRNAs able to confer oxidative stress resistance in CF submucosal gland cells targeted 444 host genes and multiple circuitries involved in oxidative stress. The most significant processes were related to alternative splicing and cell communication, motility, and remodeling (impacting cilia structure/function, and cell guidance complexes). Other relevant pathways included DNA repair and PI3K/AKT/mTOR signaling. The mTOR inhibitor everolimus, the α1-adrenergic receptor antagonist doxazosin, and the Syk inhibitor fostamatinib significantly increased the viability of CF submucosal gland cells under strong oxidative stress pressure. Thus, novel therapeutic strategies to preserve airway cell integrity from the harsh oxidative milieu of CF airways could stem from a deep understanding of the complex consequences of oxidative stress at the molecular level, followed by a rational repurposing of existing “protective” drugs. This approach could also prove useful to other respiratory pathologies.

Diurnal changes of colonic motility and regulatory factors for colonic motility in Suncus murinus.

The aim of this study was to investigate the fundamental mechanisms of colonic motility in the house musk suncus (Suncus murinus) as an established animal model of gut motility. To measure gut motility in free-moving conscious suncus, strain gauge force transducers were implanted on the serosa of the colon and gastric body. We recorded diurnal changes in colonic motility and observed the relationship between feeding and colonic motility. Giant migrating contractions (GMCs) of the colon were invariably detected during defecation and tended to increase during the dark period, thereby indicating that colonic motility has a circadian rhythm. Given that GMCs in the suncus were observed immediately after feeding during the dark period, we assume the occurrence of a gastrocolic reflex in suncus, similar to that observed in humans and dogs. We also examined the factors that regulate suncus GMCs. Intravenous administration of 5-HT (100µg/kg), substance P (10 and 100µg/kg), calcitonin gene-related peptide (10µg/kg), and α2 adrenergic receptor antagonist yohimbine (0.5, 1, and 3mg/kg) induced GMC-like contractions, as did intragastric and intracolonic administration of the transient receptor potential vanilloid 1 agonist, capsaicin (1mg/kg). These results indicate that the fundamental mechanisms of colonic motility in suncus are similar to those in humans and dogs, and we thus propose that suncus could serve as a novel small animal model for studying colonic motility.

Тривожно-депресивні розлади при хворобі Паркінсона

У статті розглянуті сучасні аспекти патогенезу, ранньої діагностики та комплексного лікування тривожно-депресивних розладів при хворобі Паркінсона (ХП). На сьогодні науковці виділяють дві форми депресивних розладів при ХП залежно від наявності або відсутності зв’язку із флуктуаціями симптомів — депресію, що пов’язана із періодами вимикання, та депресію, що не пов’язана із періодами вимикання. Для корекції депресії при ХП застосовуються селективні інгібітори зворотного захвату серотоніну (СІЗЗС) — сертралін, пароксетин, циталопрам, міансерин, трициклічні антидепресанти (ТЦА) — амітриптилін, нортриптилін, іміпрамін, дезипрамін, селективні інгібітори зворотного захвату серотоніну та норадреналіну — дулоксетин, венлафаксин, селективний інгібітор зворотного захвату норадреналіну ребоксетин, пресинаптичний антагоніст α2-адренорецепторів міртазапін. У літературі наводяться суперечливі дані щодо ефективності тих чи інших антидепресантів. Основними препаратами для лікування депресії при ХП вважаються СІЗЗС та ТЦА. Мультидисциплінарний підхід до оптимізації лікування та догляду за пацієнтами із ХП може включати фізичну та трудотерапію, логопедичну та психологічну терапію. Все частіше у неврологічній практиці застосовуються психотерапевтичні методики на основі біоадаптивного управління, що є перспективним напрямком сучасної медицини й іменується біологічним зворотним зв’язком. Актуальним є раннє виявлення немоторних порушень при ХП, зокрема психоемоційних розладів, з метою їх своєчасної корекції для покращення якості життя пацієнтів із ХП та їх родичів. А також необхідні подальші наукові дослідження для оцінки клінічної ефективності антидепресантів при лікуванні тривожно-депресивних розладів у пацієнтів із ХП та оптимізації їх лікування з використанням у комплексній терапії сучасних немедикаментозних методів лікування, таких як когнітивно-поведінкова терапія та метод біоадаптивного управління.

