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1.
J Med Chem ; 67(12): 10135-10151, 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38857067

RESUMEN

Yohimbine, a natural indole alkaloid and a nonselective adrenoceptor antagonist, possesses potential benefits in treating inflammatory disorders and sepsis. Nevertheless, its broader clinical use faces challenges due to its low receptor selectivity. A structure-activity relationship study of novel yohimbine analogues identified amino esters of yohimbic acid as potent and selective ADRA2A antagonists. Specifically, amino ester 4n, in comparison to yohimbine, showed a 6-fold higher ADRA1A/ADRA2A selectivity index (SI > 556 for 4n) and a 25-fold higher ADRA2B/ADRA2A selectivity index. Compound 4n also demonstrated high plasma and microsomal stability, moderate-to-low membrane permeability determining its limited ability to cross the blood-brain barrier, and negligible toxicity on nontumor normal human dermal fibroblasts. Compound 4n represents an important complementary pharmacological tool to study the involvement of adrenoceptor subtypes in pathophysiologic conditions such as inflammation and sepsis and a novel candidate for further preclinical development to treat ADRA2A-mediated pathologies.


Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2 , Diseño de Fármacos , Receptores Adrenérgicos alfa 2 , Yohimbina , Humanos , Receptores Adrenérgicos alfa 2/metabolismo , Yohimbina/farmacología , Yohimbina/química , Relación Estructura-Actividad , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/química , Antagonistas de Receptores Adrenérgicos alfa 2/síntesis química , Animales
2.
Cell Host Microbe ; 32(6): 950-963.e8, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38788722

RESUMEN

Inflammatory bowel disease (IBD) is characterized by dysbiosis of the gut microbiota and dysfunction of intestinal stem cells (ISCs). However, the direct interactions between IBD microbial factors and ISCs are undescribed. Here, we identify α2A-adrenergic receptor (ADRA2A) as a highly expressed GPCR in ISCs. Through PRESTO-Tango screening, we demonstrate that tyramine, primarily produced by Enterococcus via tyrosine decarboxylase (tyrDC), serves as a microbial ligand for ADRA2A. Using an engineered tyrDC-deficient Enterococcus faecalis strain and intestinal epithelial cell-specific Adra2a knockout mice, we show that Enterococcus-derived tyramine suppresses ISC proliferation, thereby impairing epithelial regeneration and exacerbating DSS-induced colitis through ADRA2A. Importantly, blocking the axis with an ADRA2A antagonist, yohimbine, disrupts tyramine-mediated suppression on ISCs and alleviates colitis. Our findings highlight a microbial ligand-GPCR pair in ISCs, revealing a causal link between microbial regulation of ISCs and colitis exacerbation and yielding a targeted therapeutic approach to restore ISC function in colitis.


Asunto(s)
Colitis , Ratones Noqueados , Receptores Adrenérgicos alfa 2 , Células Madre , Tiramina , Animales , Tiramina/metabolismo , Tiramina/farmacología , Colitis/microbiología , Colitis/inducido químicamente , Colitis/metabolismo , Ratones , Receptores Adrenérgicos alfa 2/metabolismo , Células Madre/metabolismo , Humanos , Ratones Endogámicos C57BL , Tirosina Descarboxilasa/metabolismo , Enterococcus faecalis/metabolismo , Microbioma Gastrointestinal , Mucosa Intestinal/microbiología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Yohimbina/farmacología , Modelos Animales de Enfermedad , Enterococcus/metabolismo , Intestinos/microbiología , Intestinos/patología , Proliferación Celular , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/metabolismo , Sulfato de Dextran
3.
Int J Mol Sci ; 25(10)2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38791266

RESUMEN

Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE) release from peripheral sympathetic nerve terminals. Adrenal CA production from chromaffin cells is tightly regulated by sympatho-inhibitory α2-adrenergic (auto)receptors (ARs), which inhibit both epinephrine (Epi) and NE secretion via coupling to Gi/o proteins. α2-AR function is, in turn, regulated by G protein-coupled receptor (GPCR)-kinases (GRKs), especially GRK2, which phosphorylate and desensitize them, i.e., uncouple them from G proteins. On the other hand, the short-chain free fatty acid (SCFA) receptor (FFAR)-3, also known as GPR41, promotes NE release from sympathetic neurons via the Gi/o-derived free Gßγ-activated phospholipase C (PLC)-ß/Ca2+ signaling pathway. However, whether it exerts a similar effect in adrenal chromaffin cells is not known at present. In the present study, we examined the interplay of the sympatho-inhibitory α2A-AR and the sympatho-stimulatory FFAR3 in the regulation of CA secretion from rat adrenal chromaffin (pheochromocytoma) PC12 cells. We show that FFAR3 promotes CA secretion, similarly to what GRK2-dependent α2A-AR desensitization does. In addition, FFAR3 activation enhances the effect of the physiologic stimulus (acetylcholine) on CA secretion. Importantly, GRK2 blockade to restore α2A-AR function or the ketone body beta-hydroxybutyrate (BHB or 3-hydroxybutyrate), via FFAR3 antagonism, partially suppress CA production, when applied individually. When combined, however, CA secretion from PC12 cells is profoundly suppressed. Finally, propionate-activated FFAR3 induces leptin and adiponectin secretion from PC12 cells, two important adipokines known to be involved in tissue inflammation, and this effect of FFAR3 is fully blocked by the ketone BHB. In conclusion, SCFAs can promote CA and adipokine secretion from adrenal chromaffin cells via FFAR3 activation, but the metabolite/ketone body BHB can effectively inhibit this action.


