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1.
Neurobiol Dis ; 125: 55-66, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30677495

RESUMO

Parkinson's disease (PD) presents with a constellation of non-motor symptoms, notably increased anxiety, which are currently poorly treated and underrepresented in animal models of the disease. Human post-mortem studies report loss of catecholaminergic neurons in the pre-symptomatic phases of PD when anxiety symptoms emerge, and a large literature from rodent and human studies indicate that catecholamines are important mediators of anxiety via their modulatory effects on limbic regions such as the amygdala. On the basis of these observations, we hypothesized that anxiety in PD could result from an early loss of catecholaminergic inputs to the amygdala and/or other limbic structures. To interrogate this hypothesis, we bilaterally injected the neurotoxin 6-OHDA in the mouse basolateral amygdala (BL). This produced a restricted pattern of catecholaminergic (tyrosine-hydroxylase-labeled) denervation in the BL, intercalated cell masses and ventral hippocampus, but not the central amygdala or prefrontal cortex. We found that this circuit-specific lesion did not compromise performance on multiple measures of motor function (home cage, accelerating rotarod, beam balance, pole climbing), but did increase anxiety-like behavior in the elevated plus-maze and light-dark exploration tests. Fear behavior in the pavlovian cued conditioning and passive avoidance assays was, by contrast, unaffected; possibly due to preservation of catecholamine innervation of the central amygdala from the periaqueductal gray. These data provide some of the first evidence implicating loss of catecholaminergic neurotransmission in midbrain-amygdala circuits to increased anxiety-like behavior. Our findings offer an initial step towards identifying the neural substrates for pre-motor anxiety symptoms in PD.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Ansiedade/fisiopatologia , Catecolaminas/antagonistas & inibidores , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/psicologia , Adrenérgicos/toxicidade , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxidopamina/toxicidade
2.
Neurochem Int ; 124: 193-199, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30660754

RESUMO

The psychostimulant methylphenidate (MPH) is the primary drug treatment for attention deficit hyperactivity disorder (ADHD) in children. MPH is well known to acutely block the dopamine (DAT) and noradrenaline (NET) transporters. Its effect on additional catecholamine targets is however less known. This study was aimed at comparing the effects of acute (2 mg/kg, i.p.) and chronic (2 mg/kg twice daily for 2 weeks) MPH treatment to young rats on key catecholamine protein targets in brain regions implicated in the symptoms and treatment of ADHD. For this purpose, the density of DAT, NET, the vesicular monoamine transporter 2 (VMAT2), the rate limiting enzyme for catecholamine synthesis tyrosine hydroxylase (TH) and the dopamine D1 receptor were measured in frontal (FC), parietal cortex (PCx) and the dorsal (DS) and ventral (VS) striatum. The data demonstrate that the effects of MPH depend on duration of treatment and brain region investigated. With the exception of DAT in the VS our results indicate that chronic but not acute administration of MPH increases levels of DAT, NET, TH, VMAT2 and D1. These effects were further more prominent in the VS over DS and in the PCx compared to the FC. In addition, chronic MPH enhanced DAT levels in the left DS but not in right side. To summarize, this study shows new evidence that chronic MPH to young rats preferentially alters catecholamine targets in PCx and VS over DS and FC. The effect of chronic MPH to increase levels of DAT, NET and VMAT2 suggests that the drug might long-term loose some of its acute action to increase extracellular levels of dopamine and noradrenaline. In conclusion, these findings provide novel insights into the mechanism of action by MPH in the treatment of ADHD and further suggest that the long-term effectiveness of the stimulant drug could be limited.


Assuntos
Catecolaminas/metabolismo , Estimulantes do Sistema Nervoso Central/administração & dosagem , Metilfenidato/administração & dosagem , Lobo Parietal/efeitos dos fármacos , Estriado Ventral/efeitos dos fármacos , Animais , Catecolaminas/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Esquema de Medicação , Masculino , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Lobo Parietal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Estriado Ventral/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
3.
Nature ; 564(7735): 273-277, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30542164

RESUMO

Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases1-5. Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response.


Assuntos
Catecolaminas/antagonistas & inibidores , Catecolaminas/metabolismo , Citocinas/efeitos adversos , Síndrome , Animais , Fator Natriurético Atrial/farmacologia , Complexo CD3/antagonistas & inibidores , Catecolaminas/biossíntese , Citocinas/imunologia , Epinefrina/metabolismo , Feminino , Humanos , Imunoterapia Adotiva , Técnicas In Vitro , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Norepinefrina/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , alfa-Metiltirosina/farmacologia
4.
Br J Pharmacol ; 175(10): 1669-1690, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29473948