Analysis of prescription and rationality of anti-hypertensive medication among community health centers in Beijing

Objective: Explore the usage of anti-hypertension drugs and the rationality of hypertension prescription among the primary health centers in Dongcheng District, Beijing. Method: This cross-sectional and retrospective study was applied to analyze the hypertension prescriptions from the 8 community health centers in Dongcheng District. The anatomical, therapeutic and chemical classification (ATC) codes were used to determine the drug category. ATC information was used to filter data containing antihypertensive drugs, and group the number and proportion of ATC categories. The type of drug was judged by its generic name. According to the diagnosis information in the prescription, the prescription containing the Western medicine diagnosis of hypertension was screened out. The comorbidities of hypertension in the study included 7 types of diseases including diabetes, chronic kidney disease, coronary heart disease, heart failure, atrial fibrillation, stroke, and dyslipidemia. The analysis of prescription rationality included rationality of combination medication, rationality of drug dosage and rationality of drug price. The agreed daily dose (DDD) method was used to analyze the rationality of drug dosage. The drug utilization index (DUI) was used as a quantitative indicator to estimate the rationality of medication, and overdose was expressed by DUI>1. The reasonableness of the drug price was judged based on the price of the drug and whether it was a drug in the "4+7" plan. Results: A total of 658 140 prescriptions were extracted as the final data set, involving 7 categories and 60 commonly used anti-hypertensive drugs, and the corresponding cost of medication was ￥96.58 million. Drugs were prescribed according to comorbidities, and the choice followed the international guidelines. Calcium channel blockers (CCB) were the most prescribed drugs in the prescriptions of patients with comorbidities, and α-adrenergic receptor antagonists were the least prescribed drugs. The proportion of diuretics prescribed in hypertensive patients complicating with heart failure was 21.17% (505/2 385), which was much higher than that of patients complicating with other comorbidities (P<0.05). The proportion of diuretics prescribed in hypertension patients complicating with dyslipidemia was lower than that of patients with other comorbidities (2 639 (0.94%), P<0.05), and β-blockers (BB) or angiotensin Ⅱreceptor blockers (ARB) were more likely to be selected (BB: 59 348 (21.08%), ARB: 51 356 (18.24%))in these patients. The proportion of BB in prescriptions for hypertension patients with chronic kidney disease was lower than that of patients with other comorbidities (P<0.05). The proportion of BB in prescriptions for hypertension patients with coronary heart disease was higher than that of other comorbidities (P<0.05). Hypertension patients with atrial fibrillation or stroke accounted for a higher proportion of CCB prescriptions (P<0.05). Single antihypertensive drug prescriptions accounted for the highest proportion, 61.19% (402 745/658 140). Two-combination prescriptions accounted for the highest proportion of combination prescriptions, 72.19% (184 392/255 395). CCB based two-combination prescriptions accounted for the highest proportion, 122 350(66.36%). ARB-based tri-combination prescriptions accounted for the highest proportion, 48 915(89.50%),followed by CCB based tri-combination prescriptions (44 732(81.85%)).There were 2 174 (0.33%) prescriptions with unreasonable combination therapies and DUI>1 were found in 48 out of 60 commonly used drugs. In all possible antihypertensive drugs, only 40.92% (109 227/266 993)followed the "4+7" plan. Conclusions: The anti-hypertensive agents from these prescriptions in the primary health centers are diverse, and the choice is generally complied with the guidelines, but some unreasonable situations existed, especially on the combined anti-hypertensive medication, overdose, and"4+7"plan is not followed completely.

Pacjent z nadciśnieniem tętniczym, zaburzeniami metabolicznymi i łagodnym przerostem stercza w gabinecie lekarza POZ – rola doksazosyny

In recent years, the therapy for patients with metabolic syndrome, which is a risk factor for cardiovascular complications, has become a challenge. Doxazosin – a selective α-adrenergic receptor antagonist, has emerged as a promising research target in the context of metabolic syndrome. It is pleiotropic action contributes to the reduction of metabolic syndrome indices. The results of clinical trials allow the construction of a promising, highly effective, and above all safe therapy in this group of patients.

