Α2-adrenergic Receptor Antagonist Research Articles

Prospective analysis of anatomic features predisposing patients to intraoperative floppy iris syndrome.

To aid preoperative risk assessment by identifying anatomic parameters corresponding with a higher risk of intraoperative floppy iris syndrome (IFIS) during cataract surgery. Prospective cohort study of 55 patients with α1-adrenergic receptor antagonist (α1-ARA) treatment and 55 controls undergoing cataract surgery. Anterior segment optical coherence tomography (AS-OCT), video pupilometer, and biometry measurements were performed preoperatively and analyzed regarding anatomic parameters that corresponded with a higher rate of IFIS. Those statistically significant parameters were evaluated with logistic regression analysis and receiver operating characteristic (ROC) curve. Pupil diameter was significantly smaller in patients who developed IFIS compared to those who did not develop IFIS (AS-OCT 3.29 ± 0.85 vs. 3.63 ± 0.68, p = 0.03; Pupilometer 3.56 ± 0,87 vs. 3.95 ± 0.67, p = 0.02). Biometric evaluation revealed shallower anterior chambers in the IFIS group (ACD 3.12 ± 0.40 vs. 3.32 ± 0.42, p = 0.02). Cutoff values for 50% IFIS probability (p = 0.5) were PD = 3.18mm for pupil diameter and ACD = 2.93mm for anterior chamber depth. ROC curves of combined parameters were calculated for α1-ARA medication with pupil diameter and anterior chamber depth, which yielded an AUC of 0.75 for all IFIS grades. The combination of biometric parameters with history of α1-ARA medication can improve assessment of risk stratification for IFIS incidence during cataract surgery.

Inhibitory effects of N-methyl-D-aspartate (NMDA) and α1-adrenergic receptor antagonist ifenprodil on human Kv1.5 channel.

Ifenprodil has been known to reduce cardiac contractility and cerebral vasodilation by antagonizing α1-adrenergic and N-methyl D-aspartate receptor-mediated intracellular signals. This study aimed to investigate the direct effect of ifenprodil on the human voltage-gated Kv1.5 channel (hKv1.5) by using a Xenopus oocyte expression system and a two-microelectrode voltage clamp technique. The amplitudes of hKv1.5 currents, including peak and steady state, were suppressed in a concentration-dependent manner (IC50; 43.1 and 35.5μM, respectively) after 6min of ifenprodil treatment. However, these effects were ~ 80% reversed by washout, suggesting that ifenprodil directly inhibited the hKv1.5 independent of membrane receptors or intracellular signals. The inhibition rate of steady state showed voltage dependence, wherein the rates increased according to test voltage depolarization. Ifenprodil reduced the time constants of hKv1.5 inactivation but has higher effects on activation. hKv1.5 inhibition by ifenprodil showed use dependency because the drug more rapidly reduced the current at the higher activation frequencies, and subsequent reduction in frequency after high activation frequency caused a partial channel block relief. Therefore, ifenprodil directly blocked the hKv1.5 in an open state and accelerated the time course of the channel inactivation, which provided a biophysical mechanism for the hKv1.5 blocking effects of ifenprodil.

The Lack of Standardization and Pharmacological Effect Limits the Potential Clinical Usefulness of Phytosterols in Benign Prostatic Hyperplasia.

The prevalence of benign prostatic hyperplasia (BPH) markedly increases with age. Phytotherapeutic approaches have been developed over time owing to the adverse side effects of conventional medications such as 5-reductase inhibitors and α1-adrenergic receptor antagonists. Therefore, dietary supplements (DS) containing active compounds that benefit BPH are widely available. Phytosterols (PSs) are well recognized for their role in maintaining blood cholesterol levels; however, their potential in BPH treatment remains unexplored. This review aims to provide a general overview of the available data regarding the clinical evidence and a good understanding of the detailed pharmacological roles of PSs-induced activities at a molecular level in BPH. Furthermore, we will explore the authenticity of PSs content in DS used by patients with BPH compared to the current legislation and appropriate analytical methods for tracking DS containing PSs. The results showed that PSs might be a useful pharmacological treatment option for men with mild to moderate BPH, but the lack of standardized extracts linked with the regulation of DS containing PSs and experimental evidence to elucidate the mechanisms of action limit the use of PSs in BPH. Moreover, the results suggest multiple research directions in this field.

