RESUMO
Nineteen plants from the Republic of Panama were selected by their traditional uses in the treatment of hypertension, cardiovascular, mental and feeding disorders and 149 extracts were screened using radioligand-receptor-binding assays. The methanol:dicloromethane extracts of the bark and leaves of Anacardium occidentale L., the leaves of Begonia urophylla Hook., the roots of Bocconia frutescens L., the stems and leaves of Cecropia cf.obtusifolia Bertol., the branches of Clusia coclensis Standl., the bark of Cochlospermum vitifolium (Willd.)Spreng., the roots of Dimerocostus strobilaceus Kuntze, the bark of Guazuma ulmifolia Lam., the leaves of Persea americana Mill. and the branches of Witheringia solanaceae L'Her. inhibited the [3H]-AT II binding (angiotensin II AT1 receptor) more than 50%. Only extracts of the roots of Dimerocostus strobilaceus Kuntze and the stems of Psychotria elata (Sw.) Hammel were potent inhibitors of the [3H] NPY binding (neuropeptide Y Y1 receptor) more than 50% and the ethanolic extracts of the leaves of Cecropia cf. obtusifolia Bertol., the leaves of Hedyosmum bonplandianum H.B.K., the roots of Bocconia frutescens L., the stem of Cecropia cf. obtusifolia Bertol. and the branches of Psychotria elata (Sw.) Hammel showed high inhibition of the [3H] BQ-123 binding (endothelin-1 ET(A) receptor) in a preliminary screening. These results promote the further investigation of these plants using the same assays.
Assuntos
Peptídeos Cíclicos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Plantas Medicinais , Receptores de Angiotensina/efeitos dos fármacos , Receptores de Neuropeptídeo Y/efeitos dos fármacos , Humanos , Medicina Tradicional , Panamá , Ensaio Radioligante , Receptor Tipo 1 de AngiotensinaRESUMO
INTRODUCTION: Antisense targeting refers to the use of synthetic short lengths of single stranded DNA, or RNA with base sequences complementary to a specific gene or its mRNA. Commonly, synthetic oligonucleotides are designed to hybridize to specific mRNA and thus preventing its translation in a specific protein. DEVELOPMENT: The use of this technology as research tool is well known since two decades ago, but it has been in the last few years, when it has been proposed as a promising tool for the development of a new generation of drugs with high specificity, relative ease of production and low rate of toxicity. Antisense therapeutics is currently being evaluated in clinical trials for cancer, inflammation, and viral diseases. In the field of Neuropharmacology, it has become in a very valuable tool to block the expression of specific genes in vitro as well in the living brain. In this article, we review the contributions of this technology in the field of the Neurosciences, and also give an overview concerning the advances of the antisense strategy in the design of possible new treatments for certain neurological disorders. Other clinically relevant information regarding molecular biology, pharmacokinetics, mechanism of action, and side effects of antisense oligonucleotides has been collected and summarized. CONCLUSIONS: In the neuropharmacological area is the Neurooncology the most intensively researched; nevertheless, the lack of oligos that cross the blood-brain barrier in sufficient amount continues being one of the main difficulties for the successful application of this technique on the central nervous system.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Oligodesoxirribonucleotídeos Antissenso/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Oligodesoxirribonucleotídeos Antissenso/efeitos adversos , Oligodesoxirribonucleotídeos Antissenso/farmacocinética , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de GABA/efeitos dos fármacos , Receptores de Neuropeptídeo Y/efeitos dos fármacosRESUMO
We aimed at characterizing the receptor subtype and the signaling pathway involved in the inhibitory effect of neuropeptide Y on the release of endogenous noradrenaline from rat hypothalamus. Slices of hypothalamus were stimulated with two trains of electrical pulses, and the release of noradrenaline and nitric oxide was measured. The electrical stimulation of hypothalamic slices induced a consistent release of both endogenous noradrenaline and NO. Neuropeptide Y inhibited concentration dependently the stimulated noradrenaline release. Similarly, agonists for neuropeptide Y Y1, Y2 and Y5 receptors inhibited noradrenaline release, albeit with a potency lower than neuropeptide Y. GW1229, a selective neuropeptide Y Y1 receptor antagonist counteracted the effect of neuropeptide Y, but not that of PYY-(3-36), an agonist active at neuropeptide Y Y5 and Y2 receptors. These results indicate that the inhibitory effect of neuropeptide Y is likely mediated by several receptor subtypes, including neuropeptide Y Y1, Y5 and possibly Y2 receptors. One microM NPY significantly enhanced NO release induced by the electrical stimulation. NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, abolished NO release and blocked the inhibitory effect of neuropeptide Y on noradrenaline release. We conclude that nitric oxide participates in the signaling pathway of neuropeptide Y in the rat hypothalamus.
