共查询到20条相似文献,搜索用时 15 毫秒
1.
Abstract: To clarify the effects of adenosine receptor subtypes (A 1, A 2, and A 3) on hippocampal serotoninergic function, hippocampal extracellular serotonin (5-HT) levels were determined by in vivo microdialysis in freely moving rats under various conditions. Both adenosine and an adenosine A 1 receptor agonist, 2-chloro- N6-cyclopentyladenosine, decreased extracellular 5-HT levels, whereas an adenosine A 1 receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT), and caffeine increased these levels. A selective A 2A receptor agonist (CGS-21680), an adenosine A 2 receptor agonist (PD-125944), an adenosine A 2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), and an adenosine A 3 receptor agonist, N6-2-(4-aminophenyl)ethyladenosine (APNEA), did not affect extracellular 5-HT levels. When the adenosine A 1 receptor was blocked by CPT, the hippocampal extracellular 5-HT level was increased by adenosine, CGS-21680, and PD-125944, and decreased by caffeine, DMPX, and APNEA. When both adenosine A 1 and A 2 receptors were blocked by CPT and DMPX, the extracellular 5-HT level was decreased by adenosine, caffeine, and APNEA. The hippocampal extracellular 5-HT level was not affected by administration of APNEA alone, but was decreased by this agent when the adenosine A 1 receptor was blocked, irrespective of whether the adenosine A 2 receptor was functional. These inhibitory effects of adenosine, caffeine, and APNEA on extracellular 5-HT levels, during both adenosine A 1 and A 2 receptor blockade, were inhibited by selective 5-HT reuptake inhibitors. These results indicate that the stimulatory effects of the adenosine A 2 receptor and the inhibitory effects of the A 3 receptor on hippocampal extracellular 5-HT levels are masked by the inhibitory effects of the adenosine A 1 receptor. 相似文献
2.
Adenosine has a significant role in many functions of the central nervous system. Behaviorally, adenosine and adenosine analogs have marked depressant effects. Electrophysiologically, adenosine reduces spontaneous neuronal activity and inhibits transsynaptic potentials interaction with extracellular receptors. Biochemically, adenosine inhibits adenylate cyclase a “high” affinity receptor, and activates adenylate cyclase a “low” affinity receptor. These receptors, called “A 1” and “A 2” respectively, show differing profiles for activation by adenosine analogs. Radioactive N 6-cyclohexyladenosine binds selectively to the “high” affinity receptor. One major class of antagonists is known at adenosine receptors: the alkylxanthines, including caffeine and theophylline. Radioactive 1,3-diethyl-8-phenylxanthine, a particularly potent antagonist, appears to bind to both low and high affinity adenosine receptors. Behavioral, electrophysiological, and biochemical effects of alkylxanthines are consistent with the hypothesis that the central stimulatory actions of caffeine and theophylline are due in large part to antagonism of central adenosine receptors. 相似文献
3.
Brown or beige fat activation can cause potent anti-obesity and anti-diabetic effects. In a study recently published in Nature, Gnad et al. show that adenosine is a novel activator of brown and beige fat that acts through the A 2A receptor.Brown fat is a thermogenic type of adipose tissue containing abundant mitochondria and multilocular lipid droplets, and is uniquely suited and required for cold tolerance and body weight control 1. Upon brown fat activation, intracellular cyclic AMP (cAMP) levels rise rapidly, leading to lipolysis and upregulation of uncoupling protein 1 (UCP1) which initiates uncoupling of mitochondrial respiration and heat generation 2,3. Additionally, beige or brite fat is a form of white fat that can be “browned” and induced to engage in respiratory uncoupling similarly as brown fat. Activated brown and beige fat consume substantial amounts of metabolic substrate, leading to powerful anti-obesity and anti-diabetic effects in mice. Adult humans possess brown and beige fat, making these tissues potentially important targets for treating obesity and metabolic diseases 4. Activation of brown and beige fat occurs through several mechanisms including cold, adrenergic signaling, and hormone signaling 4. However, a critical question remains of which pathway is altered therapeutically, as targeting these known activation pathways may cause discomfort, have undesirable side effects, or be insufficient alone to exert anti-obesity effects in humans. Thus, the need to discover novel pathways for brown and beige fat thermogenic activation persists.Adenosine is a purine nucleoside that alters cAMP signaling in several tissues 5,6. There is a ubiquitous presence of adenosine in the extracellular space, and adenosine levels can be increased extracellularly or intracellularly through conversion of adenine nucleotides. Adenosine binds to four P1 G-protein-coupled receptor subtypes, which include the inhibitory receptors A 1 and A 3 and the stimulatory receptors A 2A and A 2B7. Inhibitory receptor activation leads to increased adenylate cyclase activity and decreased cAMP, while stimulatory receptor activation has the opposite effect. The distribution of the adenine receptor subtypes varies widely by tissue