Involvement of dopamine D2 and glutamate NMDA receptors in the antidepressant-like effect of amantadine in mice

The present study investigated the pharmacological mechanisms of the antidepressant-like effects of amantadine in mice and their influence on hippocampal neurogenesis. To improve the translational validity of preclinical results, reproducibility across laboratories and replication in other animal models and species are crucial. Single amantadine administration at doses of 50 and 75 mg/kg resulted in antidepressant-like effects in mice in the tail suspension test (TST), reflected by an increase in immobility time. The effects of amantadine were seen at doses that did not alter locomotor activity. The tyrosine hydroxylase inhibitor α-methyl-ρ-tyrosine did not influence the anti-immobility effect of amantadine in the TST. Pretreatment with the α1 adrenergic receptor antagonist prazosin, β adrenergic receptor antagonist propranolol, α2 adrenergic receptor antagonist yohimbine, and α2 adrenergic receptor agonist clonidine did not alter the antidepressant-like effect of amantadine. However, amantadine’s effect was blocked by the dopamine D2 receptor antagonist haloperidol and glutamate receptor agonist N-methyl-D-aspartate (NMDA). Repeated amantadine administration (50 mg/kg) also exerted an antidepressant-like effect, paralleled by an increase in hippocampal neurogenesis. The present results demonstrate that the antidepressant-like effects of amantadine may be mediated by its actions on D2 and NMDA receptors and likely involve hippocampal neurogenesis.

Dexmedetomidine maintains blood-brain barrier integrity by inhibiting Drp1-related endothelial mitochondrial dysfunction in ischemic stroke.

Stroke is the second leading cause of death and long-term disability worldwide, which lacks effective treatment. Perioperative stroke is associated with much higher rates of mortality and disability. The neuroprotective role of dexmedetomidine (Dex), a highly selective agonist of alpha2-adrenergic receptor, has been reported in a stroke rat model, and it was found that pretreatment of Dex before stroke could alleviate blood-brain barrier (BBB) breakdown. However, the underlying mechanisms are still unknown. As the brain endothelial cells are the main constituents of BBB and in high demand of energy, mitochondrial function of endothelial cells plays an important role in the maintenance of BBB. Given that dynamin-related protein 1 (Drp1) is a protein mediating mitochondrial fission, with mitochondrial fusion that balances mitochondrial morphology and ensures mitochondria function, the present study was designed to investigate the possible role of Drp1 in endothelial cells involved in the neuroprotective effects of Dex in ischemic stroke. Our results showed that preconditioning with Dex reduced infarction volume, alleviated brain water content and BBB damage, and improved neurological scores in middle cerebral artery occlusion rats. Meanwhile, Dex enhanced cell activity and decreased cell apoptosis in oxygen-glucose deprivation human brain microvascular endothelial cells in vitro. These protective effects of Dex were correlated with the mitochondrial morphology integrality of endothelial cells, mediated by increased phosphorylation of serine 637 in Drp1, and could be reversed by α2-adrenergic receptor antagonist Yohimbine and AMP-activated protein kinase inhibitor Compound C. These findings suggest new molecular pathways involved in the neuroprotective effects of Dex in ischemic stroke. As Dex is routinely used as a sedative drug clinically, our findings provide molecular evidence that it has perioperative neuroprotection from ischemic stroke.

Alpha adrenergic receptors have role in the inhibitory effect of electrical low frequency stimulation on epileptiform activity in rats