RESUMO

BACKGROUND AND PURPOSE: Antiarrhythmic ß-blockers are used in patients at risk of myocardial ischaemia, but the survival benefit and mechanisms are unclear. We hypothesized that ß-blockers do not prevent ventricular fibrillation (VF) but instead inhibit the ability of catecholamines to facilitate ischaemia-induced VF, limiting the scope of their usefulness. EXPERIMENTAL APPROACH: ECGs were analysed from ischaemic Langendorff-perfused rat hearts perfused with adrenoceptor antagonists and/or exogenous catecholamines (CATs: 313 nM noradrenaline + 75 nM adrenaline) in a blinded and randomized study. Ischaemic zone (IZ) size was deliberately made small or large. KEY RESULTS: In rat hearts with large IZs, ischaemia-induced VF incidence was high in controls. Atenolol, butoxamine and trimazosin did not affect VF at concentrations with ß1 -, ß2 - or α1 - adrenoceptor specificity and selectivity (confirmed in separate rat aortae myography experiments). In hearts with small IZs and low baseline incidence of ischaemia-induced VF, CATs, delivered to the uninvolved zone (UZ), increased ischaemia-induced VF incidence. This effect was not mimicked by atrial pacing, hence, not due to sinus tachycardia. However, the CATs-facilitated increase in ischaemia-induced VF was inhibited by atenolol and butoxamine (but not trimazosin), indicative of ß1 - and ß2 - but not α1 -adrenoceptor involvement (confirmed by immunoblot analysis of downstream phosphoproteins). CATs did not facilitate VF in low-flow globally ischaemic hearts, which have no UZ. CONCLUSIONS AND IMPLICATIONS: Catecholamines facilitated ischaemia-induced VF when risk was low, acting via ß1 - and ß2 - adrenoceptors located in the UZ. There was no scope for facilitation when VF risk was high (large IZ), which may explain why ß-blockers have equivocal effectiveness in humans.


Assuntos
Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Catecolaminas/antagonistas & inibidores , Coração/efeitos dos fármacos , Isquemia/metabolismo , Fibrilação Ventricular/tratamento farmacológico , Animais , Catecolaminas/farmacologia , Masculino , Ratos , Ratos Wistar , Fibrilação Ventricular/metabolismo
5.
Arch Pharm Res ; 41(3): 333-346, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29460135

RESUMO

We investigated the influence of simvastatin, a statin, on the secretion of catecholamines (CA) in rat adrenal glands, and clarified its action mechanism. Simvastatin suppressed acetylcholine (ACh)-evoked CA release in a dose- and time-dependent fashion. In the presence of simvastatin, CA secretion evoked by 1.1-dimethyl-4-phenyl piperazinium iodide (DMPP), angiotensin II, high K+, veratridine, and Bay-K-8644 was time-dependently inhibited. However, in the simultaneous presence of simvastatin and Nω-nitro-L-arginine methyl ester hydrochloride, CA secretion evoked by angiotensin II and DMPP recovered to control levels. Adrenal NO release was increased by simvastatin-treatment. Simvastatin-inhibited CA secretion was not affected by treatment with mevalonate. Pravastatin did not influence ACh-evoked CA secretion, while atorvastatin reduced it. In the simultaneous presence of simvastatin and fimasartan, ACh-induced CA release was markedly reduced compared to that of fimasartan-treatment alone. We present the first evidence that simvastatin reduces adrenal CA secretion induced by stimulation of nicotinic and AT1-receptors. Simvastatin-induced inhibition seems to involve reducing the influx of both Ca2+ and Na+ into adrenochromaffin cells, partly via the elevation of NO production by NO synthase activation, without inhibition of 3-hydroxy-methylglutaryl coenzyme A reductase. Co-administration of simvastatin and fimasartan may be clinically helpful for the treatment of cardiovascular diseases.


Assuntos
Glândulas Suprarrenais/metabolismo , Catecolaminas/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Nicotínicos/metabolismo , Sinvastatina/farmacologia , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Catecolaminas/antagonistas & inibidores , Masculino , Agonistas Nicotínicos/farmacologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/agonistas
6.
Neurosci Lett ; 660: 79-85, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28893593

RESUMO

The genus Passiflora is popularly used to treat anxiety. Recent studies showed antidepressant-like effects of two varieties of P. edulis (edulis and flavicarpa) in mice. However, the mechanisms of antidepressant actions are still unknown. Here, the effects of P. edulis fo. edulis aqueous extract (AE, 100-300mg/kg, po), and ethyl acetate (AcOEt, 25-50mg/kg, po), butanol (BuOH, 25-50mg/kg, po) and residual aqueous (25-100mg/kg, po) fractions were investigated in the mouse forced swimming test. In addition, the involvement of monoamines in the P. edulis fractions-induced antidepressant actions was approached. HPLC analyses showed that AcOEt and BuOH, but not residual, fractions shared with AE the main peaks between 25 and 70min (UV 340nm), which are suggestive of flavonoids. Nortriptyline and fluoxetine reduced the immobility time and similar results were observed for AE, AcOEt and BuOH but not residual fractions. PCPA (inhibitor of 5-HT synthesis), AMPT (inhibitor of catecholamine synthesis) and sulpiride (selective D2 receptor antagonist), but not DSP-4 (noradrenergic neurotoxin), blocked the antidepressant actions of AcOEt and BuOH. In conclusion, AcOEt and BuOH fractions shared with AE similar phytochemical composition and antidepressant actions. Preserved 5-HT and dopamine transmissions were required for the antidepressant effects of P. edulis fractions.