Asunto(s)
Catecolaminas , Receptores Adrenérgicos alfa 2 , Receptores Acoplados a Proteínas G , Animales , Células PC12 , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Catecolaminas/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Adipoquinas/metabolismo , Células Cromafines/metabolismo , Transducción de Señal , Norepinefrina/metabolismo , Norepinefrina/farmacología
4.
Brain Behav Immun ; 119: 84-95, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38552922

RESUMEN

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that severely affects individuals' daily life and social development. Unfortunately, there are currently no effective treatments for ASD. Dexmedetomidine (DEX) is a selective agonist of α2 adrenergic receptor (α2AR) and is widely used as a first-line medication for sedation and hypnosis in clinical practice. In recent years, there have been reports suggesting its potential positive effects on improving emotional and cognitive functions. However, whether dexmedetomidine has therapeutic effects on the core symptoms of ASD, namely social deficits and repetitive behaviors, remains to be investigated. In the present study, we employed various behavioral tests to assess the phenotypes of animals, including the three-chamber, self-grooming, marble burying, open field, and elevated plus maze. Additionally, electrophysiological recordings, western blotting, qPCR were mainly used to investigate and validate the potential mechanisms underlying the role of dexmedetomidine. We found that intraperitoneal injection of dexmedetomidine in ASD model mice-BTBR T+ Itpr3tf/J (BTBR) mice could adaptively improve their social deficits. Further, we observed a significant reduction in c-Fos positive signals and interleukin-6 (IL-6) expression level in the prelimbic cortex (PrL) of the BTBR mice treated with dexmedetomidine. Enhancing or inhibiting the action of IL-6 directly affects the social behavior of BTBR mice. Mechanistically, we have found that NF-κB p65 is a key pathway regulating IL-6 expression in the PrL region. In addition, we have confirmed that the α2AR acts as a receptor switch mediating the beneficial effects of dexmedetomidine in improving social deficits. This study provides the first evidence of the beneficial effects of dexmedetomidine on core symptoms of ASD and offers a theoretical basis and potential therapeutic approach for the clinical treatment of ASD.


Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2 , Trastorno del Espectro Autista , Dexmedetomidina , Modelos Animales de Enfermedad , Interleucina-6 , FN-kappa B , Receptores Adrenérgicos alfa 2 , Conducta Social , Animales , Dexmedetomidina/farmacología , Ratones , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/metabolismo , Masculino , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , FN-kappa B/metabolismo , Interleucina-6/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Conducta Animal/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Inflamación/metabolismo , Inflamación/tratamiento farmacológico
5.
Pharmacol Biochem Behav ; 239: 173756, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38555037

RESUMEN

Prenatal opioid exposure (POE) and postnatal adverse experiences are early life adversities (ELA) that often co-occur and increase problematic alcohol (EtOH) drinking during adolescence. We investigated the relationship between POE, postnatal adversity, and adolescent EtOH drinking in rats. We also sought to determine whether ELAs affect alpha-adrenoceptor density in the brain because the noradrenergic system is involved in problematic alcohol drinking and its treatment. We hypothesized that the combination of POE and postnatal adversity will increase alcohol drinking in rats compared to rats with exposure to either adversity alone or to control. We also predicted that POE and postnatal adversity would increase α1-adrenoceptor density and decrease α2-adrenoceptor density in brain to confer a stress-responsive phenotype. Pregnant rats received morphine (15 mg/kg/day) or saline via subcutaneous minipumps from gestational day 9 until birth. Limited bedding and nesting (LBN) procedures were introduced from postnatal day (PD) 3-11 to mimic early life adversity-scarcity. Offspring rats (PD 31-33) were given opportunities to drink EtOH (20 %, v/v) using intermittent-access, two-bottle choice (with water) procedures. Rats given access to EtOH were assigned into sub-groups that were injected with either yohimbine (1 mg/kg, ip) or vehicle (2 % DMSO, ip) 30 min prior to each EtOH access session to determine the effects of α2-adrenoceptor inhibition on alcohol drinking. We harvested cortices, brainstems, and hypothalami from EtOH-naïve littermates on either PD 30 or PD 70 and conducted radioligand receptor binding assays to quantify α1- and α2-adrenoceptor densities. Contrary to our hypothesis, only LBN alone increased EtOH intake in female adolescent rats compared to female rats with POE. Neither POE nor LBN affected α1- or α2-adrenoceptor densities in the cortex, brainstem, or hypothalamus of early- or late-aged adolescent rats. These results suggest a complex interaction between ELA type and sex on alcohol drinking.


