Alpha-adrenergic Receptors Research Articles

Enhanced Vasoconstriction in Sickle Cell Disease is Dependent on ETA Receptor Activation

Sickle Cell Disease (SCD) carries a significant risk for poor vascular health and vascular dysfunction. High levels of vascular reactive oxygen species (ROS) as well as elevated plasma endothelin-1 (ET-1), a potent vasoconstrictor with actions via the ETA receptor, are both common phenotypes in SCD. Alpha-1 adrenergic receptor activation is a major mediator of stress-induced vasoconstriction. However, the mechanism of the SCD enhanced vasoconstrictive response is unknown. We hypothesized that SCD induces enhanced alpha-1 adrenergic mediated vasoconstriction through the ET-1/ETA receptor pathway in arterial tissues. Utilizing humanized SCD (HbSS) and genetic control (HbAA) mice, alpha-1a, but not alpha-1b or alpha-1d, receptor expression was significantly greater in aortic tissue from HbSS mice compared to HbAA mice. Significantly enhanced vasoconstriction in aortic and carotid arterial segments were observed from HbSS mice compared to HbAA mice. Treatment with ambrisentan, a selective ETA receptor antagonist, and a ROS scavenger normalized the aortic vasoconstrictive response in HbSS mice. In a randomized translational study, patients with SCD were treated with placebo or ambrisentan for 3 months, with the treatment group showing an increase in the percent brachial arterial diameter. Taken together, these data suggest that the ETA receptor pathway interaction with the adrenergic receptor pathway contributes to enhanced aortic vasoconstriction in SCD. Findings indicate the potential of ETA antagonism as a therapeutic avenue for improving vascular health in SCD.

Epinephrine and norepinephrine regulate the expression of virulence factors in Gallibacterium anatis

Gallibacterium anatis is a member of the Pasteurellaceae family and is an opportunistic pathogen that causes gallibacteriosis in chickens. Stress plays a relevant role in promoting the development of pathogenicity in G. anatis. Epinephrine (E) and norepinephrine (NE) are relevant to stress; however, their effects on G. anatis have not been elucidated. In this work, we evaluated the effects of E and NE on the growth, biofilm formation, expression of adhesins, and proteases of two G. anatis strains, namely, the hemolytic 12656-12 and the nonhemolytic F149T biovars. E (10μM/mL) and NE (30 and 50μM/mL) increased the growth of G. anatis 12656-12 by 20% and 25%, respectively. E did not affect the growth of F149T, whereas 40μM/mL NE decreased bacterial growth by 25%. E and NE at a dose of 30-50μM/mL upregulated five fibrinogen adhesins in the 12565-12 strain, whereas no effect was observed in the F149T strain. NE increased proteolytic activity in both strains, whereas E diminished proteolytic activity in the 12656-12 strain. E and NE reduced biofilm formation (30%) and increased Congo red binding (15%) in both strains. QseBC is the E and NE two-component detection system most common in bacteria. The qseC gene, which is the E and NE receptor in bacteria, was identified in the genomic DNA of the 12565-12 and F149TG. anatis strains via PCR amplification. Our results suggest that QseC can detect host changes in E and NE concentrations and that catecholamines can modulate the expression of several virulence factors in G. anatis.

The effects of locus coeruleus optogenetic stimulation on global spatiotemporal patterns in rats

Abstract Whole-brain intrinsic activity as detected by resting-state fMRI can be summarized by three primary spatiotemporal patterns. These patterns have been shown to change with different brain states, especially arousal. The noradrenergic locus coeruleus (LC) is a key node in arousal circuits and has extensive projections throughout the brain, giving it neuromodulatory influence over the coordinated activity of structurally separated regions. In this study, we used optogenetic-fMRI in rats to investigate the impact of LC stimulation on the global signal and three primary spatiotemporal patterns. We report small, spatially specific changes in global signal distribution as a result of tonic LC stimulation, as well as regional changes in spatiotemporal patterns of activity at 5 Hz tonic and 15 Hz phasic stimulation. We also found that LC stimulation had little to no effect on the spatiotemporal patterns detected by complex principal component analysis. We hypothesize that localized effects could be due to engagement of LC modules that support behaviors induced by our specific stimulation parameters, in addition to noradrenergic receptor profile distributions. Nonetheless, these results show that the effects of LC activity on the BOLD signal in rats may be small and regionally concentrated, as opposed to widespread and globally acting, further supporting emerging evidence of a modular LC.