Prazosin Protects the Liver Against Renal Ischemia/Reperfusion Injury in Rats.

Acute kidney injury (AKI) is a common subsequent problem after many medical conditions. AKI is associated with distant organ dysfunction where systemic inflammation and oxidative stress play major roles. In this study, the effect of Prazosin, an α1-Adrenergic receptor antagonist, was investigated on the liver injury induced by kidney ischemia-reperfusion (I/R) in rats. Male adult Wistar rats (n=21) were divided into three groups: sham, kidney I/R, and kidney I/R pre-treated with Prazosin (1 mg/kg). Kidney I/R was induced by vascular clamping of the left kidney for 45 min to reduce the blood flow. Oxidative and antioxidant factors along with apoptotic (Bax, Bcl-2, caspase3), and inflammatory (NF-κβ, IL-1β, and IL-6) factors were measured in the liver at protein levels. Prazosin could reserve liver function (p<0.01) and increase glutathione level (p<0.05) after kidney I/R significantly. Malonil dialdehyde (MDA), a lipid peroxidation marker, was diminished more significantly in Prazosin-treated rats compared to the kidney I/R group (p<0.001). Inflammatory and apoptotic factors were diminished by Prazosin pre-treatment in the liver tissue (p<0.05). Pre-administration of Prazosin could preserve liver function and decrease its inflammatory and apoptotic factors under kidney I/R conditions.

Determinación de los efectos embriotóxicos del uso de Atipamezol en modelo in ovo

Atipamezole is a specific α2-adrenergic receptor antagonist, and there exists insufficient information on its use during pregnancy. The aim of this study was to determine the embryotoxic activity of Atipamezole through an in ovo method. During the first stage of the study, 210 fertile eggs were divided into seven groups of 30 fertile eggs and placed in an incubator. On the seventh day of the first stage, no application was made to the control group. The second group was administered 50 microliters (µL) of saline solution, while the other groups were given Atipamezole at doses of 250, 125, 62.5, 31.25 and 15.62 micrograms·egg-1 (µg·egg-1) in 50 µL saline solution. In the second stage, according to the embryotoxic dose range determined from the first stage, 150 fertile eggs were divided into five groups of 30 fertile eggs and placed in an incubator. On the seventh day of the second stage, no application was made to the control group. Fifty µL of saline solution was administered to the second group. The other groups were given Atipamezole at doses of 220, 190 and 160 µg·egg-1 in 50 µL saline solution. After the incubation period, the eggs hatched, and the embryonic mortality rates were calculated. The mortality rate was determined to be 39.3% at the highest dose (250 µg·egg-1 = 5 miligrams·kilograms-1 –mg·kg-1–) (P&lt;0.05), while the mortality rate at other doses was determined to be the same as the control group (P&gt;0.05). In conclusion, it can be stated that the dose determined for Atipamezole in this study was very high compared to the recommended doses and it can be used in pregnancy as a benefit-loss calculation when necessary. However molecular or histopathological studies regarding the development of organ drafts are necessary to determine the safety of its use during pregnancy.

Glycolysis-enhancing α1-adrenergic antagonists modify cognitive symptoms related to Parkinson’s disease

Terazosin is an α1-adrenergic receptor antagonist that enhances glycolysis and increases cellular ATP by binding to the enzyme phosphoglycerate kinase 1 (PGK1). Recent work has shown that terazosin is protective against motor dysfunction in rodent models of Parkinson’s disease (PD) and is associated with slowed motor symptom progression in PD patients. However, PD is also characterized by profound cognitive symptoms. We tested the hypothesis that terazosin protects against cognitive symptoms associated with PD. We report two main results. First, in rodents with ventral tegmental area (VTA) dopamine depletion modeling aspects of PD-related cognitive dysfunction, we found that terazosin preserved cognitive function. Second, we found that after matching for demographics, comorbidities, and disease duration, PD patients newly started on terazosin, alfuzosin, or doxazosin had a lower hazard of being diagnosed with dementia compared to tamsulosin, an α1-adrenergic receptor antagonist that does not enhance glycolysis. Together, these findings suggest that in addition to slowing motor symptom progression, glycolysis-enhancing drugs protect against cognitive symptoms of PD.