Asunto(s)
Consumo de Bebidas Alcohólicas , Etanol , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Ratas , Embarazo , Consumo de Bebidas Alcohólicas/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Etanol/administración & dosificación , Etanol/farmacología , Masculino , Receptores Adrenérgicos alfa 2/metabolismo , Morfina/farmacología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Ratas Sprague-Dawley
6.
Biomed Pharmacother ; 174: 116462, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38513598

RESUMEN

BACKGROUND: Acute kidney injury (AKI) was reported to be one of the initiators of chronic kidney disease (CKD) development. Necroinflammation may contribute to the progression from AKI to CKD. Dexmedetomidine (Dex), a highly selective α2-adrenoreceptor (AR) agonist, has cytoprotective and "anti-" inflammation effects. This study was designed to investigate the anti-fibrotic properties of Dex in sepsis models. METHODS: C57BL/6 mice were randomly treated with an i.p. injection of lipopolysaccharides (LPS) (10 mg/kg) alone, LPS with Dex (25 µg/kg), or LPS, Dex and Atipamezole (Atip, an α2-adrenoreceptor antagonist) (500 µg/kg) (n=5/group). Human proximal tubular epithelial cells (HK2) were also cultured and then exposed to LPS (1 µg/ml) alone, LPS and Dex (1 µM), transforming growth factor-beta 1 (TGF-ß1) (5 ng/ml) alone, TGF-ß1 and Dex, with or without Atip (100 µM) in culture media. Epithelial-mesenchymal transition (EMT), cell necrosis, necroptosis and pyroptosis, and c-Jun N-terminal kinase (JNK) phosphorylation were then determined. RESULTS: Dex treatment significantly alleviated LPS-induced AKI, myofibroblast activation, NLRP3 inflammasome activation, and necroptosis in mice. Atip counteracted its protective effects. Dex attenuated LPS or TGF-ß1 induced EMT and also prevented necrosis, necroptosis, and pyroptosis in response to LPS stimulation in the HK2 cells. The anti-EMT effects of Dex were associated with JNK phosphorylation. CONCLUSIONS: Dex reduced EMT following LPS stimulation whilst simultaneously inhibiting pyroptosis and necroptosis via α2-AR activation in the renal tubular cells. The "anti-fibrotic" and cytoprotective properties and its clinical use of Dex need to be further studied.


Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2 , Dexmedetomidina , Fibrosis , Ratones Endogámicos C57BL , Receptores Adrenérgicos alfa 2 , Animales , Humanos , Ratones , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Línea Celular , Dexmedetomidina/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/patología , Inflamación/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Lipopolisacáridos/farmacología , Necroptosis/efectos de los fármacos , Fenotipo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo
7.
Toxicol Appl Pharmacol ; 484: 116881, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38437958

RESUMEN

Pain has a negative impact on public health, reducing quality of life. Unfortunately, current treatments are not fully effective and have adverse effects. Therefore, there is a need to develop new analgesic compounds. Due to promising results regarding the antinociceptive effect of N-(3-(phenylselanyl)prop-2-in-1-yl)benzamide (SePB), this study aimed to evaluate the participation of the dopaminergic and noradrenergic systems in this effect in mice, as well as its toxicity. To this, the antagonists sulpiride (D2/D3 receptor antagonist, 5 mg/kg), SCH-23390 (D1 receptor antagonist, 0.05 mg/kg), prazosin (α1 adrenergic receptor antagonist, 0.15 mg/kg), yohimbine (α2-adrenergic receptors, 0.15 mg/kg) and propranolol (non-selective ß-adrenergic antagonist, 10 mg/kg) were administered intraperitoneally to mice 15 min before SePB (10 mg/kg, intragastrically), except for propranolol (20 min). After 26 min of SePB administration, the open field test was performed for 4 min to assess locomotor activity, followed by the tail immersion test to measure the nociceptive response. For the toxicity test, animals received a high dose of 300 mg/kg of SePB. SePB showed an increase in the latency for nociceptive response in the tail immersion test, and this effect was prevented by SCH-23390, yohimbine and propranolol, indicating the involvement of D1, α2 and ß-adrenergic receptors in the antinociceptive mechanism of the SePB effect. No changes were observed in the open field test, and the toxicity assessment suggested that SePB has low potential to induce toxicity. These findings contribute to understanding SePB's mechanism of action, with a focus on the development of new alternatives for pain treatment.