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

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

Advancing Glaucoma Therapy by Exploring the Efficacy and Potential of Brimonidine Niosomal Gel

Glaucoma is a leading cause of permanent vision loss worldwide and is characterised by progressive optic neuropathy with elevated intraocular pressure (IOP) as a major risk factor. Although successful, the current therapeutic strategies are often severely limited by their need for chronic dosing, systemic side effects and poor patient compliance. Brimonidine, an alpha-2 adrenergic receptor agonist which acts selectively, has been beneficial through its IOP-lowering effects by diminishing aqueous humor production and improving uveoscleral outflow. A novel medication delivery technology to enhance ocular bioavailability and extended drug release is brimonidine, formulated as a niosomal gel. The aim of this study is to highlight its clinical efficacy, formulation strategies and mechanism of action that significantly improved glaucoma therapy. Key studies illuminate its potential benefits in reducing dosing frequency, avoiding side effects and increasing patient compliance. Additional study and optimization required to scale-up manufacturing or ensure long-term stability. Possible future directions: combination medications and delivery systems personalized medicine possible future directions in the treatment of glaucoma might include combination medicines and personalized medicine techniques tailored to patient-specific needs. Brimonidine niosomal gel may be a new approach for glaucoma management and it can change the concept of intraocular drug delivery in the future.

B - 61 Psilocybin as a First-Line Treatment of ADHD in Adult Populations

Abstract Objectives The first line for symptom management of attention deficit hyperactivity disorder (ADHD) is a class of medications that act on dopamine and noradrenaline receptors, which leads to symptom reduction at the cost of significant side effects. These side effects have led to community searching for alternative methods that manage ADHD symptoms in adults that lead to less side effects. Microdosing Psilocybin has emerged as a course of treatment that could provide benefits for those who may experience serious side effects to stimulant medication. Method This literature review was conducted using search terms such as, ADHD attention deficit hyperactivity disorder, psychedelic treatment, stimulant treatment of ADHD, naturalistic treatment of ADHD, 5-HT, neural plasticity. Journals that reported about the benefits and concerns of Psilocybin use for ADHD are Neurochemistry International, American College of Neuropharmacology, European Psychology, Movement and Nutrition in Health and Disease, Journal of Psychopharmacology, and Psychiatry Research. Results Research shows that not only does microdosing Psilocybin have less adverse effects than stimulant medications when being used to treat ADHD, but it also leads to an alternative method that focuses on serotonin receptors when other avenues are unsuccessful. Conclusions This poster illustrates the alternative use of Psilocybin for treatment in ADHD and highlights neurological underpinnings that may lead to explaining success. Limitations of stimulant medications are also reviewed.

Association Between Alpha-1 Adrenoreceptor Antagonist Use and Cognitive Impairment: A Systematic Review.

Alpha-1 adrenergic receptor (α1-AR) antagonists are commonly used for management of benign prostatic hyperplasia or hypertension. Some studies have shown a potential link between α1-AR antagonist use and cognitive impairment. Given the conflicting data surrounding α1-AR antagonists association with cognitive dysfunction, we aim to systematically review the association of cognitive dysfunction with α1-AR antagonist use to aid clinician decision both with medication initiation and continuation. A systematic review was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We searched Ovid Cochrane, Ovid Embase, Ovid MEDLINE, Scopus, and Web of Science on March 7, 2023, with an update run on January 22, 2024. The primary outcome was cognitive dysfunction. We used Cochrane risk of bias for randomized controlled trials (RCTs) and MINORS (Methodological Index for Non-Randomized Studies) criteria for non-RCTs to evaluate study quality. This study was registered with PROSPERO (CRD42024505751). We identified 7 studies for our systematic review (3 RCTs, 4 non-RCTs). Tamsulosin was the most studied medication (6 of 7 studies). Tamsulosin was associated with no cognitive dysfunction in 2 RCTs, increased risk for dementia in 2 non-RCTs, no change in cognition in 1 non-RCT, and decreased risk for dementia in 1 non-RCT. Among 3 non-RCTs analyzing alfuzosin, it was associated with decreased risk of or no association with dementia in 2 studies and increased risk for dementia in 1 study. Doxazosin, prazosin, and terazosin were neutral or showed a negative risk for dementia. Our systematic review did not show a convincing causal association between α1-AR antagonists, including tamsulosin, and cognitive dysfunction. Considering the existing literature, it is appropriate to use α1-AR antagonists without concern for cognitive dysfunction. Future research, through robust study designs considering the multifactorial nature of cognitive dysfunction, is required to further evaluate this association.