Assuntos
Antidepressivos/administração & dosagem , Monoaminas Biogênicas/metabolismo , Depressão/metabolismo , Passiflora/química , Extratos Vegetais/administração & dosagem , Transmissão Sináptica , Acetatos/administração & dosagem , Animais , Antidepressivos/isolamento & purificação , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos Tricíclicos/administração & dosagem , Comportamento Animal , Benzilaminas/administração & dosagem , Butanóis/administração & dosagem , Catecolaminas/antagonistas & inibidores , Catecolaminas/metabolismo , Depressão/tratamento farmacológico , Antagonistas de Dopamina/administração & dosagem , Fluoxetina/administração & dosagem , Masculino , Camundongos , Nortriptilina/administração & dosagem , Extratos Vegetais/isolamento & purificação , Sulpirida/administração & dosagem
7.
J Neurochem ; 143(2): 171-182, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28815595

RESUMO

Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca2+ channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT1A receptors to control secretion. In addition to blocking the serotonin transporter, some selective serotonin reuptake inhibitors (SSRIs) are also agonists at sigma-1 receptors which function as intracellular chaperone proteins and can translocate to the plasma membrane to modulate ion channels. Therefore, we investigated whether SSRIs and other sigma-1 receptor ligands can modulate stimulus-secretion coupling in ACCs. Escitalopram and fluvoxamine (100 nM to 1 µM) reversibly inhibited nAChR currents. The sigma-1 receptor antagonists NE-100 and BD-1047 also blocked nAChR currents (≈ 50% block at 100 nM) as did PRE-084, a sigma-1 receptor agonist. Block of nAChR currents by fluvoxamine and NE-100 was not additive suggesting a common site of action. VGCC currents were unaffected by the drugs. Neither the increase in cytosolic [Ca2+ ] nor the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs was altered by fluvoxamine or NE-100. However, both Ca2+ entry and catecholamine secretion evoked by the cholinergic agonist carbachol were significantly reduced by fluvoxamine or NE-100. Together, our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, SSRIs and other sigma-1 receptor ligands inhibit secretion evoked by cholinergic stimulation because of direct block of Ca2+ entry via nAChRs.


Assuntos
Medula Suprarrenal/metabolismo , Catecolaminas/metabolismo , Células Cromafins/metabolismo , Antagonistas Nicotínicos/farmacologia , Receptores Nicotínicos/fisiologia , Receptores sigma/fisiologia , Medula Suprarrenal/citologia , Medula Suprarrenal/efeitos dos fármacos , Animais , Anisóis/farmacologia , Catecolaminas/antagonistas & inibidores , Bovinos , Células Cultivadas , Células Cromafins/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Propilaminas/farmacologia , Receptores sigma/agonistas
8.
Toxicology ; 371: 17-28, 2016 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-27744045

RESUMO

Catecholamines may undergo iron-promoted oxidation resulting in formation of reactive intermediates (aminochromes) capable of redox cycling and reactive oxygen species (ROS) formation. Both of them induce oxidative stress resulting in cellular damage and death. Iron chelation has been recently shown as a suitable tool of cardioprotection with considerable potential to protect cardiac cells against catecholamine-induced cardiotoxicity. However, prolonged exposure of cells to classical chelators may interfere with physiological iron homeostasis. Prochelators represent a more advanced approach to decrease oxidative injury by forming a chelating agent only under the disease-specific conditions associated with oxidative stress. Novel prochelator (lacking any iron chelating properties) BHAPI [(E)-N-(1-(2-((4-(4,4,5,5-tetramethyl-1,2,3-dioxoborolan-2-yl)benzyl)oxy)phenyl)ethylidene) isonicotinohydrazide] is converted by ROS to active chelator HAPI with strong iron binding capacity that efficiently inhibits iron-catalyzed hydroxyl radical generation. Our results confirmed redox activity of oxidation products of catecholamines isoprenaline and epinephrine, that were able to activate BHAPI to HAPI that chelates iron ions inside H9c2 cardiomyoblasts. Both HAPI and BHAPI were able to efficiently protect the cells against intracellular ROS formation, depletion of reduced glutathione and toxicity induced by catecholamines and their oxidation products. Hence, both HAPI and BHAPI have shown considerable potential to protect cardiac cells by both inhibition of deleterious catecholamine oxidation to reactive intermediates and prevention of ROS-mediated cardiotoxicity.