Asunto(s)
Propranolol , Calidad de Vida , Ratones , Animales , Propranolol/farmacología , Propranolol/uso terapéutico , Analgésicos/toxicidad , Dolor/tratamiento farmacológico , Norepinefrina , Yohimbina/toxicidad , Yohimbina/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Dopamina , Sulpirida , Receptores Adrenérgicos alfa 2
8.
Molecules ; 29(5)2024 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-38474611

RESUMEN

The α2A adrenergic receptor (α2A-AR) serves as a critical molecular target for sedatives and analgesics. However, α2A-AR ligands with an imidazole ring also interact with an imidazoline receptor as well as other proteins and lead to undesirable effects, motivating us to develop more novel scaffold α2A-AR ligands. For this purpose, we employed an ensemble-based ligand discovery strategy, integrating long-term molecular dynamics (MD) simulations and virtual screening, to identify new potential α2A-AR agonists with novel scaffold. Our results showed that compounds SY-15 and SY-17 exhibited significant biological effects in the preliminary evaluation of protein kinase A (PKA) redistribution assays. They also reduced levels of intracellular cyclic adenosine monophosphate (cAMP) in a dose-dependent manner. Upon treatment of the cells with 100 µM concentrations of SY-15 and SY-17, there was a respective decrease in the intracellular cAMP levels by 63.43% and 53.83%. Subsequent computational analysis was conducted to elucidate the binding interactions of SY-15 and SY-17 with the α2A-AR. The binding free energies of SY-15 and SY-17 calculated by MD simulations were -45.93 and -71.97 kcal/mol. MD simulations also revealed that both compounds act as bitopic agonists, occupying the orthosteric site and a novel exosite of the receptor simultaneously. Our findings of integrative computational and experimental approaches could offer the potential to enhance ligand affinity and selectivity through dual-site occupancy and provide a novel direction for the rational design of sedatives and analgesics.


Asunto(s)
Analgésicos , Receptores Adrenérgicos alfa 2 , Ligandos , Receptores Adrenérgicos alfa 2/metabolismo , Hipnóticos y Sedantes
9.
Neuropsychopharmacology ; 49(6): 1014-1023, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38368493

RESUMEN

In the central nervous system, noradrenaline transmission controls the degree to which we are awake, alert, and attentive. Aberrant noradrenaline transmission is associated with pathological forms of hyper- and hypo-arousal that present in numerous neuropsychiatric disorders often associated with dysfunction in serotonin transmission. In vivo, noradrenaline regulates the release of serotonin because noradrenergic input drives the serotonin neurons to fire action potentials via activation of excitatory α1-adrenergic receptors (α1-AR). Despite the critical influence of noradrenaline on the activity of dorsal raphe serotonin neurons, the source of noradrenergic afferents has not been resolved and the presynaptic mechanisms that regulate noradrenaline-dependent synaptic transmission have not been described. Using an acute brain slice preparation from male and female mice and electrophysiological recordings from dorsal raphe serotonin neurons, we found that selective optogenetic activation of locus coeruleus terminals in the dorsal raphe was sufficient to produce an α1-AR-mediated excitatory postsynaptic current (α1-AR-EPSC). Activation of inhibitory α2-adrenergic receptors (α2-AR) with UK-14,304 eliminated the α1-AR-EPSC via presynaptic inhibition of noradrenaline release, likely via inhibition of voltage-gated calcium channels. In a subset of serotonin neurons, activation of postsynaptic α2-AR produced an outward current through activation of GIRK potassium conductance. Further, in vivo activation of α2-AR by systemic administration of clonidine reduced the expression of c-fos in the dorsal raphe serotonin neurons, indicating reduced neural activity. Thus, α2-AR are critical regulators of serotonin neuron excitability.


Asunto(s)
Núcleo Dorsal del Rafe , Locus Coeruleus , Receptores Adrenérgicos alfa 2 , Neuronas Serotoninérgicas , Transmisión Sináptica , Animales , Núcleo Dorsal del Rafe/efectos de los fármacos , Núcleo Dorsal del Rafe/fisiología , Núcleo Dorsal del Rafe/metabolismo , Masculino , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos alfa 2/fisiología , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/fisiología , Femenino , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/fisiología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Ratones , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Optogenética , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Ratones Endogámicos C57BL , Norepinefrina/metabolismo , Ratones Transgénicos
10.
Naunyn Schmiedebergs Arch Pharmacol ; 397(7): 5303-5315, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38277039