CARDIORESPIRATORY EFFECTS OF VATINOXAN IN BLESBOK (DAMALISCUS PYGARGUS PHILLIPSI) IMMOBILIZED WITH THIAFENTANIL-MEDETOMIDINE.

Combinations of a low dose of opioid, such as thiafentanil, and a high dose of medetomidine, are increasingly being used for immobilization of African ungulates. Both drugs can have undesirable cardiorespiratory effects. In this study we assessed whether vatinoxan, a peripherally acting alpha2-adrenergic receptor antagonist, can be used to alleviate some of these effects without affecting the immobilization quality. Eight healthy, female, boma-confined blesbok (Damaliscus pygargus phillipsi), weighing a mean (SDtion) of 56.8 (4.4) kg, were immobilized twice in a randomized cross-over study with a 2-wk washout period using (1) 0.5 mg thiafentanil + 1.5 mg medetomidine (TM), (2) TM + vatinoxan: 0.5 mg thiafentanil + 1.5 mg medetomidine + 15 mg vatinoxan per milligram medetomidine (total of 22.5 mg, administered intramuscularly at 10 min post recumbency). Heart rate, respiratory rate, rectal temperature, oxygen saturation (SpO2), arterial blood pressure, and sedation scores from 1 to 5 (1 = limited effect; 5 = excessively deep) were measured every 5 min. Arterial blood gases (PaO2 and PaCO2) were measured at 10, 15, 25, and 35 min postrecumbency and the alveolar--arterial oxygen gradient (P[A-a]O2) was calculated. Induction times and immobilization quality did not differ between groups. The heart rate was significantly higher and the mean arterial pressure significantly lower in blesbok after receiving vatinoxan. All animals were hypoxemic and there were no significant differences in the respiratory rates, PaO2, PaCO2, SpO2, or P(A-a)O2 gradients at any time point. Although vatinoxan did not improve respiratory variables and blood oxygenation in these animals, the change in cardiovascular variables may suggest that it improves tissue perfusion, a positive outcome that requires further investigation.

An Investigation of Novel Series of 2-Thioxo-1,3-dithiol-carboxamides as Potential Antispasmodic Agents: Design, Synthesis via Coupling Reactions, Density Functional Theory Calculations, and Molecular Docking.

This study reports the synthesis of 2-thioxo-1,3-dithiol-carboxamides (TDTCAs) under mild conditions at room temperature using HBTU as a coupling agent, which significantly improved amide bond formation. The synthesized compounds were characterized using several analytical techniques, including 1H and 13C NMR spectroscopy, and HRMS, confirming their intended structures and structural integrity. A DFT computational study at the B3LYP/6-31G(d,p) level was conducted on the four synthesized compounds to compare their electronic properties and molecular structures. The results showed that these compounds demonstrated antispasmodic effects on jejunum contractions. Molecular docking revealed that compounds c and d displayed the highest docking scores on potassium and voltage-gated calcium channels and adrenergic receptors. In summary, compounds c and d exhibit antispasmodic effects, potentially blocking alpha-adrenergic receptors and calcium channels, thus providing a scientific basis for their potential use in treating gastrointestinal disorders.

Chromogranin A Deficiency Attenuates Tauopathy by Altering Epinephrine-Alpha-Adrenergic Receptor Signaling.

Metabolic disorders such as insulin resistance and hypertension are potential risk factors for aging and neurodegenerative diseases. These conditions are reversed in Chromogranin A knockout (CgA-KO) mice. This study investigates the role of CgA in Alzheimer's disease (AD) and corticobasal degeneration (CBD). CgA ablation in tauopathy mice (hTau) (CgA-KO/hTau) exhibited reduced tau aggregation, spreading, extended lifespan, and improved cognitive function. Transcriptomic and metabolite analysis of mouse cortices revealed altered alpha1-adrenergic receptors (Adra1) and high epinephrine (EPI) levels in hTau mice compared to WT mice, mirroring observations in AD and CBD patients. CgA-KO/hTau mice exhibited a reversal of EPI levels in the cortex and the expression of Adra1, nearly returning them to WT levels. Treatment of hippocampal slices with EPI or Adra1 agonist intensified, while an Adra1 antagonist inhibited tau hyperphosphorylation and aggregation. These findings highlight the interplay between the EPI-Adra signaling system and CgA in tauopathy.