Aim: Low frequency stimulation (LFS) inhibits neuronal hyperexcitability following epileptic activity. However, knowledge about LFS’ inhibitory mechanisms is lacking. Here, α1 and α2 adrenergic receptors’ roles in mediating LFS inhibitory action on high-K+ induced epileptiform activity (EA) was examined in rat hippocampal slices. Materials and methods: LFS (1 Hz, 900 pulses) was applied to the Schaffer collaterals. Whole-cell, patch clamp recording was used to measure changes in CA1 pyramidal neurons’ excitability. By applying high-K+ on hippocampal slices, EA was induced, and neuronal excitability increased. Results: When administered at the beginning of EA, LFS reduced neuronal excitability. In the presence of prazosin (10 µM, an α1 adrenergic receptor antagonist) and yohimbine (5 µM, an α2 adrenergic receptor antagonist), LFS’ typically has a restorative impact on EA-induced membrane potential hyperpolarization and spike firing frequency, but this effect was reduced after high-K+ washout; These antagonists did not have a significant effect on LFS’ inhibitory action on spike firing during EA. Conclusion: These findings suggest that LFS’ anticonvulsant effect, on neuronal hyperexcitability following high-K+ EA, may be mediated partly through α adrenergic receptors in hippocampal slices.

Adrenaline May Contribute to Prothrombotic Condition via Augmentation of Platelet Procoagulant Response, Enhancement of Fibrin Formation, and Attenuation of Fibrinolysis.

Background: Adrenaline is believed to play a role in thrombosis and hemostasis. The complex effect of its clinically relevant concentrations on thrombus formation, coagulation and fibrinolysis in human blood has never been specifically studied.Methods: Confocal microscopy was used to study thrombus formation under flow, exposure of phosphatidylserine (PS) in adhered platelets, to evaluate clots density, and to measure kinetics of fibrin formation and external fibrinolysis under flow. Flow cytometry was utilized to assess PS exposure in non-adhered platelets. Kinetics of clot formation and internal fibrinolysis was evaluated by thromboelastometry. Platelet aggregation was measured by optical aggremometry. Kinetics of clot retraction was assessed by using digital camera.Results: We found that adrenaline (1–10 nM) is able to enhance platelet activation evoked by subthreshold collagen (150 ng/ml), resulting in augmentation of platelet aggregation, thrombus formation under arterial flow conditions, platelet PS exposure, and formation of platelet-fibrin clots. The development of platelet procoagulant response evoked by adrenaline + low collagen was associated with the formation of denser platelet-fibrin clots and the decrease in rate of fibrinolysis despite whether lysis was initiated inside (internal fibrinolysis) or outside the clot (external fibrinolysis). The above phenomena were abolished by the α2-adrenergic receptor antagonist, rauwolscine. Adrenaline-collagen synergism, expressed as PS exposure, was significantly reduced by cyclooxygenase inhibitor (acetylsalicic acid), GPIIb/IIIa receptor blocker (tirofiban), and P2Y12 receptor antagonist (PSB 0739).Conclusion: Clinically relevant concentrations of adrenaline may significantly augment responses of human platelets in the presence of subthreshold concentrations of collagen, which should be considered during therapies involving adrenaline infusion. Routinely used antiplatelet drugs may reduce the prothrombotic state evoked by adrenaline-collagen synergism.

The role of α adrenergic receptors in mediating the inhibitory effect of electrical brain stimulation on epileptiform activity in rat hippocampal slices

The Inhibitory effect of electrical low-frequency stimulation (LFS) on neuronal excitability and seizure occurrence has been indicated in experimental models, but the precise mechanism has not established. This investigation was intended to figure out the role of α1 and α2 adrenergic receptors in LFS' inhibitory effect on neuronal excitability. Epileptiform activity induced in an in vitro rat hippocampal slice preparation by high K+ ACSF and LFS (900 square wave pulses at 1 Hz) was administered at the beginning of epileptiform activity to the Schaffer collaterals. In CA1 pyramidal neurons, the electrophysiological properties were measured at the baseline, before high K+ ACSF washout, and at 15 min after high K+ ACSF washout using whole-cell, patch-clamp recording. Results indicated that after high K+ ACSF washout, prazosine (10 µM; α1 adrenergic receptor antagonist) and yohimbine (5 µM; α2 adrenergic receptor antagonist) suppressed the LFS’ effect of reducing rheobase current and utilization time following depolarizing ramp current, the latency to the first spike following a depolarizing current and latency to the first rebound action potential following hyperpolarizing current pulses. Thus, it may be proposed that LFS’ inhibitory action on the neuronal hyperexcitability, in some way, is mediated by α1 and α2 adrenergic receptors.