Assuntos
Compostos de Boro/farmacologia , Cardiotônicos/farmacologia , Catecolaminas/antagonistas & inibidores , Catecolaminas/toxicidade , Quelantes de Ferro/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Semicarbazonas/farmacologia , Animais , Biocatálise , Ácidos Borônicos/farmacologia , Linhagem Celular , Epinefrina/antagonistas & inibidores , Epinefrina/toxicidade , Glutationa/metabolismo , Humanos , Radical Hidroxila/metabolismo , Ferro/química , Isoproterenol/antagonistas & inibidores , Isoproterenol/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pró-Fármacos/farmacologia , Ratos
9.
Arch Pharm Res ; 39(9): 1307-12, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27457068

RESUMO

A human study of the effects on hemodynamics of caffeine and epigallocatechin-3-O-gallate (EGCG) was performed. Caffeine tablets (200 mg) were orally administered to healthy males aged between 25 and 35 years 30 min after oral administration of EGCG tablets (100 and 200 mg). The increase in BP induced by caffeine was inhibited when co-administrated with EGCG. We found that caffeine slightly decreased heart rate (HR) in the volunteers. Although EGCG enhanced HR reduction, the effect was not significant. In addition, caffeine increased blood catecholamine levels, but EGCG inhibited the increase in noradrenaline, adrenaline and dopamine levels induced by caffeine. Whether EGCG decreases the elevated HR and systolic perfusion pressure, and ventricular contractility induced by adrenergic agonists in the isolated rat heart was investigated. The modified Krebs-Henseleit solution was perfused through a Langendorff apparatus to the isolated hearts of rats. HR, systolic perfusion pressure, and developed maximal rates of contraction (+dP/dtmax) and relaxation (-dP/dtmax) were increased by epinephrine (EP) and isoproterenol (IP). In contrast, EGCG decreased the elevated HR, systolic perfusion pressure, and left ventricular ±dp/dtmax induced by EP and/or IP. In conclusion, EGCG could attenuate the hemodynamics stimulated by caffeine through decreasing catecholamine release.


Assuntos
Cafeína/administração & dosagem , Catequina/análogos & derivados , Catecolaminas/antagonistas & inibidores , Hemodinâmica/efeitos dos fármacos , Adulto , Animais , Cafeína/metabolismo , Catequina/administração & dosagem , Catequina/metabolismo , Catecolaminas/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Hemodinâmica/fisiologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
10.
Angew Chem Int Ed Engl ; 55(31): 9041-4, 2016 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-27239950

RESUMO

The pretreatment of cultured pheochromocytoma (PC12) cells with cis-diamminedichloroplatinum (cisplatin), an anti-cancer drug, influences the exocytotic ability of the cells in a dose-dependent manner. Low concentrations of cisplatin stimulate catecholamine release whereas high concentrations inhibit it. Single-cell amperometry reflects that 2 µm cisplatin treatment increases the frequency of exocytotic events and reduces their duration, whereas 100 µm cisplatin treatment decreases the frequency of exocytotic events and increases their duration. Furthermore, the stability of the initial fusion pore that is formed in the lipid membrane during exocytosis is also regulated differentially by different cisplatin concentrations. This study thus suggests that cisplatin influences exocytosis by multiple mechanisms.


Assuntos
Antineoplásicos/farmacologia , Catecolaminas/metabolismo , Cisplatino/farmacologia , Exocitose/efeitos dos fármacos , Neurotransmissores/metabolismo , Análise de Célula Única , Animais , Catecolaminas/antagonistas & inibidores , Catecolaminas/química , Relação Dose-Resposta a Droga , Neurotransmissores/antagonistas & inibidores , Neurotransmissores/química , Células PC12 , Ratos , Células Tumorais Cultivadas
11.
Brain Behav Immun ; 56: 209-220, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26944000