Dexmedetomidine Protects against Airway Inflammation and Airway Remodeling in a Murine Model of Chronic Asthma through TLR4/NF-κB Signaling Pathway.

Asthma is a common respiratory disease characterized by chronic airway inflammation. Dexmedetomidine (DEX), a highly selective α2 adrenergic receptor agonist, has been shown to participate in regulating inflammatory states and thus exert organ protective actions. However, the potential of DEX in asthma is still unknown. This study is aimed at investigating the role of DEX in a mouse model of house dust mite- (HDM-) induced asthma and exploring its underlying mechanism. Here, we found that DEX treatment significantly ameliorated airway hyperresponsiveness, airway inflammation, and airway remodeling in the asthmatic mice, which were similar to the efficacy of the reference anti-inflammatory drug dexamethasone. In addition, DEX reversed the increased expression of toll-like receptor 4 (TLR4) and its downstream signaling adaptor molecule nuclear factor-κB (NF-κB) in the lung tissue of asthmatic mice. Furthermore, these protective effects of DEX were abolished by yohimbine, an α2 adrenergic receptor antagonist. These results indicate that DEX is capable of ameliorating airway inflammation and remodeling in asthmatic mice, and this protective effect is associated with the inhibition of the TLR4/NF-κB signaling pathway.

Nicotine suppresses central post-stroke pain via facilitation of descending noradrenergic neuron through activation of orexinergic neuron

Central post-stroke pain (CPSP) is a type of central neuropathic pain, whose underlying mechanisms remain unknown. We previously reported that bilateral carotid artery occlusion (BCAO)-induced CPSP model mice showed mechanical hypersensitivity and decreased mRNA levels of preproorexin, an orexin precursor, in the hypothalamus. Recently, nicotine was shown to regulate the neuronal activity of orexin in the lateral hypothalamus (LH) and suppress inflammatory and neuropathic pain. In this study, we evaluated whether nicotine could suppress BCAO-induced mechanical allodynia through the activation of orexinergic neurons. Mice were subjected to BCAO for 30 min. Mechanical hypersensitivity was assessed by the von Frey test. BCAO mice showed hypersensitivity to mechanical stimuli three days after BCAO surgery. The intracerebroventricular injection of nicotine suppressed BCAO-induced mechanical hypersensitivity in a dose-dependent manner. These effects were inhibited by α7 or α4β2-nicotinic receptor antagonists. After nicotine injection, the level of c-fos, a neuronal activity marker, increased in the LH and locus coeruleus (LC) of Sham and BCAO mice. Increased number of c-Fos-positive cells partly colocalized with orexin A-positive cells in the LH, as well as tyrosine hydroxylase-positive cells in the LC.Orexinergic neurons project to the LC area. Nicotine-induced antinociception tended to cancel by the pretreatment of SB334867, an orexin receptor1 antagonist into the LC. Intra-LH microinjection of nicotine attenuated BCAO-induced mechanical hypersensitivity. Nicotine-induced antinociception was inhibited by intrathecal pre-treatment with yohimbine, an α2 adrenergic receptor antagonist. These results indicated that nicotine may suppress BCAO-induced mechanical hypersensitivity through the activation of the descending pain control system via orexin neurons.

The Effect of Long-Term Tamsulosin Monotherapy and Tamsulosin - Dutasteride Combination Therapy on PKC-α Enzyme Expression in Prostate Stromal Tissue.