and species, and the response is dependent on the level of receptor expression, thus the actions of adenosine can be highly disparate depending on the tissue context 8.In adipose tissue, adenosine was previously found to inhibit cAMP production in studies performed in hamster and rat, where oxygen consumption and lipolysis also decreased 9,10. In a study recently published in Nature, Gnad et al. 11 show that adenosine activates lipolysis and the thermogenic program in brown and white human and murine adipocytes (). This phenomenon occurs at significantly lower concentrations of adenosine in brown adipocytes than in white adipocytes. The difference is accounted for by differential expression of the A 2A receptor, which is highly expressed in human and murine brown fat relative to white fat. It is also due to the ratio of expression compared to the inhibitory A 1 receptor, which is expressed at low levels in brown fat compared to white fat. Moreover, the authors show that hamster brown fat expresses almost equal amounts of A 1 and A 2A receptors, explaining the lack of activating effects of adenosine in those cells. Open in a separate windowAdenosine activates brown or beige adipocytes through the A 2A receptor. Adenosine activates the A 2A receptor, leading to increased cAMP- and PGC-1α-dependent signaling that enhances thermogenesis and lipolysis in brown and beige adipocytes. Crosstalk occurs with adrenergic signaling, which increases cAMP and adenosine levels. Adenosine is released both through efflux from brown adipocytes and through breakdown of extracellular ATP by the ecto-5′-nucleotidase CD73. AR, adrenergic receptor.The determination of the source of the adenosine driving brown fat activation was also pursued. Adenosine could be derived from breakdown of ATP released from sympathetic neurons and brown adipocytes, or from brown adipocyte efflux of adenosine itself. The authors find that activated brown fat both releases adenosine through efflux and converts extracellular ATP to adenosine, as inhibition of the ecto-5′-nucleotidase CD73, which converts ATP to adenosine, only partially blocks the adenosine increase. Noradrenaline also enhances adenosine release from brown fat without any change in extracellular ATP, suggesting an intracellular crosstalk between catecholamine and adenosine signaling.The author further show that A 2A receptor knockout mice exposed to cold exhibit defective thermogenesis, oxygen consumption, and lipolysis, demonstrating the importance of the A 2A receptor in mediating the thermogenic response. Moreover, pharmacological activation with an A 2A receptor agonist increases oxygen consumption in mice, while inhibition with a specific A 2A antagonist decreases cold-induced oxygen consumption. A 2A receptor agonism acts synergistically with noradrenaline in driving lipolysis, revealing an additive thermogenic effect of adenosine with catecholamine signaling. An A 2A agonist protects against diet-induced obesity in mice, leading to increases in lean mass, oxygen consumption, glucose tolerance, and browning of white fat, which signifies the potential therapeutic importance of adenosine signaling. Importantly, overexpression of the A 2A receptor in inguinal white fat increases its browning, indicating that bolstering of A 2A adenosine receptor expression is sufficient to initiate a thermogenic response in the presence of physiological concentration of adenosine.This study reveals an endogenous purinergic signaling pathway that activates brown and beige fat. The critical signaling effector involved is cAMP, therefore the mechanism of activation is similar to those of other agents that act through the sympathetic nervous system or adrenergic signaling. It is unclear whether adenosine would contribute any additional anti-obesity effects than what has already been achieved with these other agents.While this study demonstrates substantial effects of adenosine on thermogenesis, further studies would better elucidate the specificity toward the A 2A receptor in adipocytes. Treatment of A 2A knockout mice with the receptor agonist would help demonstrate whether there are effects of the agonist independent of the A 2A receptor in vivo. Additionally, adipose tissue-specific A 2A knockout mice would reveal whether there are any phenotypic contributions from knockout in other tissues.Another question is whether A 2A receptor agonism could be used chronically as an anti-obesity therapy in the clinic, since adenosine receptors are expressed in many tissues. This study did not explore the potentially confounding effects of A 2A receptor agonism on tissues such as the brain or heart, including complications from vasodilation or cardiotoxicity. Indeed, A 2A receptor antagonists have been used in clinical trials for Parkinson''s disease, highlighting the possible adverse effects of A 2A receptor agonism on the brain. The effect of adenosine on lipolysis also raises the question of whether this pathway is involved in the lipoatrophy caused by nucleoside analogues used as anti-retroviral drugs. Nevertheless, this work adds important information about a cellular signaling pathway that may be leveraged in finding new therapies for obesity and metabolic diseases. 相似文献
4.