The Locus Coeruleus in Chronic Pain.

Pain perception is the consequence of a complex interplay between activation and inhibition. Noradrenergic pain modulation inhibits nociceptive transmission and pain perception. The main source of norepinephrine (NE) in the central nervous system is the Locus Coeruleus (LC), a small but complex cluster of cells in the pons. The aim of this study is to review the literature on the LC-NE inhibitory system, its influence on chronic pain pathways and its frequent comorbidities. The literature research showed that pain perception is the consequence of nociceptive and environmental processing and is modulated by the LC-NE system. If perpetuated in time, nociceptive inputs can generate neuroplastic changes in the central nervous system that reduce the inhibitory effects of the LC-NE complex and facilitate the development of chronic pain and frequent comorbidities, such as anxiety, depression or sleeping disturbances. The exact mechanisms involved in the LC functional shift remain unknown, but there is some evidence that they occur through plastic changes in the medial and lateral pathways and their brain projections. Additionally, there are other influencing factors, like developmental issues, neuroinflammatory glial changes, NE receptor affinity and changes in LC neuronal firing rates.

Methylphenidate Reversal of Dexmedetomidine-Induced Versus Ketamine-Induced Sedation in Rats.

Dexmedetomidine and ketamine have long elimination half-lives in humans and have no clinically approved reversal agents. Methylphenidate enhances dopaminergic and noradrenergic neurotransmission by inhibiting reuptake transporters for these arousal-promoting neurotransmitters. Previous studies in rats demonstrated that intravenous methylphenidate induces emergence from isoflurane and propofol general anesthesia. These 2 anesthetics are thought to act primarily through enhancement of inhibitory Gamma-aminobutyric acid type A (GABAA) receptors. In this study, we tested the behavioral and neurophysiological effects of methylphenidate in rats after low and high doses of dexmedetomidine (an alpha-2 adrenergic receptor agonist) and ketamine (an N-methyl-D-aspartate [NMDA] receptor antagonist) that induce sedation and unconsciousness, respectively. All experiments used adult male and female Sprague-Dawley rats (n = 32 total) and all drugs were administered intravenously in a crossover, blinded experimental design. Locomotion after sedating doses of dexmedetomidine (10 µg/kg) or ketamine (10 mg/kg) with and without methylphenidate (5 mg/kg) was tested using the open field test (n = 16). Recovery of righting reflex after either high-dose dexmedetomidine (50 µg/kg) or high-dose ketamine (50 mg/kg) with and without methylphenidate (1-5 mg/kg) was assessed in a second cohort of rats (n = 8). Finally, in a third cohort of rats (n = 8), frontal electroencephalography (EEG) was recorded for spectral analysis under both low and high doses of dexmedetomidine and ketamine with and without methylphenidate. Low-dose dexmedetomidine reduced locomotion by 94% in rats. Methylphenidate restored locomotion after low-dose dexmedetomidine (rank difference = 88.5, 95% confidence interval [CI], 70.8-106) and the effect was blocked by coadministration with a dopamine D1 receptor antagonist (rank difference = 86.2, 95% CI, 68.6-104). Low-dose ketamine transiently attenuated mobility by 58% and was not improved with methylphenidate. Methylphenidate did not affect the return of righting reflex latency in rats after high-dose dexmedetomidine nor ketamine. Frontal EEG analysis revealed that methylphenidate reversed spectral changes induced by low-dose dexmedetomidine (F [8,87] = 3.27, P = .003) but produced only transient changes after high-dose dexmedetomidine. Methylphenidate did not induce spectral changes in the EEG after low- or high-dose ketamine. Methylphenidate reversed behavioral and neurophysiological correlates of sedation, but not unconsciousness, induced by dexmedetomidine. In contrast, methylphenidate did not affect sedation, unconsciousness, nor EEG signatures in rats after ketamine. These findings suggest that methylphenidate may be efficacious to reverse dexmedetomidine sedation in humans.