The α-adrenergic receptor antagonist is the most effective medical therapy to reduce the dynamic component in patients with BPH. However, long-term administration of receptor antagonists can cause upregulation of mRNA receptor expression, resulting in tolerance of drug effectiveness. PKC-α is involved in the process of prostate smooth muscle contraction through activation of the voltage-gated Ca2+ conducted canal, influenced by androgen hormones, especially testosterone, and has an isoform with Twist1, a transcription factor that plays a role in up-regulation of androgen receptors. The aim of the study was to compare the effect of long-term tamsulosin monotherapy and tamsulosin - dutasteride combination therapy in PKC-α enzyme expression in prostate stromal tissue of Rattus norvegicus rats of Wistar strain. Out of 80 samples of Rattus norvegicus rats were divided into 8 groups with different interventions: negative control group, positive control group, tamsulosin monotherapy administration for 1 day, 3 day, and 6 day groups, and tamsulosin - dutasteride combination therapy for 1 day, 3 day, and 6 day groups. BPH was induced with 3 mg/kg of testosterone proprionate for 3 weeks, continued with drugs administration according to intervention grouping. Prostate stromal tissue was taken and prepared for PKC-α enzyme measurement with ELISA method. There was a significant difference (p<0.05) in the effect of tamsulosin monotherapy and tamsulosin-dutasteride combination therapy on the PKC-α expression. There was a strong positive relationship between the duration of tamsulosin-dutasteride combination therapy on the PKC-α expression, which means the longer the duration of the combination of tamsulosin-dutasteride combination the higher the PKC-α expression. Administration of long-term tamsulosin - dutasteride combination therapy causes upregulation PKC-α expression more than tamsulosin only.

A-80426 suppresses CFA-induced inflammatory pain by suppressing TRPV1 activity via NFκB and PI3K pathways in mice

ObjectivesPain is associated with many circumstances, including inflammatory reactions, which arise from modification of the features of signaling pathways. α2-adrenergic receptor antagonists are widely utilized in narcosis. Here, the authors focused on the narcotic effect of A-80426 (A8) on Complete Freund's Adjuvant (CFA) injections-triggered chronic inflammation pain in WT and TRPV1-/- mice and explored whether its antinociceptive impact was modulated via Transient Receptor Potential Vanilloid 1 (TRPV1). MethodCFA with or without A8 was co-administered to the mice, which were categorized randomly into four groups: CFA, A8, control, and vehicle. Pain behaviors underwent evaluation through mechanical withdrawal threshold, abdominal withdrawal reflex, and thermal withdrawal latency of WT animals. ResultsQuantitative polymerase chain reaction revealed that inflammation-promoting cytokines (IL-1β, IL-6, and TNF-α) were upregulated in Dorsal Root Ganglion (DRG) and Spinal Cord Dorsal Horn (SCDH) tissues of WT animals. A8 administration reduced the pain behaviors and production of pro-inflammatory cytokines; however, this effect was significantly reduced in TRPV1-/- mice. Further analysis showed that CFA treatment reduced the TRPV1 expression in WT mice and A8 administration increased its expression and activity. The co-administration of SB-705498, a TRPV1 blocker, did not influence the pain behaviors and inflammation cytokines in CFA WT mice; however, SB-705498 the effect of A8 in WT mice. In addition, the TRPV1 block decreased the NFκB and PI3K activation in the Dorsal Root Ganglia (DRG) and Spinal Cord Dorsal Horn (SCDH) tissues of WT mice. ConclusionsTogether, A8 exerted a narcotic impact on CFA-supplemented mice via the TRPV1-modulated NFκB and PI3K pathway.

Evaluation of the effects of phenylephrine and prazosin injection into basolateral amygdala on the post-stress experience of memory retrieval in rats

The present study explored the effect of α1-adrenergic receptors in the basolateral amygdala (BLA) on memory formation in the hippocampus under repeated stress. Male rats received injections of the α1-adrenergic receptor agonist (phenylephrine) or antagonist (prazosin) bilaterally into the BLA five min before foot-shock stress, and emotional and spatial memory and in-vivo long-term potentiation (LTP) in the Cornu Ammonis (CA1) region of the hippocampus were examined. Foot-shock stress impaired performance in emotional and spatial memory tests. However, it had no significant effect on any of the LTP parameters in the hippocampus. Intra-BLA phenylephrine injection significantly impaired emotional and spatial memory performance in stressed animals. On the other hand, administration of intra-BLA prazosin significantly reduced emotional and spatial memory in the control (intact) animals. Neither of the two drugs had any significant effects on LTP parameters. Prazosin effectively impaired memory in the control, but not in the stressed rats. Stress appears to have suppressed the effect of prazosin, and it seems to be a significantly stronger stimulus than prazosin. Taken together, these findings provide new insights into the effects of α1-adrenergic receptors in the BLA on memory storage, during the stress experience.