RESUMEN

One of the reasons of the development of pathologies causing death is hypoxia. The purposes of this study were (1) to study some physiological and biochemical mechanisms of α2-adrenoblockers, which ensure the tissue resistance increase to hypoxia; (2) to offer new drugs contributing to the increase of tissues' stability towards the hypoxic affection; and (3) to submit new medications to surpass by their anti-hypoxic activity of those already used in modern medicine and have some advantages. The reactivity of postsynaptic vascular α2-adrenoceptors was determined on the damaged spinal cord expressed by the blood pressure increase in response to intravenous administration of azepexole that selectively binds to α2-adrenoceptors. Determination of the systemic hemodynamic values and the vascular resistance to the blood flow was performed by the method with plastic microspheres of marked isotopes. pO2 in the blood and the oxygen-transporting function were determined in a sample of 0.1 ml of blood in 30, 90, and 180 min after the α2-adrenoblockers' injections. It has been found that one of the major hemodynamic effects of mesedin and beditin was an improvement in cardiac output, as well as a prolonged increase in coronary blood flow and vasodilation of the heart vessels. Some anti-hypoxic mechanisms of the studied α2-adrenoblockers are an improvement of blood oxygen-transporting function followed by tissue oxygenation and the increased level of corticosterone and resistance to hypoxia. Revealing the mechanisms of action of the postsynaptic α2-adrenoceptors suggests that mesedin and beditin are potentially effective therapeutic means for many hypoxic conditions.


Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2 , Hipoxia , Ratas Wistar , Animales , Masculino , Hipoxia/tratamiento farmacológico , Hipoxia/fisiopatología , Hipoxia/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Ratas , Sistema Cardiovascular/efectos de los fármacos , Sistema Cardiovascular/metabolismo , Presión Sanguínea/efectos de los fármacos , Resistencia Vascular/efectos de los fármacos , Oxígeno/metabolismo , Hemodinámica/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Corticosterona/sangre
11.
Drug Des Devel Ther ; 18: 71-80, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38229917

RESUMEN

Introduction: Nicotine is a major component of cigarette smoke with various detrimental cardiovascular effects, including increased oxidative stress in the heart. Agonism of α2-adrenergic receptors (ARs), such as with dexmedetomidine, has been documented to exert cardioprotective effects against oxidative stress and related apoptosis and necroptosis. α2-ARs are membrane-residing G protein-coupled receptors (GPCRs) that primarily activate Gi/o proteins. They are also subjected to GPCR-kinase (GRK)-2-dependent desensitization, which entails phosphorylation of the agonist-activated receptor by GRK2 to induce its decoupling from G proteins, thus terminating α2AR-mediated G protein signaling. Objective: In the present study, we sought to examine the effects of nicotine on α2AR signaling and effects in H9c2 cardiomyocytes exposed to H2O2 to induce oxidative cellular damage. Methods and Results: As expected, treatment of H9c2 cardiomyocytes with H2O2 significantly decreased cell viability and increased oxidative stress, as assessed by reactive oxygen species (ROS)-associated fluorescence levels (DCF assay) and superoxide dismutase activity. Both H2O2 effects were partly rescued by α2AR activation with brimonidine in control cardiomyocytes but not in cells pretreated with nicotine for 24 hours, in which brimonidine was unable to reduce H2O2-induced cell death and oxidative stress. This was due to severe α2AR desensitization, manifested as very low Gi protein activation by brimonidine, and accompanied by GRK2 upregulation in nicotine-treated cardiomyocytes. Finally, pharmacological inhibition of adenylyl cyclase (AC) blocked H2O2-dependent oxidative damage in nicotine-pretreated H9c2 cardiomyocytes, indicating that α2AR activation protects against oxidative injury via its classic coupling to Gai-mediated AC inhibition. Discussion/Conclusions: Nicotine can negate the cardioprotective effects of α2AR agonists against oxidative injury, which may have important implications for patients treated with this class of drugs that are chronic tobacco smokers.


Asunto(s)
Miocitos Cardíacos , Nicotina , Humanos , Nicotina/farmacología , Nicotina/metabolismo , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Estrés Oxidativo , Apoptosis , Tartrato de Brimonidina/metabolismo , Tartrato de Brimonidina/farmacología
12.
Epilepsia Open ; 9(2): 534-547, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38071480