Stress Alters the Effect of Alcohol on Catecholamine Dynamics in the Basolateral Amygdala

The current rodent study applied in vivo fast-scan cyclic voltammetry (FSCV), paired with a pharmacological approach, to measure the release of the catecholamines (CA) dopamine (DA) and norepinephrine (NE) in the basolateral amygdala (BLA) following locus coeruleus (LC) stimulation. The primary goal was to determine if exposure to either social (social defeat) or non-social (forced swim) stress altered LC-evoked catecholamine release dynamics in the BLA. We used idazoxan (α2 adrenergic receptor antagonist) and raclopride (D2 dopamine receptor antagonist) to confirm the presence of NE and DA, respectively, in the measured CA signal. In non-stressed rats, injection of idazoxan, but not raclopride, resulted in a significant increase in the detected CA signal, indicating the presence of NE but not DA. Following exposure to either stress paradigm, the measured CA release was significantly greater after injection of either drug, suggesting the presence of both NE and DA in the LC-induced CA signal after social or non-social stress. Furthermore, acute administration of alcohol significantly decreased the CA signal in stressed rats, while it did not have an effect in naïve animals. Together, these data reveal that, while LC stimulation primarily elicits NE release in the BLA of control animals, both social and non-social stress unmask a novel dopaminergic component of LC catecholamine signaling. Future studies will be needed to identify the specific neural mechanism(s) responsible for these plastic changes in LC-BLA catecholamine signaling and to assess the possible contribution of these changes to the maladaptive behavioral phenotypes that develop following exposure to these stressors.

Blood pressure in the chronically hypoxaemic fetus is regulated by α-adrenergic receptors on the peripheral vasculature.

Blood pressure in the chronically hypoxaemic fetus is regulated by α-adrenergic receptors on the peripheral vasculature.

Dexmedetomidine Attenuates Ischemia/Reperfusion-Induced Myocardial Inflammation and Apoptosis Through Inhibiting Endoplasmic Reticulum Stress Signaling.

BackgroundEndoplasmic reticulum stress (ERS)-mediated myocardial inflammation and apoptosis plays an important role in myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine has been used clinically with sedative, analgesic, and anti-inflammatory properties. This study aimed to determine the effects of dexmedetomidine pretreatment on inflammation, apoptosis, and the expression of ERS signaling during myocardial I/R injury.MethodsRats underwent myocardial ischemia for 30 min and reperfusion for 6 h, and H9c2 cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury (OGD for 12 h and reoxygenation for 3 h). Dexmedetomidine was administered prior to myocardial ischemia in rats or ODG in cardiomyocytes. In addition, the α2-adrenergic receptor antagonist (yohimbine) or the PERK activator (CCT020312) was given prior to dexmedetomidine treatment.ResultsDexmedetomidine pretreatment decreased serum levels of cardiac troponin I, reduced myocardial infarct size, alleviated histological structure damage, and improved left ventricular function following myocardial I/R injury in rats. In addition, dexmedetomidine pretreatment increased cell viability and reduced cytotoxicity following OGD/R injury in cardiomyocytes. Mechanistically, the cardioprotection offered by dexmedetomidine was mediated via the inhibition of inflammation and apoptosis through downregulating the expression of the ERS signaling pathway, including glucose-regulated protein 78 (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), C/EBP homologous protein (CHOP), inositol-requiring protein 1 (IRE1), and activating transcription factor 6 (ATF6). Conversely, the protective effects of dexmedetomidine were diminished by blocking the α2 adrenergic receptors with yohimbine or promoting PERK phosphorylation with CCT020312.ConclusionDexmedetomidine pretreatment protects the hearts against I/R injury via inhibiting inflammation and apoptosis through downregulation of the ERS signaling pathway. Future clinical studies are needed to confirm the cardioprotective effects of dexmedetomidine in patients at risk of myocardial I/R injury.

Catecholaminergic Vasopressors Reduce Toll-Like Receptor Agonist-Induced Microvascular Endothelial Cell Permeability But Not Cytokine Production.