The Effect of α2-Adrenoreceptors Blockade on the Isolated Rat Heart during the Formation of Sympathetic Innervation.

We studied the effects of the α2-adrenergic receptor antagonist yohimbine (10-9-10-6 M) on inotropy, chronotropy, and coronary flow in the Langendorff-isolated heart from 3- and 6-week-old rats. Yohimbine affected all the studied functional parameters of the isolated heart. The force of contraction of the left ventricular myocardium, HR, and coronary flow decreased at all studied concentrations of the antagonist. The maximum chronotropic effect was observed in the heart from 6-week-old rats in the presence of 10-6 M yohimbine in the perfused solution and in the heart from 3-week-old rats in the presence of 10-9 M yohimbine. The minimum chronotropic and inotropic effect was recorded in the hearts from 6-week-old animals after application of 10-9 M α2-adrenergic receptor blocker and in the hearts from 3-week-old animals at yohimbine concentration of 10-7 M. The least pronounced decrease in coronary flow in 3- and 6-week-old rats was observed at the minimum concentration of yohimbine.

DEXMEDETOMIDINE PREVENTS PDIA3 DECREASE BY ACTIVATING α2-ADRENERGIC RECEPTOR TO ALLEVIATE INTESTINAL I/R IN MICE.

Background: Dexmedetomidine (DEX) attenuates intestinal I/R injury, but its mechanism of action remains to be further elucidated. Protein disulfide isomerase A3 (PDIA3) has been reported as a therapeutic protein for the prevention and treatment of intestinal I/R injury. This study was to investigate whether PDIA3 is involved in intestinal protection of DEX and explore the underlying mechanisms. Methods: The potential involvement of PDIA3 in DEX attenuation of intestinal I/R injury was tested in PDIA3 Flox/Flox mice and PDIA3 conditional knockout (cKO) in intestinal epithelium mice subjected to 45 min of superior mesenteric artery occlusion followed by 4 h of reperfusion. Furthermore, the α2-adrenergic receptor (α2-AR) antagonist, yohimbine, was administered in wild-type C57BL/6N mice intestinal I/R model to investigate the role of α2-AR in the intestinal protection conferred by DEX. Results: In the present study, we identified intestinal I/R-induced obvious inflammation, endoplasmic reticulum (ER) stress-dependent apoptosis, and oxidative stress, and all the aforementioned changes were improved by the administration of DEX. PDIA3 cKO in the intestinal epithelium have reversed the protective effects of DEX. Moreover, yohimbine also reversed the intestinal protection of DEX and downregulated the messenger RNA and protein levels of PDIA3. Conclusion: DEX prevents PDIA3 decrease by activating α2-AR to inhibit intestinal I/R-induced inflammation, ER stress-dependent apoptosis, and oxidative stress in mice.

α-Adrenergic blockade prevented environmental temperature reduction-induced transient portal pressure surge in cirrhotic and portal hypertensive rats.