RESUMEN

OBJECTIVE: The objective of the study was to propose a candidate animal model of absence status epilepticus induced by specific alpha-2a adrenergic receptor (α2AR) activation. We also aim to investigate the responsiveness of this model to classical anti-status or anti-absence medications. METHODS: An α2AR agonist, dexmedetomidine (DEX), was injected intracerebroventricularly into adult rats with genetic absence epilepsy, and their electroencephalography (EEG) was recorded. The total duration, number, and mean duration of each spike-and-wave discharges (SWDs) were evaluated. The blocks of absence status events were classified as the initial and second sets of absence statuses. Ethosuximide (ETX) was administered as a pretreatment to another group of rats and later injected with 2.5 µg DEX. In addition, ETX, valproic acid (VPA), diazepam (DIAZ), and atipamezole (ATI) were administered after induced status-like events following DEX administration. Power spectral characteristics and coherence analysis were performed on the EEG to assess the absence status events and sleep. RESULTS: The 2.5 µg dose of DEX increased the total SWD duration and induced continuous SWDs up to 26 min. Following the initial absence status event, sleep was induced; then, the second period of absence status-like activities were initiated. ETX pretreatment blocked the occurrence of absence status-like activities. Power spectral density analyses revealed that DEX-induced post-sleep activities had higher power in delta frequency band (1-4 Hz) and attenuated power of 7 Hz harmonics (14 and 21 Hz) than the pre-injection seizure. The mean duration of SWDs were decreased in all the groups, but occasional prolonged activities were seen in ETX or VPA-injected rats but not with DIAZ or ATI. SIGNIFICANCE: This study presents an absence status epilepticus animal model that is activated by α2AR activation to investigate the pathophysiological role of absence status. Unlike other agents ATI switched off the second set of absence statuses to normal SWDs, without sedation or lethargy, can show it may preferentially block absence status-like activity. THE PLAIN LANGUAGE SUMMARY: This study proposes a rat model for prolonged seizures, resembling absence status epilepticus. Activating the brain's alpha-2a adrenergic receptor with dexmedetomidine induced seizures lasting up to 26 minutes. Ethosuximide pretreatment and post-treatment with valproic acid, diazepam, and atipamezole decreased induced seizures. The findings suggest this model is valuable for studying absence status epilepticus. In addition, atipamezole normalized abnormal seizures without sedation, hinting at its potential for targeted treatment and further research.


Asunto(s)
Dexmedetomidina , Epilepsia Tipo Ausencia , Estado Epiléptico , Animales , Ratas , Diazepam/efectos adversos , Epilepsia Tipo Ausencia/tratamiento farmacológico , Epilepsia Tipo Ausencia/genética , Etosuximida , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/uso terapéutico , Convulsiones/tratamiento farmacológico , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico , Ácido Valproico
13.
Int J Mol Sci ; 24(24)2023 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-38139390

RESUMEN

The G protein-coupled α2-adrenoceptor subtype C (abbreviated α2C-AR) has been implicated in peripheral vascular conditions and diseases such as cold feet-hands, Raynaud's phenomenon, and scleroderma, contributing to morbidity and mortality. Microvascular α2C-adrenoceptors are expressed in specialized smooth muscle cells and mediate constriction under physiological conditions and the occlusion of blood supply involving vasospastic episodes and tissue damage under pathological conditions. A crucial step for receptor biological activity is the cell surface trafficking of intracellular receptors, triggered by cAMP-Epac-Rap1A GTPase signaling, which involves protein-protein association with the actin-binding protein filamin-2, mediated by critical amino acid residues in the last 14 amino acids of the receptor carboxyl (C)-terminus. This study assessed the role of the C-terminus in Rap1A GTPase coupled receptor trafficking by domain-swapping studies using recombinant tagged receptors in transient co-transfections and compared with wild-type receptors using immunofluorescence microscopy. We further tested the biological relevance of the α2C-AR C-terminus, when introduced as competitor peptides, to selectively inhibit intracellular α2C-AR surface translocation in transfected as well as in microvascular smooth muscle cells expressing endogenous receptors. These studies contribute to establishing proof of principle to target intracellular α2C-adrenoceptors to reduce biological activity, which in clinical conditions can be a target for therapy.


Asunto(s)
Miocitos del Músculo Liso , Péptidos , Receptores Adrenérgicos alfa 2 , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Péptidos/metabolismo , Péptidos/farmacología , Receptores Adrenérgicos/metabolismo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Transducción de Señal/fisiología
14.
Comput Biol Med ; 167: 107693, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37976818

RESUMEN

Sinusitis is one of the most common respiratory inflammatory conditions and a significant health issue that affects millions of people worldwide with a global prevalence of 10-15%. The side effects of available drug regimens of sinus infection demand the urgent development of new drug candidates to combat sinusitis. With the aim of identifying new drug-like candidates to control sinus, we have conducted multifold comprehensive screening of drug-like molecules targeting α2-adrenergic receptor (α2-AR), which serve as the primary drug target in sinusitis. By structure-based virtual screening of in-house compound's database, ten molecules (CP1-CP10) with agonistic effects for α2-AR were selected, and their binding mechanism with critical residues of α2-AR and their physicochemical properties were studied. Moreover, the process of receptor activation by these compounds and the conformational changes in α2-AR caused by these molecules, were further explored by molecular dynamic simulation. The MM-PBSA estimated free energies of compounds are higher than that of reference agonist (ΔGTOTAL = -39.0 kcal/mol). Among all, CP2-CP3, CP7-CP8 and CP6 have the highest binding free energies of -78.9 kcal/mol, -77.3 kcal/mol, -75.60 kcal/mol, -64.8 kcal/mol, and -61.6 kcal/mol, respectively. While CP4 (-55.0 kcal/mol), CP5 (-49.2 kcal/mol), CP9 (-54.8 ± 0.07 kcal/mol), CP10 (-56.7 ± 0.10 kcal/mol) and CP1 (-46.0 ± 0.08 kcal/mol) also exhibited significant binding free energies. These energetically favorable binding energies indicate strong binding affinity of our compounds for α2-AR as compared to known partial agonist. Therefore, these molecules can serve as excellent drug-like candidates for sinusitis.