Amyotrophic lateral sclerosis (ALS) is a fatal progressing neurodegenerative disease; to date, despite the intense research effort, only two therapeutic options, with very limited effects, are available. The purinergic system has been indicated as a possible new therapeutic target for ALS, but the results are often contradictory and generally confused. The present study was designed to determine whether P1 adenosine receptor ligands affected disease progression in a transgenic model of ALS. SOD1G93A mice were chronically treated, from presymptomatic stage, with a selective adenosine A2A receptor agonist (CGS21680), antagonist (KW6002) or the A1 receptor antagonist DPCPX. Body weight, motor performance and survival time were evaluated. The results showed that neither the stimulation nor the blockade of adenosine A2A receptors modified the progressive loss of motor skills or survival of mSOD1G93A mice. Conversely, blockade of adenosine A1 receptors from the presymptomatic stage significantly attenuated motor disease progression and induced a non-significant increase of median survival in ALS mice. Our data confirm that the modulation of adenosine receptors can elicit very different (and even opposite) effects during the progression of ALS course, thus strengthens the importance of further studies to elucidated their real therapeutic potential in this pathology. 相似文献
5.
Abstract The use of xanthine adenosine receptor antagonists such as 1,3-dipropyl-8-phenylxanthine (DPX) as radioligands for the characterization of adenosine receptor Pharmacology have been limited by their high lipophilicity, low specific activity, and their general lack of selectivity and affinity for adenosine receptors. Recent attempts to address the technical problems associated with this class of compounds has resulted in the development of several xanthine derivatives (e.g. the functionalized xanthine congeners [ 3H]XCC and [ 3H]XAC 2, and [ 3H]CPX 3) which bind with high and selective affinity to the adenosine A 1 receptor subtype. Based on efforts to optimize non-xanthine adenosine receptor antagonists, CGS 15943, a derivative of the pyrazoloquinazoline benzodiazepine receptor inverse agonist CGS 8216 5, represents the first reported non-xanthine structure that potently blocks adenosine receptors 6. CGS 15943 has nanomolar affinity for both A 1 and A 2 receptor subtypes 6. However, in contrast to many of the xanthine adenosine receptor antagonists, CGS 15943 is not a phosphodiesterase inhibitor and does not interact with adenosine transporter sites 6. This compound is a potent and selective adenosine receptor antagonist in vivo 7 with a solubility/affinity ratio of greater than 1000 7. In the present studies, the binding of [ 3H]CGS 15943 to the adenosine A 1 receptor was characterized. 相似文献
6.
Guanosine (GUO) is an endogenous modulator of glutamatergic excitotoxicity and has been shown to promote neuroprotection in in vivo and in vitro models of neurotoxicity. This study was designed to understand the neuroprotective mechanism of GUO against oxidative damage promoted by oxygen/glucose deprivation and reoxygenation (OGD). GUO (100 μM) reduced reactive oxygen species production and prevented mitochondrial membrane depolarization induced by OGD. GUO also exhibited anti‐inflammatory actions as inhibition of nuclear factor kappa B activation and reduction of inducible nitric oxide synthase induction induced by OGD. These GUO neuroprotective effects were mediated by adenosine A 1 receptor, phosphatidylinositol‐3 kinase and MAPK/ERK. Furthermore, GUO recovered the impairment of glutamate uptake caused by OGD, an effect that occurred via a Pertussis toxin‐sensitive G‐protein‐coupled signaling, blockade of adenosine A 2A receptors (A 2AR), but not via A 1 receptor. The modulation of glutamate uptake by GUO also involved MAPK/ERK activation. In conclusion, GUO, by modulating adenosine receptor function and activating MAPK/ERK, affords neuroprotection of hippocampal slices subjected to OGD by a mechanism that implicates the following: (i) prevention of mitochondrial membrane depolarization, (ii) reduction of oxidative stress, (iii) regulation of inflammation by inhibition of nuclear factor kappa B and inducible nitric oxide synthase, and (iv) promoting glutamate uptake. 相似文献
7.