Catecholaminergic vasopressors are the cornerstone of circulatory shock management. Nevertheless, catecholamines have problematic side effects, arousing a growing interest in noncatecholaminergic agents such as vasopressin or angiotensin-II. However, their respective effects on sepsis-associated microvascular endothelial dysfunction such as permeability or inflammation remain elusive. We investigated the role of catecholamines and other vasopressors on Toll-like receptor agonists-induced microvascular endothelial permeability and inflammation. University research laboratory/cell research. Human pulmonary microvascular endothelial cells from multiple donors. Confluent monolayers of human pulmonary microvascular endothelial cells were treated with Toll-like receptor agonists (lipopolysaccharide, Poly[I:C], or tripalmitoyl-S-glyceryl cysteine) in the presence or absence of epinephrine, norepinephrine, vasopressin, and angiotensin-II. Permeability was inferred from transendothelial resistance, measured using electrical cell impedance sensing, where decreased transendothelial resistance is consistent with increased permeability. Cell-cell junction molecule expression was assessed via immunofluorescence microscopy and flow cytometry. We quantified cytokines in supernatants of Toll-like receptor agonist-treated human pulmonary microvascular endothelial cells. Epinephrine and norepinephrine both ameliorate lipopolysaccharide, polyinosinic:polycytidylic acid, or tripalmitoyl-S-glyceryl cysteine-induced reductions in transendothelial resistance, a surrogate for endothelial permeability. In contrast, the noncatecholaminergic agents, vasopressin, and angiotensin-II did not affect Toll-like receptor agonists-induced reductions in transendothelial resistance. β1- and β2-adrenergic receptor antagonists reduced the effects of the catecholamines on transendothelial resistance, whereas α-adrenergic receptor antagonists did not. We observed that epinephrine and norepinephrine induced actin cytoskeletal rearrangement and normalized the membrane expression of proteins involved with adherens-junctions (vascular endothelial-cadherin) and tight-junctions (zona occludens-1). Despite having a substantial effect on endothelial permeability, epinephrine and norepinephrine did not affect human pulmonary microvascular endothelial cell survival or production of interleukin-8, interleukin-6, or monocyte chemoattractant protein-1 (CCL-2) induced by Toll-like receptor agonists, suggesting that these functions are regulated separately from permeability. Our findings demonstrate that treatment with epinephrine or norepinephrine strongly reduces endothelial permeability induced by agonists of multiple Toll-like receptors (Toll-like receptor-2, Toll-like receptor-3, Toll-like receptor-4) in vitro. Our studies suggest that both β1- and β2-adrenergic receptors mediate the stabilizing effects of epinephrine and norepinephrine on the endothelial barrier.

Appraisal of the Antiarthritic Potential of Prazosin via Inhibition of Proinflammatory Cytokine TNF-α: A Key Player in Rheumatoid Arthritis

Prazosin, a selective α1 adrenergic receptor antagonist, with documented anti-inflammatory potential, was evaluated for its antiarthritic efficacy by targeting specifically TNF-α. The antiarthritic attribute of prazosin validated through in vitro screening comprised thermally provoked denaturation of bovine serum albumin (BSA) and egg albumin along with membrane stabilization evaluation at a concentration of 100–6400 μg/mL, while in vivo screening comprised formaldehyde-instigated arthritis at the doses of 5, 10, and 20 mg/kg and complete Freund’s adjuvant (CFA)-induced arthritis at 20 mg/kg dose. Paw swelling, body weight, arthritic score, hematological parameters, and histological and radiographic examination of ankle joints were assessed for a period of 28 days after CFA immunization. Moreover, the proinflammatory cytokine TNF-α level was also assessed through quantitative real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Prazosin revealed significant antiarthritic effect evident through protein denaturation inhibition in the egg albumin and the BSA model, stabilization of red blood cell membrane in the membrane stabilizing assay, and reduction in paw volume in formaldehyde-induced arthritis. Likewise, prazosin exhibited propitious antiarthritic effects in the CFA-provoked arthritis model manifested by paw volume and arthritic score alleviation, substantial weight loss prevention, and preservation of the normal hematological and biochemical profile. Histological and X-ray investigation unveiled no substantive structural alterations in treated rat’s ankle joints. The TNF-α expression level was also reduced. Thus, the current study is suggestive that prazosin exhibits a strong antiarthritic potential possibly through inhibition of TNF-α.