Asunto(s)
Receptores Adrenérgicos alfa 2 , Sinusitis , Humanos , Simulación de Dinámica Molecular , Sinusitis/tratamiento farmacológico , Simulación del Acoplamiento Molecular
15.
Cell Mol Life Sci ; 80(12): 354, 2023 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-37945921

RESUMEN

The communication between the nervous and immune systems plays a crucial role in regulating immune cell function and inflammatory responses. Sympathetic neurons, which innervate the spleen, have been implicated in modulating immune cell activity. The neurotransmitter norepinephrine (NE), released by sympathetic neurons, influences immune cell responses by binding to adrenergic receptors on their surface. The alpha-2 adrenergic receptor (α2AR), expressed predominantly on sympathetic neurons, has received attention due to its autoreceptor function and ability to modulate NE release. In this study, we used fast-scan cyclic voltammetry (FSCV) to provide the first subsecond measurements of NE released in the white pulp region of the spleen and validated it with yohimbine, a known antagonist of α2AR. For further application of FSCV in neuroimmunology, we investigated the extent to which subsecond NE from sympathetic neurons is important for immune cell physiology and cytokine production, focusing on tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and interleukin-6 (IL-6). Our findings provide insights into the regulatory mechanisms underlying sympathetic-immune interactions and show the significance of using FSCV, a traditional neurochemistry technique, to study these neuroimmune mechanisms.


Asunto(s)
Receptores Adrenérgicos alfa 2 , Bazo , Animales , Ratones , Fenómenos Fisiológicos Celulares , Neuronas , Interleucina-6 , Norepinefrina/farmacología
16.
BMC Anesthesiol ; 23(1): 327, 2023 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-37784079

RESUMEN

BACKGROUND AND OBJECTIVES: Dexmedetomidine (DEX) is widely used in clinical sedation which has little effect on cardiopulmonary inhibition, however the mechanism remains to be elucidated. The basal forebrain (BF) is a key nucleus that controls sleep-wake cycle. The horizontal limbs of diagonal bundle (HDB) is one subregions of the BF. The purpose of this study was to examine whether the possible mechanism of DEX is through the α2 adrenergic receptor of BF (HDB). METHODS: In this study, we investigated the effects of DEX on the BF (HDB) by using whole cell patch clamp recordings. The threshold stimulus intensity, the inter-spike-intervals (ISIs) and the frequency of action potential firing in the BF (HDB) neurons were recorded by application of DEX (2 µM) and co-application of a α2 adrenergic receptor antagonist phentolamine (PHEN) (10 µM). RESULTS: DEX (2 µM) increased the threshold stimulus intensity, inhibited the frequency of action potential firing and enlarged the inter-spike-interval (ISI) in the BF (HDB) neurons. These effects were reversed by co-application of PHEN (10 µM). CONCLUSION: Taken together, our findings revealed DEX decreased the discharge activity of BF (HDB) neuron via α2 adrenergic receptors.


Asunto(s)
Dexmedetomidina , Ratones , Animales , Dexmedetomidina/farmacología , Receptores Adrenérgicos alfa 2 , Transducción de Señal , Neuronas , Agonistas de Receptores Adrenérgicos alfa 2/farmacología
17.
Nat Commun ; 14(1): 6156, 2023 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-37828025

RESUMEN

Raynaud's phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. We conducted a genome-wide association study including 5,147 RP cases and 439,294 controls, based on diagnoses from electronic health records, and identified three unreported genomic regions associated with the risk of RP (p < 5 × 10-8). We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p < 9.6 × 10-27) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.12-1.22, p < 4.8 × 10-13) as candidate causal genes through integration of gene expression in disease relevant tissues. We further identified a likely causal detrimental effect of low fasting glucose levels on RP risk (rG = -0.21; p-value = 2.3 × 10-3), and systematically highlighted drug repurposing opportunities, like the antidepressant mirtazapine. Our results provide the first robust evidence for a strong genetic contribution to RP and highlight a so far underrated role of α2A-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms.