RESUMO

We recently reported that immune stimulation can be compromised if animals are simultaneously subjected to stressful conditions. To test the generalizability of these findings, and to elucidate neuroendocrine mediating mechanisms, we herein employed CpG-C, a novel TLR-9 immune-stimulating agent. Animals were subjected to ongoing stress (20-h of wet cage exposure) during CpG-C treatment, and antagonists to glucocorticoids, ß-adrenoceptor, COX2, or opioids were employed (RU486, nadolol, etodolac, naltrexone). In F344 rats, marginating-pulmonary NK cell numbers and cytotoxicity were studied, and the NK-sensitive MADB106 experimental metastasis model was used. In Balb/C mice, experimental hepatic metastases of the CT-26 colon tumor were studied; and in C57BL/6J mice, survival rates following excision of B16 melanoma was assessed - both mouse tumor models involved surgical stress. The findings indicated that simultaneous blockade of glucocorticoid and ß-adrenergic receptors improved CpG-C efficacy against MADB106 metastasis. In mice bearing B16 melanoma, long-term survival rate was improved by CpG-C only when employed simultaneously with blockers of glucocorticoids, catecholamines, and prostaglandins. Prolonged stress impaired CpG-C efficacy in potentiating NK activity, and in resisting MADB106 metastasis in both sexes, as also supported by in vitro studies. This latter effect was not blocked by any of the antagonists or by adrenalectomy. In the CT26 model, prolonged stress only partially reduced the efficacy of CpG-C. Overall, our findings indicate that ongoing behavioral stress and surgery can jeopardize immune-stimulatory interventions and abolish their beneficial metastasis-reducing impacts. These findings have implications for the clinical setting, which often involve psychological and physiological stress responses during immune-stimulation.


Assuntos
Catecolaminas/antagonistas & inibidores , Glucocorticoides/antagonistas & inibidores , Fatores Imunológicos/farmacologia , Células Matadoras Naturais , Metástase Neoplásica/prevenção & controle , Neoplasias/tratamento farmacológico , Oligodesoxirribonucleotídeos/farmacologia , Antagonistas de Prostaglandina/farmacologia , Estresse Psicológico/imunologia , Animais , Modelos Animais de Doenças , Feminino , Fatores Imunológicos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/administração & dosagem , Ratos , Ratos Endogâmicos F344
12.
Naunyn Schmiedebergs Arch Pharmacol ; 388(12): 1259-69, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26257152

RESUMO

Ikarisoside A is a natural flavonol glycoside derived from plants of the genus Epimedium, which have been used in Traditional Chinese Medicine as tonics, antirheumatics, and aphrodisiacs. Here, we report the effects of ikarisoside A and three other flavonol glycosides on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. We found that ikarisoside A (1-100 µM), but not icariin, epimedin C, or epimedoside A, concentration-dependently inhibited the secretion of catecholamines induced by acetylcholine, a physiological secretagogue and agonist of nicotinic acetylcholine receptors. Ikarisoside A had little effect on catecholamine secretion induced by veratridine and 56 mM K(+). Ikarisoside A (1-100 µM) also inhibited (22)Na(+) influx and (45)Ca(2+) influx induced by acetylcholine in a concentration-dependent manner similar to that of catecholamine secretion. In Xenopus oocytes expressing α3ß4 nicotinic acetylcholine receptors, ikarisoside A (0.1-100 µM) directly inhibited the current evoked by acetylcholine. It also suppressed (14)C-catecholamine synthesis and tyrosine hydroxylase activity induced by acetylcholine at 1-100 µM and 10-100 µM, respectively. The present findings suggest that ikarisoside A inhibits acetylcholine-induced catecholamine secretion and synthesis by suppression of nicotinic acetylcholine receptor-ion channels in bovine adrenal medullary cells.


Assuntos
Acetilcolina/antagonistas & inibidores , Medula Suprarrenal/efeitos dos fármacos , Catecolaminas/antagonistas & inibidores , Flavonoides/farmacologia , Glicosídeos/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Receptores Nicotínicos , Acetilcolina/toxicidade , Medula Suprarrenal/metabolismo , Animais , Canais de Cálcio/metabolismo , Catecolaminas/biossíntese , Catecolaminas/metabolismo , Bovinos , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Flavonoides/isolamento & purificação , Glicosídeos/isolamento & purificação , Ativação do Canal Iônico/fisiologia , Antagonistas Nicotínicos/isolamento & purificação , Antagonistas Nicotínicos/farmacologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Folhas de Planta , Receptores Nicotínicos/metabolismo , Canais de Sódio/metabolismo , Xenopus laevis
13.
Psychopharmacology (Berl) ; 232(7): 1313-23, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25323625

RESUMO

RATIONALE: Depressed people show effort-related motivational symptoms, such as anergia, retardation, lassitude, and fatigue. Animal tests can model these motivational symptoms, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, at low doses, preferentially depletes dopamine. OBJECTIVES: The current studies investigated the effects of tetrabenazine on effort-based decision making using the T-maze barrier task. METHODS: Rats were tested in a T-maze in which the choice arms of the maze contain different reinforcement densities, and under some conditions, a vertical barrier was placed in the high-density arm to provide an effort-related challenge. The first experiment assessed the effects of tetrabenazine under different maze conditions: a barrier in the arm with 4 food pellets and 2 pellets in the no barrier arm (4-2 barrier), 4 pellets in one arm and 2 pellets in the other with no barrier in either arm (no barrier), and 4 pellets in the barrier arm with no pellets in the other (4-0 barrier). RESULTS: Tetrabenazine (0.25-0.75 mg/kg IP) decreased selection of the high cost/high reward arm when the barrier was present, but had no effect on choice under the no barrier and 4-0 barrier conditions. The effects of tetrabenazine on barrier climbing in the 4-2 condition were reversed by the adenosine A2A antagonist MSX-3 and the catecholamine uptake inhibitor and antidepressant bupropion. CONCLUSIONS: These studies have implications for the development of animal models of the motivational symptoms of depression and other disorders.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Bupropiona/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Xantinas/farmacologia , Animais , Antidepressivos/farmacologia , Catecolaminas/antagonistas & inibidores , Catecolaminas/metabolismo , Comportamento de Escolha/fisiologia , Tomada de Decisões/efeitos dos fármacos , Tomada de Decisões/fisiologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor A2A de Adenosina/fisiologia , Proteínas Vesiculares de Transporte de Monoamina/fisiologia
14.
Br J Dermatol ; 172(1): 24-32, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25196392