Long-Lasting and Additive Analgesic Effects of Combined Treatment of Bee Venom Acupuncture and Venlafaxine on Paclitaxel-Induced Allodynia in Mice.

Paclitaxel, a primary chemotherapeutic agent used to treat numerous solid malignancies, is commonly associated with debilitating peripheral neuropathy. However, a satisfactory gold-standard monotherapy for this neuropathic pain is not currently available. A combination strategy of two or more medications with different properties may achieve more beneficial effects than monotherapy. Thus, we investigated the analgesic efficacies and spinal mechanisms of the combination strategy, including bee venom acupuncture (BVA) and venlafaxine (VLX) against paclitaxel-induced allodynia in mice. Four intraperitoneal infusions of paclitaxel on alternating days (2 mg/kg/day) induced cold and mechanical allodynia for at least 1 week as assessed using acetone and the von Frey hair test, respectively. Co-treatment of BVA (1.0 mg/kg, s.c., ST36) with VLX (40 mg/kg, i.p.) at the medium dose produced a longer-lasting and additive effect than each monotherapy at the highest dose (BVA, 2.5 mg/kg; VLX, 60 mg/kg). Spinal pre-administration of idazoxan (α2-adrenergic receptor antagonist, 10 μg), methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 10 μg), or MDL-72222 (5-HT3 receptor antagonist, 10 μg) abolished this analgesia. These results suggest that the combination therapy with BVA and VLX produces long-lasting and additive analgesic effects on paclitaxel-induced allodynia, via the spinal noradrenergic and serotonergic mechanism, providing a promising clinical strategy.

Local α1-adrenergic blockers: An alternative for sheep cervix dilation?

To facilitate transcervical artificial insemination in sheep, the effects of local treatment with α1-adrenergic receptor antagonists on cervix dilation and hemodynamics were evaluated. Ewes (n = 7) were subjected to oestrous synchronisation every 40 days and assigned to treatments in a Latin square experimental design (seven animals × seven periods) with a factorial treatment arrangement (A × B), Factors A (prazosin or tamsulosin) and B (1, 2, or 4 mg/animal). Ewes of the six treatment groups (P1, P2, P4, T1, T2, and T4) were administered α1-adrenergic receptor antagonists while those of the control group (CG) were administered only α1-adrenergic antagonist carrier agent. Distance that the transcervical catheter penetrated without cervical resistance, mean arterial pressure, and uterine artery dopplerfluxometry were evaluated before and after 30 min, 1, 2, 4, 8, and 10 h of treatment. Catheter penetration distance was greater in ewes of the T4 and P4 groups (P < 0.01), with there being a positive correlation between dose and distance (r = 0.243). The penetration distance was similar (P = 0.84) for treated groups, with the greatest penetration occurring 2, 4, and 6 h after treatment (P < 0.01). The passage into the uterine lumen was greater (P = 0.013) in ewes of the P4 (17.9 %) and T4 (19.6 %) groups. There were no effects on blood pressure or uterine blood flow (P> 0.05). These preliminary results indicate there are benefits of treatment with 4 mg/animal of tamsulosin or prazosin in catheter passage through the sheep cervix 2–6 h after administration without hemodynamic effects.

Anti-nociceptive effect of Arbutus andrachneL. methanolic leaf extract mediated by CB1, TRPV1 and PPARs in mouse pain models.