Asunto(s)
Estudio de Asociación del Genoma Completo , Enfermedad de Raynaud , Humanos , Úlcera , Enfermedad de Raynaud/genética , Enfermedad de Raynaud/complicaciones , Dolor/complicaciones , Factores de Transcripción/genética , Proteínas de Homeodominio , Receptores Adrenérgicos alfa 2/genética
18.
Sci Rep ; 13(1): 17990, 2023 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-37863979

RESUMEN

Innervation of the intestinal mucosa by the sympathetic nervous system is well described but the effects of adrenergic receptor stimulation on the intestinal epithelium remain equivocal. We therefore investigated the effect of sympathetic neuronal activation on intestinal cells in mouse models and organoid cultures, to identify the molecular routes involved. Using publicly available single-cell RNA sequencing datasets we show that the α2A isoform is the most abundant adrenergic receptor in small intestinal epithelial cells. Stimulation of this receptor with norepinephrine or a synthetic specific α2A receptor agonist promotes epithelial proliferation and stem cell function, while reducing differentiation in vivo and in intestinal organoids. In an anastomotic healing mouse model, adrenergic receptor α2A stimulation resulted in improved anastomotic healing, while surgical sympathectomy augmented anastomotic leak. Furthermore, stimulation of this receptor led to profound changes in the microbial composition, likely because of altered epithelial antimicrobial peptide secretion. Thus, we established that adrenergic receptor α2A is the molecular delegate of intestinal epithelial sympathetic activity controlling epithelial proliferation, differentiation, and host defense. Therefore, this receptor could serve as a newly identified molecular target to improve mucosal healing in intestinal inflammation and wounding.


Asunto(s)
Células Epiteliales , Intestinos , Animales , Ratones , Proliferación Celular , Mucosa Intestinal , Receptores Adrenérgicos , Receptores Adrenérgicos alfa 2/genética , Cicatrización de Heridas/fisiología
19.
Eur J Histochem ; 67(3)2023 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-37548252

RESUMEN

Lots of adrenergic receptors (ARs) are widely present across the auditory pathways and are positioned to affect auditory and vestibular functions. However, noradrenergic regulation in the cochlea has not been well characterized. In this study, a rat model of noise-induced hearing loss was developed to investigate the expression of α2A-adrenergic receptor (AR) after acoustic trauma, then, we investigated the expression of α2A-AR in the developing rat cochlea using immunofluorescence, qRT-PCR, and Western blotting. We found that the expression of α2A-AR significantly increased in rats exposed to noise compared with controls. Immunofluorescence analysis demonstrated that α2A-AR is localized on hair cells (HCs), spiral ganglion neurons (SGNs), and the stria vascularis (SV) in the postnatal developing cochlea from post-natal day (P) 0 to P28. Furthermore, we observed α2A-AR mRNA reached a maximum level at P14 and P28 when compared with P0, while no significant differences in α2A-AR protein levels at the various stages when compared with P0. This study provides direct evidence for the expression of α2A-AR in HCs, SGNs, and the SV of the cochlea, indicating that norepinephrine might play a vital role in hearing function within the cochlea through α2A-AR.


Asunto(s)
Cóclea , Receptores Adrenérgicos alfa 2 , Ganglio Espiral de la Cóclea , Animales , Ratas , Cóclea/metabolismo , Norepinefrina , Ratas Sprague-Dawley , Ganglio Espiral de la Cóclea/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo
20.
Adv Exp Med Biol ; 1423: 79-99, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37525034

RESUMEN

Mental disorders are strongly connected with several psychiatric conditions including depression, bipolar disorder, schizophrenia, eating disorder, and suicides. There are many biological conditions and pathways that define these complicated illnesses. For example, eating disorders are complex mental health conditions that require the intervention of geneticists, psychiatrists, and medical experts in order to alleviate their symptoms. A patient with suicidal ideation should first be identified and consequently monitored by a similar team of specialists. Both genetics and epigenetics can shed light on eating disorders and suicides as they are found in the main core of such investigations. In the present study, an analysis has been performed on two specific members of the GPCR family toward drawing conclusions regarding their functionality and implementation in mental disorders. Specifically, evolutionary and structural studies on the adrenoceptor alpha 2b (ADRA2B) and the 5-hydroxytryptamine receptor 1A (HTR1A) have been carried out. Both receptors are classified in the biogenic amine receptors sub-cluster of the GPCRs and have been connected in many studies with mental diseases and malnutrition conditions. The major goal of this study is the investigation of conserved motifs among biogenic amine receptors that play an important role in this family signaling pathway, through an updated evolutionary analysis and the correlation of this information with the structural features of the HTR1A and ADRA2B. Furthermore, the structural comparison of ADRA2B, HTR1A, and other members of GPCRs related to mental disorders is performed.


Asunto(s)
Trastornos Mentales , Receptor de Serotonina 5-HT1A , Receptores de Amina Biogénica , Humanos , Trastornos Mentales/genética , Trastornos Mentales/metabolismo , Receptor de Serotonina 5-HT1A/genética , Receptores Adrenérgicos alfa 2 , Receptores de Amina Biogénica/genética , Receptores de Amina Biogénica/metabolismo , Serotonina , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Ideación Suicida
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