Antihyperalgesic effect of γ-terpinene complexed in β-cyclodextrin on neuropathic pain model induced by tumor cells

Neuropathic pain is a high-intensity pain that can be caused by compression, transection, injury, nerve infiltration and drug treatment of cancer. Furthermore, drug therapy has low clinical efficacy, many adverse effects and remission of painful symptoms. In this way, natural products derived from plants constitute a promising therapeutic alternative. Therefore, the aim of this study was to evaluate the antihyperalgesic effect of γ-terpinene (γ-TPN) e γ-terpinene in β-cyclodextrin inclusion complexes (TPN/CD) on neuropathic pain induced by tumor cells. Complexation extended the effect time for another 5 h and daily treatment for six days with γ-TPN (50 mg/kg, p.o.) and γ-TPN/β-CD (50 mg/kg, p.o.) significantly reduced (p < 0.001) the mechanical hyperalgesia induced by the administration of 2x106 sarcoma cells 180 in the around the sciatic nerve. In addition, the Grip and Rota-rod techniques demonstrated that there was no interference on the muscle strength and motor coordination of the animals, suggesting that the compound under study does not have central nervous system depressant effects at the doses used. Molecular docking studies demonstrate favorable binding energies between γ-TPN and β-CD, and alpha-2 adrenergic, glutamatergic, opioid and cholinergic receptors. Thus, this study demonstrates the potential of terpinene complexation in controlling neuropathic pain induced by tumor cells.

Naltrexone augmented with prazosin for alcohol use disorder: results from a randomized controlled proof-of-concept trial.

We conducted a proof-of-concept randomized controlled trial of the mu-opioid receptor antagonist, naltrexone, augmented with the alpha-1 adrenergic receptor antagonist, prazosin, for alcohol use disorder in veterans. We sought a signal that the naltrexone plus prazosin combination regimen would be superior to naltrexone alone. Thirty-one actively drinking veterans with alcohol use disorder were randomized 1:1:1:1 to naltrexone plus prazosin (NAL-PRAZ [n = 8]), naltrexone plus placebo (NAL-PLAC [n = 7]), prazosin plus placebo (PRAZ-PLAC [n = 7]), or placebo plus placebo (PLAC-PLAC [n = 9]) for 6weeks. Prazosin was titrated over 2weeks to a target dose of 4mg QAM, 4mg QPM, and 8mg QHS. Naltrexone was administered at 50mg QD. Primary outcomes were the Penn Alcohol Craving Scale (PACS), % drinking days (PDD), and % heavy drinking days (PHDD). In the NAL-PRAZ condition, % reductions from baseline for all three primary outcome measures exceeded 50% and were at least twice as large as % reductions in the NAL-PLAC condition (PACS: 57% vs. 26%; PDD: 51% vs. 22%; PHDD: 69% vs. 15%) and in the other two comparator conditions. Standardized effect sizes between NAL-PRAZ and NAL-PLAC for each primary outcome measure were >0.8. All but one participant assigned to the two prazosin containing conditions achieved the target prazosin dose of 16mg/day and maintained that dose for the duration of the trial. These results suggest that prazosin augmentation of naltrexone enhances naltrexone benefit for alcohol use disorder. These results strengthen rationale for an adequately powered definitive randomized controlled trial.

The astrocyte α1A-adrenoreceptor is a key component of the neuromodulatory system in mouse visual cortex.

Noradrenaline (norepinephrine) is known to modulate many physiological functions and behaviors. In this study, we tested to what extent astrocytes, a type of glial cell, participate in noradrenergic signaling in mouse primary visual cortex (V1). Astrocytes are essential partners of neurons in the central nervous system. They are central to brain homeostasis, but also dynamically regulate neuronal activity, notably by relaying and regulating neuromodulator signaling. Indeed, astrocytes express receptors for multiple neuromodulators, including noradrenaline, but the extent to which astrocytes are involved in noradrenergic signaling remains unclear. To test whether astrocytes are involved in noradrenergic neuromodulation in mice, we employed both short hairpin RNA mediated knockdown as well as pharmacological manipulation of the major noradrenaline receptor in astrocytes, the α1A-adrenoreceptor. Using acute brain slices, we found that the astrocytic α1A-adrenoreceptor subtype contributes to the generation of large intracellular Ca2+ signals in visual cortex astrocytes, which are generally thought to underlie astrocyte function. To test if reduced α1A-adrenoreceptor signaling in astrocytes affected the function of neuronal circuits in V1, we used both patch-clamp and field potential recordings. These revealed that noradrenergic signaling through the astrocyte α1A-adrenoreceptor is important to not only modulate synaptic activity but also to regulate plasticity in V1, through the potentiation of synaptic responses in circuits involved in visual information processing.