RESUMO

Currently, propranolol is the preferred treatment for problematic proliferating infantile haemangiomas (IHs). The rapid action of propranolol has been shown to be especially dramatic in IHs involving dyspnoea, haemodynamic compromise, palpebral occlusion or ulceration. Another remarkable aspect of propranolol treatment revealed that the growth of the IHs was not only stabilized, but also that the improvement continued until complete involution was achieved, leading to a considerable shortening of the natural course of IH. However, the mechanisms underlying the effects of propranolol have not been fully elucidated. Recent studies have offered evidence of a variety of mechanisms. These include the promotion of pericyte-mediated vasoconstriction, the inhibition of vasculogenesis and catecholamine-induced angiogenesis, the disruption of haemodynamic force-induced cell survival, and the inactivation of the renin-angiotensin system. This review summarizes these mechanisms and the new concepts that are emerging in this area of research. Moreover, several molecular mechanisms by which propranolol may modify neovascularization in IH have also been proposed. The antihaemangioma effect of propranolol may not be attributable to a single mechanism, but rather to a combination of events that have not yet been elucidated or understood. Further studies are needed to evaluate and verify these mechanisms to gain a greater understanding of the effects of the intake of propranolol on haemangioma involution.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Hemangioma/tratamento farmacológico , Propranolol/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Antagonistas Adrenérgicos beta/farmacologia , Inibidores da Angiogênese/farmacologia , Apoptose/efeitos dos fármacos , Catecolaminas/antagonistas & inibidores , Humanos , Lactente , Pericitos/efeitos dos fármacos , Propranolol/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-25149042

RESUMO

Using embryonic chickens (Gallus gallus domesticus), we examined the role of the renin-angiotensin system (RAS) in cardiovascular and osmotic homeostasis through chronic captopril, an angiotensin-converting enzyme (ACE) inhibitor. Captopril (5 mg kg⁻¹ embryo wet mass) or saline (control) was delivered via the egg air cell daily from embryonic day 5-18. Mean arterial pressure (MAP), heart rate (ƒ(H)), fluid osmolality and ion concentration, and embryonic and organ masses were measured on day 19. Exogenous angiotensin I (ANG I) injection did not change MAP or ƒ(H) in captopril-treated embryos, confirming ACE inhibition. Captopril-treated embryos were significantly hypotensive, with MAP 15% lower than controls, which we attributed to the loss of vasoconstrictive ANG II action. Exogenous ANG II induced a relatively greater hypertensive response in captopril-treated embryos compared to controls. Changes in response to ANG II following pre-treatment with phentolamine (α-adrenergic antagonist) indicated a portion of the ANG II response was due to circulating catecholamines in captopril-treated embryos. An increase in MAP and ƒ(H) in response to hexamethonium indicated vagal tone was also increased in the absence of ACE activity. Captopril-treated embryos had lower osmolality, lower Na⁺ and higher K⁺ concentration in the blood, indicating osmoregulatory changes. Larger kidney mass in captopril-treated embryos suggests disrupting the RAS may stimulate kidney growth by decreasing resistance at the efferent arteriole and increasing the fraction of cardiac output to the kidneys. This study suggests that the RAS, most likely through ANG II action, influences the development of the cardiovascular and osmoregulatory systems.