Exposure to low temperatures has been associated with increased gastroesophageal variceal bleeding in patients with cirrhosis and portal hypertension; however, the mechanism remains unclear. Therefore, the aim of the present study was to evaluate the impact of environmental temperature reduction on portal hypertension and the role of adrenergic signaling pathways in this phenomenon. Male Sprague-Dawley rats underwent common bile duct ligation or partial portal vein ligation to induce liver cirrhosis and/or portal hypertension. The impacts of acute or chronic changes in environmental temperature were surveyed. The results showed that acute cooling from 25 to 15°C and 5°C increased the portal pressure by 10.6% and 15.5% in cirrhotic rats, and by 22.2% and 36.1% in portal hypertensive rats, respectively. The transient portal pressure surge started shortly after cooling, reached a peak within 5 min and returned to baseline after 10 min. Systemic vascular resistance, mean arterial pressure and splanchnic blood flow increased significantly at the same time. Plasma epinephrine and norepinephrine concentrations, phospholipase C, protein kinase C activity and myosin phosphorylation of peripheral arteries increased significantly in response to cooling. Phentolamine (an α-blocker) but not propranolol (a non-selective β-blocker) dose-dependently inhibited the transient portal pressure surge and aforementioned molecular changes. In conclusion, environmental temperature reduction induced peripheral vasoconstriction via α-adrenergic pathways, and redistribution of blood flow to the splanchnic system led to a surge in transient portal pressure. Treatment with α-adrenergic receptor antagonists may exert additional benefits in controlling portal hypertension, especially on exposure to low temperatures.

2-pentadecyl-2-oxazoline prevents cognitive and social behaviour impairments in the Amyloid β-induced Alzheimer-like mice model: Bring the α2 adrenergic receptor back into play

The 2-pentadecyl-2-oxazoline (PEA-OXA) is a natural compound with protective action in neuro-inflammation. We have previously shown that PEA-OXA behaves as an α2 adrenergic receptor (α2AR) antagonist and a putative protean agonist on histamine H3 receptors. Recently, neuroinflammation and monoaminergic neurotransmission dysfunction has drawn particular attention in Alzheimer Disease (AD) pathophysiology. In this context, the objective of this study was to investigate the effects of the dual-acting PEA-OXA in an AD-like model in mice. A combined computational and experimental approach was used to evaluate the ability of PEA-OXA to bind α2A-AR subtype, and to investigate the effects of PEA-OXA treatment on neuropathological (behavioural and functional) effects induced by soluble Amyloid β 1–42 (sAβ1–42) intracerebroventricular injection. Computational analysis revealed the PEA-OXA ability to bind the α2A-AR, a pharmacological target for AD, in two alternative poses, one overlapping the Na+ binding site. In vivo studies indicated that chronic treatment with PEA-OXA (10 mg/kg, os) restored the cognitive (discriminative and spatial memory) deficits and social impairments induced by sAβ injection. Consistently, electrophysiological analysis showed a recovery of the long-term potentiation in the hippocampus (Lateral Entorhinal Cortex-Dentate Gyrus pathway), while neuroinflammation, i.e., increased pro-inflammatory cytokines levels and microglia cells density were reduced. These data provide the basis for further investigation of the pro-cognitive aptitude of PEA-OXA by proposing it as an adjuvant in the treatment in AD, for which the available pharmacological approaches remain unsatisfactory. Moreover, this study offers new future direction in research investigating the role of α2AR in neuropsychiatric illness and therapies.

Vasoconstrictor and hemodynamic effects of a methanolic extract from Rhinella marina toad poison

Rhinella marina toad is abundant in Brazil. Its poison contains cardiac glycosides called bufadienolides, which are extensively investigated for their bioactivity. Our aim was to characterize the vasoactivity of Rhinella marina poison (RmP) on the aorta of male Wistar rats. For this, the RmP was first collected and processed to obtain an alcoholic extract. To determine cardiovascular effects of RmP, we performed in vivo tests by administering RmP intravenously in doses of 0.1–0.8 mg/kg. Vascular reactivity was also performed through concentration-response curves to RmP (10 ng/mL to 200 μg/mL) in aortic segments with and without endothelium. RmP induced a concentration-dependent contraction in rat aorta which was partly endothelium-mediated. Nitric oxide contributes with this response in view that incubation with L-NAME increased the contractile response. Additionally, treatment with indomethacin [cyclooxygenase, (COX) inhibitor], nifedipine (L-type voltage-gated calcium channels blocker), and BQ-123 (ETA receptors antagonist) decreased maximum response, and ketanserin (5-HT2 receptors antagonist) decreased pEC50, suggesting active participation of these pathways in the contractile response. On the other hand, apocynin (NADPH oxidase inhibitor) did not alter contractility. Incubation with prazosin (α1-adrenergic receptor antagonist) abolished the contractile response, suggesting that the RmP-induced contraction is dependent on the adrenergic pathway. In the Na+/K+ ATPase protocol, a higher Emax was observed in the RmP experimental group, suggesting that RmP potentiated Na+/K+ATPase hyperpolarizing response. When this extract was injected (i.v.) in vivo, increase in blood pressure and decrease in heart rate were observed. The results were immediate and transitory, and occurred in a dose-dependent manner. Overall, these data suggest that the poison extract of R. marina toad has an important vasoconstrictor action and subsequent vasopressor effects, and its use can be investigated to some cardiovascular disorders.