Evaluation of Tamsulosin 0.4 mg versus 0.8 mg in Management of Patients Suffering from Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia

Abstract Introduction Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) are common among older men. Beside watchful waiting and surgery, medical therapy includes alpha adrenergic blockers, 5 alpha reductase inhibitors, and phytotherapy. Alpha blockers are considered to be the main treatment for BPH-associated LUTS depending on the evidence that prostatic smooth muscle contraction is responsible for bladder outlet obstruction via alpha adrenergic receptor- mediated mechanism. Tamsulosin is a super selective alpha blocker. Improvement of LUTS can be assessed by maximum flow rate (Qmax), average flow rate (Qavg), post void residual (PVR) urine volume and international prostate symptom score questionnaire (IPSS). Objectives To compare the efficacy and the safety of Tamsulosin 0.4 mg/day and 0.8 mg/day in patients suffering from lower urinary tract symptoms due to benign prostatic hyperplasia. Patients and Methods A Prospective Interventional, double-blinded, controlled study was carried out on 93 patients who met the criteria and divided randomly into 2 groups; group A for Tamsulosin 0.4 mg/day and group B for Tamsulosin 0.8 mg/day. International prostate symptom score, Post void residual urine volume, and maximum flow rate of urine were assessed before and after 4 weeks of treatment. Results Both study groups showed a significant reduction in storage sub-score but only frequency was significantly reduced in group B (P &amp;lt; 0.001). On the other hand, Tamsulosin 0.8 mg was superior to Tamsulosin 0.4 mg regarding voiding sub score except for straining (P = 0.325). Accordingly, the total international prostate symptom score was significantly improved in group B (P &amp;lt; 0.001). Furthermore, maximum flow rate and post-void residual urine volume were notably improved with Tamsulosin 0.8 mg compared to Tamsulosin 0.4 mg (P &amp;lt; 0.001). Although the adverse events; such as headache, orthostatic hypotension, and retrograde ejaculation were more frequent, but not significant, to occur with Tamsulosin 0.8 mg, only dizziness was noted to be significant. Conclusion Tamsulosin 0.8 mg has shown better outcomes in treating patients who suffer from lower urinary tract symptoms due to benign prostatic hyperplasia than Tamsulosin 0.4 mg, and besides that, it is well tolerated.

Norepinephrine regulates TNF expression via the A1AR-p38 MAPK-Relish pathway in granulocytes of oyster Crassostrea gigas

Norepinephrine (NE) is involved in regulating cytokine expression and phagocytosis of immune cells in the innate immunity of vertebrates. In the present study, the modulation mechanism of NE on the biosynthesis of TNFs in oyster granulocytes was explored. The transcripts of CgTNF-1, CgTNF-2 and CgTNF-3 were highly expressed in granulocytes, and they were significantly up-regulated after LPS stimulation, while down-regulated after NE treatment. The phagocytic rate and apoptosis index of oyster granulocytes were also triggered by LPS stimulation and suppressed by NE treatment. The mRNA expressions of CgMAPK14 and CgRelish were significantly induced after NE treatment, and the translocation of CgRelish from cytoplasm to nucleus was observed. The concentration of intracellular Ca2+ in granulocytes was significantly up-regulated upon NE incubation, and this trend reverted after the treatment with DOX (specific antagonist for NE receptor, CgA1AR-1). No obvious significance was observed in intracellular cAMP concentrations in the PBS, NE and NE + DOX groups. Once CgA1AR-1 was blocked by DOX, the mRNA expressions of CgMAPK14 and CgRelish were significantly inhibited, and the translocation of CgRelish from cytoplasm to nucleus was also dramatically suppressed, while the mRNA expression of CgTNF-1 and the apoptosis index increased significantly to the same level with those in LPS group, respectively. These results collectively suggested that NE modulated TNF expression in oyster granulocyte through A1AR-p38 MAPK-Relish signaling pathway.

Chromogranin A (CgA) Deficiency Attenuates Tauopathy by Altering Epinephrine-Alpha-Adrenergic Receptor Signaling.