Assuntos
Proteínas Aviárias/fisiologia , Sistema Cardiovascular/embriologia , Embrião de Galinha/fisiologia , Frequência Cardíaca , Osmorregulação , Sistema Renina-Angiotensina , Resistência Vascular , Antagonistas Adrenérgicos alfa/farmacologia , Angiotensina I/antagonistas & inibidores , Angiotensina I/fisiologia , Angiotensina II/fisiologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Proteínas Aviárias/antagonistas & inibidores , Sistema Cardiovascular/efeitos dos fármacos , Catecolaminas/antagonistas & inibidores , Catecolaminas/fisiologia , Embrião de Galinha/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/embriologia , Antagonistas Nicotínicos/farmacologia , Organogênese/efeitos dos fármacos , Osmorregulação/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
16.
Amino Acids ; 46(1): 111-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23722414

RESUMO

Taurine, a ubiquitous endogenous sulfur-containing amino acid, possesses numerous pharmacological and physiological actions, including antioxidant activity, modulation of calcium homeostasis and antiapoptotic effects. There is mounting evidence supporting the utility of taurine as a pharmacological agent against heart disease, including chronic heart failure (CHF). In the past decade, angiotensin II blockade and ß-adrenergic inhibition have served as the mainstay in the treatment of CHF. Both groups of pharmaceutical agents decrease mortality and improve the quality of life, a testament to the critical role of the sympathetic nervous system and the renin--angiotensin system in the development of CHF. Taurine has also attracted attention because it has beneficial actions in CHF, in part by its demonstrated inhibition of the harmful actions of the neurohumoral factors. In this review, we summarize the beneficial actions of taurine in CHF, focusing on its antagonism of the catecholamines and angiotensin II.


Assuntos
Angiotensina II , Catecolaminas/antagonistas & inibidores , Insuficiência Cardíaca/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Taurina/uso terapêutico , Animais , Catecolaminas/metabolismo , Doença Crônica , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos
17.
J Ethnopharmacol ; 147(2): 447-55, 2013 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-23524165

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicine (TCM) operates on the general principle that compatible components of different herbal decoction may work together to synergistically enhance therapeutic efficacy or reduce adverse effects. Cortex Periplocae is an herb that has been used in TCM clinics for a long time in the treatment of chronic heart failure. However, recently, the use of this herb has been restricted because of widespread abuse and misapplications. Radix Notoginseng is another herb that is used in TCM because of its protective role on cardiomyocytes. From our previous studies on these two herbs in a mouse model, we observed an increased LD50 after oral administration of Cortex Periplocae extract (CPE) and Panax notoginseng saponins (PNS) in a ratio of 1:1 compared with Cortex Periplocae extract used alone. AIM OF THE STUDY: This study aimed to investigate whether there are mutual synergistic effects of the two herbal extracts, CPE and PNS, on catecholamines (CAs) secretion, and their possible underlying mechanism(s) for such effects. MATERIALS AND METHODS: CPE and PNS were quantified by the LC-MS/MS method. HPLC-ECD was used to determine the CAs secreted into the medium by bovine adrenal medulla cells (BAMCs) and calcium influx was measured using a Calcium 4 reagent kit. RESULTS: We found that the stimulatory effect of CPE on CAs secretion was inhibited when used together with PNS. For a better clarification of the different constituents of the extracts, a quantitative analysis was carried out. Periplocin was found to be the main active component of CPE valued as 0.99% and saponins were the principal constituents of PNS. These results also showed that CPE increased the secretion of CAs in a dose-dependent manner while the actions of PNS were seen to be inhibitory. Periplocin monomer of CPE could be implicated for the actions of CPE since it plays the role of increasing the ACh-induced CAs secretion in a calcium-dependent manner. We therefore conclude that; CPE and PNS exert antagonistic effects in regulating the concentration of intracellular calcium. CONCLUSIONS: PNS inhibits CPE-induced CAs secretion by suppressing calcium influx in bovine adrenal medulla cells while periplocin, one of the main components of CPE has the same secretagogue effect as CPE.


Assuntos
Catecolaminas/metabolismo , Panax notoginseng , Periploca , Extratos Vegetais/administração & dosagem , Saponinas/administração & dosagem , Medula Suprarrenal/citologia , Animais , Catecolaminas/antagonistas & inibidores , Bovinos , Células Cultivadas , Interações Medicamentosas , Casca de Planta , Raízes de Plantas
18.
Auton Neurosci ; 175(1-2): 9-16, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23245583

RESUMO

In efforts to assess baroreflex and cardiovascular responses in rats in which substance P (SP) or catecholamine transmission had been eliminated we studied animals after bilateral injections into the nucleus tractus solitarii (NTS) of SP or stabilized SP (SSP) conjugated to saporin (SP-SAP or SSP-SAP respectively) or SAP conjugated to an antibody to dopamine-ß-hydroxylase (anti-DBH-SAP). We found that SP- and SSP-SAP eliminated NTS neurons that expressed the SP neurokinin-1 receptor (NK1R) while anti-DBH-SAP eliminated NTS neurons expressing tyrosine hydroxylase (TH) and DBH. The toxins were selective. Thus SP- or SSP-SAP did not eliminate TH/DBH neurons and anti-DBH-SAP did not eliminate NK1R neurons in the NTS. Each toxin, however, led to chronic lability of arterial blood pressure, diminished baroreflex function, cardiac ventricular irritability, coagulation necrosis of cardiac myocytes and, in some animals, sudden death associated with asystole. However, when TH/DBH neurons were targeted and eliminated by injection of 6-hydroxydopamine (6-OHDA), none of the cardiovascular or cardiac changes occurred. The studies reviewed here reveal that selective lesions of the NTS lead to altered baroreflex control and to cardiac changes that may lead to sudden death. Though the findings could support a role for SP or catecholamines in baroreflex transmission neither is proven in that NK1R colocalizes with glutamate receptors. Thus neurons with both are lost when treated with SP- or SSP-SAP. In addition, loss of catecholamine neurons after treatment with 6-OHDA does not affect cardiovascular control. Thus, the effect of the toxins may depend on an action of SAP independent of the effects of the SAP conjugates on targeted neuronal types.