Anticancer potential of yohimbine in drug-resistant oral cancer KB-ChR-8-5 cells.

The demand for environmentally friendly and cost-effective plant-based products for the development of cancer therapeutics has been increasing. Yohimbine (α2-adrenergic receptor antagonist) is a stimulant and aphrodisiac used to improve erectile dysfunction. In this study, we aimed to evaluate the anticancer potential of yohimbine in drug-resistant oral cancer KB-ChR-8-5 cells using different biomolecular techniques. We estimated the anticancer efficacy of yohimbine using different assays, such asMTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell cytotoxicity, cell morphology, cell apoptosis, reactive oxygen species (ROS) formation, and modulation in the mitochondrial membrane potential (MMP). Yohimbine showed a dose-dependent increase in cytotoxicity with a 50% inhibitory concentration (IC50) of 44µM against KB-ChR-8-5 cancer cell lines. Yohimbine treatment at 40µM and 50µM resulted in a considerable change in cell morphology, including shrinkage, detachment, membrane blebbing, and deformed shape. Moreover, at the dose of IC50 and above, a significant induction was observed in the generation of ROS and depolarization of MMP. The possible mechanisms of action of yohimbine underlying the dose-dependent increase in cytotoxicity may be due to the induction of apoptosis, ROS generation, and modulation of MMP. Overall, yohimbine showed a significant anticancer potential against drug-resistant oral cancer KB-ChR-8-5 cells. Our study suggests that besides being an aphrodisiac, yohimbine can be used as a drug repurposing agent. However, more research is required in different in vitro and in vivo models to confirm the feasibility of yohimbine in clinics.

Dexmedetomidine Ameliorated Cognitive Dysfunction Induced by Intestinal Ischemia Reperfusion in Mice with Possible Relation to the Anti-inflammatory Effect Through the Locus Coeruleus Norepinephrine System

Cognitive impairment is a common central nervous system complication that occurs following surgery or organs damage outside the nervous system. Neuroinflammation plays a key role in the molecular mechanisms of cognitive impairment. Dexmedetomidine alleviates neuroinflammation and reduces cognitive dysfunction incidence; however, the mechanism by which dexmedetomidine alleviates cognitive dysfunction remains unclear. This study evaluated the effect of dexmedetomidine on attenuation of early cognitive impairment induced by intestinal ischemia–reperfusion in mice and examined whether the locus coeruleus norepinephrine (LCNE) system participates in the anti-inflammatory effect of dexmedetomidine. The superior mesenteric artery was clamped for 45 min to induce intestinal ischemia reperfusion injury. Dexmedetomidine alone or combined with DSP-4, a selective locus coeruleus noradrenergic neurotoxin, was used for pretreatment. Postoperative cognition was assessed using the Morris water maze. Serum and hippocampal levels of IL-1β, TNF-α, norepinephrine (NE), and malondialdehyde (MDA) were assessed by enzyme-linked immunosorbent assay. Immunofluorescence, immunohistochemistry, and hematoxylin and eosin staining were used to evaluate the expression of tyrosine hydroxylase (TH) in the locus coeruleus, hippocampal microglia, and intestinal injury. Pretreatment with dexmedetomidine alleviated intestinal injury and decreased the serum and hippocampal levels of NE, IL-1β, TNF-α, and MDA at 24 h after intestinal ischemia reperfusion, decreased TH-positive neurons in the locus coeruleus, and ameliorated cognitive impairment. Similarly, DSP-4 pre-treatment alleviated neuroinflammation and improved cognitive function. Furthermore, α2-adrenergic receptor antagonist atipamezole or yohimbine administration diminished the neuroprotective effects and improved cognitive function with dexmedetomidine. Therefore, dexmedetomidine attenuated early cognitive dysfunction induced by intestinal ischemia–reperfusion injury in mice, which may be related to its anti-inflammatory effects through the LCNE system.