Arbutus andrachneL. is a medicinal plant that grows in Jordan and has many valuable effects. In the present study, the anti-nociceptive effect of A.andrachne methanolic leaf extract was determined in mice using thermal and chemical tests. Our findings show that different doses of A.andrachne extract reduced the number of writhings significantly compared to control group. The leaf extract also reduced the time of paw licking in the early and late phases of formalin test. In all the conducted tests, 300mg/kg body wt. was the best effective dose. A peroxisome proliferator-activated receptor alpha (PPARα) antagonist reversed the action of the plant extract in the early phase of formalin test while antagonists of the PPARα, PPAR gamma (PPARγ) and cannabinoid1 (CB1) receptors were responsible for abolishing its effect in the late phase of this test. Also, the extract administration increased the latency time in hot plate and tail flick, an effect that was reversed by the antagonists of PPARγ, CB1 and transient receptor potential vanilloid 1 (TRPV1). No effect was noticed for α2-adrenergic receptor antagonist in the action of A.andrachne in any of the conducted tests in this study. Furthermore, analysis of the constituents in the methanolic leaf extract using liquid chromatography mass spectrometry (LCMS) showed that the extract is rich in compounds that have anti-nociceptive and/or anti-inflammatory effects such as arbutin, rutin, linalool, linoleic acid, gallic acid, lauric acid, myristic acid, hydroquinone, β-sitosterol, ursolic acid, isoquercetin, quercetin, (+)-gallocatechin, kaempferol, α-tocopherol, myricetin 3-O-rhamnoside and catechin gallate. In conclusion, A.andrachne showed promising anti-nociceptive effects in thermal and chemical models of pain. These findings can open an avenue for natural pain relief.

Noradrenergic Components of Locomotor Recovery Induced by Intraspinal Grafting of the Embryonic Brainstem in Adult Paraplegic Rats.

Intraspinal grafting of serotonergic (5-HT) neurons was shown to restore plantar stepping in paraplegic rats. Here we asked whether neurons of other phenotypes contribute to the recovery. The experiments were performed on adult rats after spinal cord total transection. Grafts were injected into the sub-lesional spinal cord. Two months later, locomotor performance was tested with electromyographic recordings from hindlimb muscles. The role of noradrenergic (NA) innervation was investigated during locomotor performance of spinal grafted and non-grafted rats using intraperitoneal application of α2 adrenergic receptor agonist (clonidine) or antagonist (yohimbine). Morphological analysis of the host spinal cords demonstrated the presence of tyrosine hydroxylase positive (NA) neurons in addition to 5-HT neurons. 5-HT fibers innervated caudal spinal cord areas in the dorsal and ventral horns, central canal, and intermediolateral zone, while the NA fiber distribution was limited to the central canal and intermediolateral zone. 5-HT and NA neurons were surrounded by each other’s axons. Locomotor abilities of the spinal grafted rats, but not in control spinal rats, were facilitated by yohimbine and suppressed by clonidine. Thus, noradrenergic innervation, in addition to 5-HT innervation, plays a potent role in hindlimb movement enhanced by intraspinal grafting of brainstem embryonic tissue in paraplegic rats.

Drug Repositioning of the α1-Adrenergic Receptor Antagonist Naftopidil: A Potential New Anti-Cancer Drug?

Failure of conventional treatments is often observed in cancer management and this requires the development of alternative therapeutic strategies. However, new drug development is known to be a high-failure process because of the possibility of a lower efficacy than expected for the drug or appearance of non-manageable side effects. Another way to find alternative therapeutic drugs consists in identifying new applications for drugs already approved for a particular disease: a concept named “drug repurposing”. In this context, several studies demonstrated the potential anti-tumour activity exerted by α1-adrenergic receptor antagonists and notably renewed interest for naftopidil as an anti-cancer drug. Naftopidil is used for benign prostatic hyperplasia management in Japan and a retrospective study brought out a reduced incidence of prostate cancer in patients that had been prescribed this drug. Further studies showed that naftopidil exerted anti-proliferative and cytotoxic effects on prostate cancer as well as several other cancer types in vitro, as well as ex vivo and in vivo. Moreover, naftopidil was demonstrated to modulate the expression of Bcl-2 family pro-apoptotic members which could be used to sensitise cancer cells to targeting therapies and to overcome resistance of cancer cells to apoptosis. For most of these anti-cancer effects, the molecular pathway is either not fully deciphered or shown to involve α1-adrenergic receptor-independent pathway, suggesting off target transduction signals. In order to improve its efficacy, naftopidil analogues were designed and shown to be effective in several studies. Thereby, naftopidil appears to display anti-cancer properties on different cancer types and could be considered as a candidate for drug repurposing although its anti-cancerous activities need to be studied more deeply in prospective randomized clinical trials.