Our previous studies have indicated that insulin resistance, hyperglycemia, and hypertension in aged wild-type (WT) mice can be reversed in mice lacking chromogranin-A (CgA-KO mice). These health conditions are associated with a higher risk of Alzheimer's disease (AD). CgA, a neuroendocrine secretory protein has been detected in protein aggregates in the brains of AD patients. Here, we determined the role of CgA in tauopathies, including AD (secondary tauopathy) and corticobasal degeneration (CBD, primary tauopathy). We found elevated levels of CgA in both AD and CBD brains, which were positively correlated with increased phosphorylated tau in the frontal cortex. Furthermore, CgA ablation in a human P301S tau (hTau) transgenic mice (CgA-KO/hTau) exhibited reduced tau aggregation, resistance to tau spreading, and an extended lifespan, coupled with improved cognitive function. Transcriptomic analysis of mice cortices highlighted altered levels of alpha-adrenergic receptors (Adra) in hTau mice compared to WT mice, akin to AD patients. Since CgA regulates the release of the Adra ligands epinephrine (EPI) and norepinephrine (NE), we determined their levels and found elevated EPI levels in the cortices of hTau mice, AD and CBD patients. CgA-KO/hTau mice exhibited reversal of EPI levels in the cortex and the expression of several affected genes, including Adra1 and 2, nearly returning them to WT levels. Treatment of hippocampal slice cultures with EPI or an Adra1 agonist intensified, while an Adra1 antagonist inhibited, tau hyperphosphorylation and aggregation. These findings reveal a critical role of CgA in regulation of tau pathogenesis via the EPI-Adra signaling axis.

Ingestion of Fluids of the Ocular Surface Containing Eye Drops of Imidazole Derivatives-Alpha Adrenergic Receptor Agonists as Paragons.

Accidental poisonings by ingesting conjunctival fluid mixed with eye drops commonly involve alpha-2 adrenergic receptor agonists and tetrahydrozoline. These substances are recognized in commonly reported ingestions. Victims of all ages, otherwise in good health, often present as pale and lethargic to the emergency department (ED) after unintentionally ingesting topical eye medication. While eye drop poisoning cases in childhood include accidents during the play and poisonings in adults mean either suicide attempts or side effects caused by the systemic absorption of the substance, fluid of the ocular surface is a risk to all age groups. With this in mind, this study aimed to summarize data in the literature on tetrahydrozoline and alpha-2 adrenergic receptor agonists as dangerous medications, even when administered in low-bioavailability forms, such as eye drops. With this aim, a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review of relevant studies was conducted. A search of PubMed, Scopus, Web of Science, and EBSCOhost yielded nine studies that met the rigorous inclusion criteria. The primary studies were subject to a meta-analysis once a quality appraisal of the studies and a narrative synthesis of the extracted data had been conducted. The author hopes that this information will provide observations that will lead to better designs for over-the-counter eye drops, off-label drug usage policies, and parental attention.

The alpha2-adrenergic receptor agonist clonidine protects against cerebral ischemia/reperfusion induced neuronal apoptosis in rats.

Apoptosis is the crucial pathological mechanism following cerebral ischemic injury. Our previous studies demonstrated that clonidine, one agonist of alpha2-adrenergic receptor (α2-AR), could attenuate cerebral ischemic injury in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). However, it's unclear whether clonidine exerts neuroprotective effects by regulating neuronal apoptosis. In this study, we elucidated whether clonidine can exert anti-apoptotic effects in cerebral ischemic injury, and further explored the possible mechanisms. Neurological deficit score was measured to evaluate the neurological function. TTC staining was used for the measurement of brain infarct size. Hematoxylin-Eosin (HE) staining was applied to examine the cell morphology. TUNEL and DAPI fluorescent staining methods were used to analyze the cell apoptosis in brain tissue. Fluorescence quantitative real-time PCR was performed to assess the gene expression of Caspase-3 and P53. Western blotting assay was applied to detect the protein expression of Caspase-3 and P53. The results showed that clonidine improved neurological function, reduced brain infarct size, alleviated neuronal damage, and reduced the ratio of cell apoptosis in the brain with MCAO/R injury. moreover, clonidine down-regulated the gene and protein expression of Caspase-3 and P53 which were over-expressed after MCAO/R injury. Whereas, yohimbine (one selective α2-AR antagonist) mitigated the anti-apoptosis effects of clonidine, accompanied by reversed gene and protein expression changes. The results indicated that clonidine attenuated cerebral MCAO/R injury via suppressing neuronal apoptosis, which may be mediated, at least in part, by activating α2-AR.