Assuntos
Hipotálamo/efeitos dos fármacos , Neuropeptídeo Y/farmacologia , Óxido Nítrico/metabolismo , Norepinefrina/metabolismo , Receptores de Neuropeptídeo Y/efeitos dos fármacos , Animais , Estimulação Elétrica , Hipotálamo/metabolismo , Masculino , Oligopeptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/metabolismoRESUMO
The microvascular effects of neuropeptide Y, and two analogs with preferential affinity for different neuropeptide Y receptor subtypes, were assessed by intravital microscopy on the hamster cheek pouch. The interaction of neuropeptide Y and its analogs with noradrenaline was also studied. Superfusion with 0.1-300 nM neuropeptide Y caused a concentration-dependent reduction in microvascular conductance that was paralleled by reductions in arteriolar and venular diameters. These effects of neuropeptide Y were equipotent with noradrenaline, but slower to develop and longer-lasting than that of noradrenaline. Neuropeptide Y did not affect permeability to macromolecules, as measured by extravasation of fluorescent dextran. The neuropeptide Y Y1 receptor agonist, [Leu31,Pro34]neuropeptide Y, mimicked neuropeptide Y with similar potency but shorter duration, while neuropeptide Y-(13-36), a neuropeptide Y Y2 receptor agonist, was at least 10-fold less potent than neuropeptide Y to induce a delayed and prolonged reduction in microvascular conductance. The joint superfusion of 1 nM neuropeptide Y plus 0.1 mu M noradrenaline did not cause synergism, nor even summation of effects, but reduced the contractile effect of noradrenaline. No synergism was observed after a 10 min priming with 1 nM neuropeptide Y, followed by its joint application with 0.1 mu M noradrenaline, but a significant vasodilation and hyperemia ensued upon stopping noradrenaline application. Priming with 1 nM [Leu31,Pro34]neuropeptide Y prolonged noradrenaline vasoconstriction without evidence of hyperemia. In contrast, priming with 1 nM neuropeptide Y-(13-36) significantly antagonized noradrenaline vasoconstriction. These findings indicate that both neuropeptide Y receptor subtypes are present in arterioles and venules of the hamster, and suggest that their activation with neuropeptide Y induces a rapid (Y1 receptor subtype activation) and a delayed (Y2 receptor subtype activation) vasocontractile response. The interaction with noradrenaline is complex, without evidence for synergism, but neuropeptide Y Y2 receptor activation seems to antagonize noradrenaline and/or to facilitate auto-regulatory vasodilation after the catecholamine-induced vasoconstriction.
Assuntos
Neuropeptídeo Y/farmacologia , Norepinefrina/farmacologia , Receptores de Neuropeptídeo Y/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Cricetinae , Masculino , Mesocricetus , Microcirculação/efeitos dos fármacos , Neuropeptídeo Y/análogos & derivados , Fragmentos de Peptídeos/farmacologiaRESUMO
In studies conducted in patients undergoing cardiac catheterizations, some hemodynamic changes were observed after the acute sublingual administration of the angiotensin converting enzyme inhibitors (ACEI) captopril, enalapril, and lisinopril. These changes consisted of an increase in pulmonary artery pressure, pulmonary vascular resistance (PVR) and induction of hypoxia. The pressure changes were transitory and disappeared after 25 min. The possible mechanisms involved in these changes may relate to interactions of the ACEI with peripheral receptor systems for hormones and neurotransmitters. We have thus undertaken the task of evaluating the potential effect of ACEI on biological receptor molecules. We have begun with studies on muscarinic receptors, and the recently characterized neuropeptide Y (NPY) receptors of endothelial cells. Equilibrium binding assays with 3H-QNB have been conducted for muscarinic receptors using rat brain synaptosomes, due to its expression of multiple muscarinic receptors subtypes. In addition 125BH-NPY binding assays were conducted on intact adrenal medullary endothelial cells. Enalapril and captopril, 10(-7) to 10(-3) M, were not able to produce significant inhibition of either muscarinic or NPY receptor probes. The paradoxical changes elicited by sublingual ACEI seems not to involve interaction with muscarinic or NPY receptors.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Química Encefálica , Endotélio Vascular/efeitos dos fármacos , Receptores Muscarínicos/efeitos dos fármacos , Receptores de Neuropeptídeo Y/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacos , Medula Suprarrenal/irrigação sanguínea , Animais , Bovinos , Células Cultivadas , Endotélio Vascular/química , Endotélio Vascular/citologia , Hemodinâmica/efeitos dos fármacos , Quinuclidinil Benzilato/metabolismo , Ratos , Receptores Muscarínicos/metabolismo , Sinaptossomos/químicaRESUMO
In studies conducted in patients undergoing cardiac catheterizations, some hemodynamic changes were observed after the acute sublingual administration of the angiotensin converting enzyme inhibitors (ACEI) captopril, enalapril, and lisinopril. These changes consisted of an increase in pulmonary artery pressure, pulmonary vascular resistance (PVR) and induction of hypoxia. The pressure changes were transitory and disappeared after 25 min. The possible mechanisms involved in these changes may relate to interactions of the ACEI with peripheral receptor systems for hormones and neurotransmitters. We have thus undertaken the task of evaluating the potential effect of ACEI on biological receptor molecules. We have begun with studies on muscarinic receptors, and the recently characterized neuropeptide Y (NPY) receptors of endothelial cells. Equilibrium binding assays with 3H-QNB have been conducted for muscarinic receptors using rat brain synaptosomes, due to its expression of multiple muscarinic receptors subtypes. In addition 125BH-NPY binding assays were conducted on intact adrenal medullary endothelial cells. Enalapril and captopril, 10(-7) to 10(-3) M, were not able to produce significant inhibition of either muscarinic or NPY receptor probes. The paradoxical changes elicited by sublingual ACEI seems not to involve interaction with muscarinic or NPY receptors