The effects of N 6-cyclohexyladenosine, a selective adenosine A 1 receptor agonist, on the capsaicin-induced cough reflex in mice were examined. I.c.v. administration of N 6-cyclohexyladenosine in doses that ranged from 0.03 to 0.3 nmol decreased the number of coughs in a dose-dependent manner. Pretreatment with 8-cyclopentyl-1,3-theophylline, a selective adenosine A 1 receptor antagonist, significantly reduced the antitussive effect of N 6-cyclohexyladenosine. On the other hand, CGS21680 (0.3 and 1 nmol, i.c.v.), a selective adenosine A 2 receptor agonist, had no significant effect on the number of capsaicin-induced coughs. These data suggest that adenosine A 1 agonist may have a marked antitussive effect in mice. 相似文献
8.
Adenosine (ADO) is a well-known regulator of a variety of physiological functions in the heart. In stress conditions, like hypoxia or ischemia, the concentration of adenosine in the extracellular fluid rises dramatically, mainly through the breakdown of ATP. The degradation of adenosine in the ischemic myocytes induced damage in these cells, but it may simultaneously exert protective effects in the heart by activation of the adenosine receptors. The contribution of ADO to stimulation of protective effects was reported in human and animal hearts, but not in rat hearts. The aim of this study was to evaluate the role of adenosine A 1 and A 3 receptors (A 1R and A 3R), in protection of isolated cardiac myocytes of newborn rats from ischemic injury. The hypoxic conditions were simulated by exposure of cultured rat cardiomyocytes (4–5 days in vitro), to an atmosphere of a N 2 (95%) and CO 2 (5%) mixture, in glucose-free medium for 90 min. The cardiotoxic and cardioprotective effects of ADO ligands were measured by the release of lactate dehydrogenase (LDH) into the medium. Morphological investigation includes immunohistochemistry, image analysis of living and fixed cells and electron microscopy were executed. Pretreatment with the adenosine deaminase considerably increased the hypoxic damage in the cardiomyocytes indicating the importance of extracellular adenosine. Blocking adenosine receptors with selective A 1 and A 3 receptor antagonists abolished the protective effects of adenosine. A 1R and A 3R activation during the hypoxic insult delays onset of irreversible cell injury and collapse of mitochondrial membrane potential as assessed using DASPMI fluorochrom. Cardioprotection induced by the A 1R agonist, CCPA, was abolished by an A 1R antagonist, DPCPX, and was not affected by an A 3R antagonist, MRS1523. Cardioprotection caused by the A 3R agonist, Cl-IB-MECA, was antagonized completely by MRS1523 and only partially by DPCPX. Activation of both A 1R and A 3R together was more efficient in protection against hypoxia than by each one alone. Our study indicates that activation of either A 1 or A 3 adenosine receptors in the rat can attenuate myocyte injury during hypoxia. Highly selective A 1R and A 3R agonists may have potential as cardioprotective agents against ischemia or heart surgery. 相似文献
9.
The excitatory glutamatergic neurons in the hippocampus are modulated by inhibitory GABA-releasing interneurons. The neuromodulator adenosine is known to inhibit the presynaptic release of neurotransmitters and to hyperpolarize postsynaptic neurons in the hippocampus, which would imply that it is an endogenous protective agent against cerebral ischemia and excitotoxic neuronal damage. Interactions of the GABAergic and adenosinergic systems in regulating neuronal excitability in the hippocampus is of crucial importance, particularly under cell-damaging conditions. We now characterized the effects of adenosine receptor agonists and antagonists on the release of preloaded [ 3H]GABA from hippocampal slices prepared from adult (3-month-old) mice, using a superfusion system. The effects were tested both under normal conditions and in ischemia induced by omitting glucose and oxygen from the superfusion medium. Basal and K +-evoked GABA release in the hippocampus were depressed by adenosinergic compounds. Under normal conditions activation of both adenosine A 1 and A 2A receptors by the agonists R(-) N6-(2-phenylisopropyl)adenosine and CGS 21680 inhibited the K +-evoked release, which effects were blocked by their specific antagonists, 8-cyclopentyl-1,3-dipropyl-xanthine and 3,7-dimethyl-1-propargylxanthine, respectively. Under ischemic conditions the release of both GABA and adenosine is markedly enhanced. The above receptor agonists then depressed both the basal and K +-evoked GABA release, only the action of A 2A receptors being however receptor-mediated. The demonstrated depression of GABA release by adenosine in the hippocampus could be deleterious to neurons and contribute to excitotoxicity. 相似文献
10.