Sex differences in α-adrenergic receptor function contribute to impaired hypothalamic metaplasticity following chronic intermittent ethanol exposure.

Individuals with alcohol use disorder (AUD) exhibit maladaptive responses of the hypothalamic-pituitary-adrenal (HPA) axis to stress, which has been linked to high rates of relapse to drinking among abstinent individuals. Corticotropin-releasing factor (CRF) parvocellular neuroendocrine cells (PNCs) within the paraventricular nucleus of the hypothalamus (PVN) are critical to stress-induced HPA axis activation. Here, we investigate sex differences in synaptic transmission and plasticity in PNCs following the application of the stress-associated neurotransmitter norepinephrine (NE) in a rat model of AUD. Adult Sprague-Dawley rats were exposed to 40 days of chronic intermittent ethanol (CIE) vapor and 30 to 108 days of protracted withdrawal. We measured changes in holding current, evoked synaptic currents, and short-term glutamatergic plasticity (STP) in putative PNCs following the application of NE (10μM) with and without the selective α1 adrenergic receptor (AR) antagonist prazosin (10μM) or the α2AR antagonist atipamezole (10μM). The experiments were performed using whole-cell patch clamp recordings in slices from CIE rats and air-exposed controls. NE application caused two distinct effects: a depolarizing, inward, postsynaptic current and a reduction in amplitude of an evoked glutamatergic excitatory postsynaptic current (eEPSC). Both effects were sex- and CIE-specific. Prazosin blocked the postsynaptic inward current, while atipamezole blocked the NE-mediated suppression of eEPSCs. Additionally, STP formation was facilitated following NE application only in stress-naïve males and this response was lost in stressed animals exposed to a 30-min restraint stress following CIE exposure. Furthermore, NE + prazosin restored STP formation in stressed CIE males. NE exerts excitatory and inhibitory effects on CRF PVN PNCs, and both effects are influenced by sex and CIE. Behavioral and hormonal responses to stress are influenced by STP formation within the PVN, which is lost following CIE and restored with the preapplication of prazosin. The selective blockade of α1AR may, therefore, ameliorate CIE-induced deficits in HPA responses to stress in a sex-specific manner.

Dopamine D2-Subtype Receptors Outside the Blood-Brain Barrier Mediate Enhancement of Mesolimbic Dopamine Release and Conditioned Place Preference by Intravenous Dopamine.

Dopamine (DA) is a cell-signaling molecule that does not readily cross the blood-brain barrier. Despite this, peripherally administered DA enhances DA levels in the nucleus accumbens and alters DA-related behaviors. This study was designed to investigate whether DA subtype-2 receptors are involved in the enhancement of nucleus accumbens (NAc) DA levels elicited by intravenous DA administration. This was accomplished by using microdialysis in the NAc and extracellular single unit recordings of putative DA neurons in the ventral tegmental area (VTA). Additionally, the reinforcing properties of intravenous DA were investigated using a place conditioning paradigm and the effects of intravenous DA on ultrasonic vocalizations were assessed. Following administration of intravenous dopamine, the firing rate of putative DA neurons in the VTA displayed a biphasic response and DA levels in the nucleus accumbens were enhanced. Pretreatment with domperidone, a peripheral-only DA D2 receptor (D2R) antagonist, reduced intravenous DA mediated increases in VTA DA neuron activity and NAc DA levels. Pretreatment with phentolamine, a peripheral α-adrenergic receptor antagonist, did not alter the effects of IV DA on mesolimbic DA neurotransmission. These results provide evidence for peripheral D2R mediation of the effects of intravenous DA on mesolimbic DA signaling.