Assuntos
Fenômenos Fisiológicos Cardiovasculares , Morte Súbita Cardíaca , Neurônios/patologia , Núcleo Solitário/patologia , Núcleo Solitário/fisiopatologia , Animais , Catecolaminas/antagonistas & inibidores , Imunofluorescência , Microscopia Confocal , Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Ratos , Ratos Sprague-Dawley , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , Núcleo Solitário/efeitos dos fármacos , Substância P/análogos & derivados , Substância P/antagonistas & inibidores
19.
Clin Cancer Res ; 18(18): 4895-902, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22753587

RESUMO

Surgery is a crucial intervention in most cancer patients, but the perioperative period is characterized by increased risks for future outbreak of preexisting micrometastases and the initiation of new metastases-the major cause of cancer-related death. Here we argue that the short perioperative period is disproportionately critical in determining long-term recurrence rates, discuss the various underlying risk factors that act synergistically during this period, and assert that this time frame presents an unexplored opportunity to reduce long-term cancer recurrence. We then address physiologic mechanisms that underlie these risk factors, focusing on excess perioperative release of catecholamines and prostaglandins, which were recently shown to be prominent in facilitating cancer recurrence through their direct impact on the malignant tissue and its microenvironment, and through suppressing antimetastatic immunity. The involvement of the immune system is further discussed in light of accumulating evidence in cancer patients, and given the recent identification of endogenously activated unique leukocyte populations which, if not suppressed, can destroy autologous "immune-resistant" tumor cells. We then review animal studies and human correlative findings, suggesting the efficacy of blocking catecholamines and/or prostaglandins perioperatively, limiting metastasis and increasing survival rates. Finally, we propose a specific perioperative pharmacologic intervention in cancer patients, based on simultaneous ß-adrenergic blockade and COX-2 inhibition, and discuss specific considerations for its application in clinical trials, including our approved protocol. In sum, we herein present the rationale for a new approach to reduce long-term cancer recurrence by using a relatively safe, brief, and inexpensive intervention during the perioperative period.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Neoplasias/tratamento farmacológico , Antagonistas de Prostaglandina/uso terapêutico , Antagonistas Adrenérgicos beta/administração & dosagem , Animais , Catecolaminas/antagonistas & inibidores , Catecolaminas/metabolismo , Humanos , Imunidade Celular , Metástase Neoplásica/imunologia , Neoplasias/cirurgia , Período Perioperatório , Antagonistas de Prostaglandina/administração & dosagem , Prostaglandinas/metabolismo , Recidiva , Resultado do Tratamento
20.
Bull Exp Biol Med ; 152(6): 723-7, 2012 Apr.
Artigo em Inglês, Russo | MEDLINE | ID: mdl-22803174

RESUMO

Effects of a sympatholytic drug on bone marrow stromal and hemopoietic precursors were studied on the model of cyclophosphamide-induced myelosuppression. Sympatholytic treatment increased the content of hemopoietic stem cells of different classes in the bone marrow. Selective stimulation of differentiation of polypotent precursors into granulocyte-macrophage precursors was noted. Acceleration of proliferation and maturation of granulocytic precursors was observed at later terms during regeneration of the hemopoietic tissue. The sympatholytic inhibited proliferation of stromal precursors and reduced feeder activity of fibroblasts for granulocyte precursors.


Assuntos
Inibidores da Captação Adrenérgica/administração & dosagem , Medula Óssea/efeitos dos fármacos , Catecolaminas/antagonistas & inibidores , Células-Tronco Hematopoéticas/efeitos dos fármacos , Reserpina/administração & dosagem , Células Estromais/efeitos dos fármacos , Animais , Medula Óssea/metabolismo , Catecolaminas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Ciclofosfamida/administração & dosagem , Citostáticos/administração & dosagem , Granulócitos/efeitos dos fármacos , Granulócitos/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos CBA , Células-Tronco Multipotentes/efeitos dos fármacos , Células-Tronco Multipotentes/metabolismo , Mielopoese/efeitos dos fármacos , Células Estromais/metabolismo
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