AimsWe investigated the effects induced by exogenous adenosine on the spontaneous contractile activity of the longitudinal muscle of a mouse ileum, the receptor subtypes activated, the involvement of enteric nerves and whether opening of K + channels was a downstream event leading to the observed effects. Main methodsMechanical responses of the mouse ileal longitudinal muscle to adenosine were examined in vitro as changes in isometric tension. Key findingsAdenosine caused a concentration-dependent reduction of the spontaneous contraction amplitude of the ileal longitudinal muscle up to its complete disappearance. This effect induced was markedly reduced by an A 1 receptor antagonist, but not by A 2 and A 3 receptor antagonists and mimicked only by the A 1 receptor agonist. Adenosine uptake inhibitors did not change adenosine potency. A 1 receptor expression was detected at the smooth muscle level. Adenosine responses were insensitive to tetrodotoxin, atropine or nitric oxide synthase inhibitor. Tetraethylammonium and iberiotoxin, BK Ca channel blockers, significantly reduced adenosine effects, whilst 4-aminopyridine, a K v blocker, apamin, a small conductance Ca 2+-activated K + (SK Ca) channel blocker, charybdotoxin, an intermediate conductance Ca 2+-activated K + (IK Ca) and BK Ca channel blocker, or glibenclamide, an ATP-sensitive K + channel blocker, had no effects. The combination of apamin plus iberiotoxin caused a reduction of the purinergic effects greater than iberiotoxin alone. SignificanceAdenosine acts as an inhibitory modulator of the contractility of mouse ileal longitudinal muscle through postjunctional A 1 receptors, which in turn would induce opening of BK Ca and SK Ca potassium channels. This study would provide new insight in the pharmacology of purinergic receptors involved in the modulation of the gastrointestinal contractility. 相似文献
11.
In this work, the metabolism of adenosine by isolated BLM associated-enzymes and the implications of this process for the cAMP-signaling pathway are investigated. Inosine was identified as the major metabolic product, suggesting the presence of adenosine deaminase (ADA) activity in the BLM. This was confirmed by immunoblotting and ADA-specific enzyme assay. Implications for the enzymatic deamination of adenosine on the receptor-modulated cAMP-signaling pathway were also investigated. We observed that inosine induced a 2-fold increase in [ 35S] GTPγS binding to the BLM and it was inhibited by 10 −6 M DPCPX, an A 1 receptor-selective antagonist. Inosine (10 −7 M) inhibited protein kinase A activity in a DPCPX-sensitive manner. Molecular association between ADA and G αi-3 protein-coupled A 1 receptor was demonstrated by co-immunoprecipitation assay. These data show that adenosine is deaminated by A 1 receptor-associated ADA to inosine, which in turn modulates PKA in the BLM through A 1 receptor-mediated inhibition of adenylyl cyclase. 相似文献
12.
Caffeine, a stimulant largely consumed around the world, is a non-selective adenosine receptor antagonist, and therefore caffeine actions at synapses usually, but not always, mirror those of adenosine. Importantly, different adenosine receptors with opposing regulatory actions co-exist at synapses. Through both inhibitory and excitatory high-affinity receptors (A1R and A2R, respectively), adenosine affects NMDA receptor (NMDAR) function at the hippocampus, but surprisingly, there is a lack of knowledge on the effects of caffeine upon this ionotropic glutamatergic receptor deeply involved in both positive (plasticity) and negative (excitotoxicity) synaptic actions. We thus aimed to elucidate the effects of caffeine upon NMDAR-mediated excitatory post-synaptic currents (NMDAR-EPSCs), and its implications upon neuronal Ca2+ homeostasis. We found that caffeine (30–200 μM) facilitates NMDAR-EPSCs on pyramidal CA1 neurons from Balbc/ByJ male mice, an action mimicked, as well as occluded, by 1,3-dipropyl-cyclopentylxantine (DPCPX, 50 nM), thus likely mediated by blockade of inhibitory A1Rs. This action of caffeine cannot be attributed to a pre-synaptic facilitation of transmission because caffeine even increased paired-pulse facilitation of NMDA-EPSCs, indicative of an inhibition of neurotransmitter release. Adenosine A2ARs are involved in this likely pre-synaptic action since the effect of caffeine was mimicked by the A2AR antagonist, SCH58261 (50 nM). Furthermore, caffeine increased the frequency of Ca2+ transients in neuronal cell culture, an action mimicked by the A1R antagonist, DPCPX, and prevented by NMDAR blockade with AP5 (50 μM). Altogether, these results show for the first time an influence of caffeine on NMDA receptor activity at the hippocampus, with impact in neuronal Ca2+ homeostasis. 相似文献
13.
The G protein-coupled A 2A adenosine receptor represents an important drug target. Crystal structures and modeling studies indicated that three disulfide bonds are formed between ECL1 and ECL2 (I, Cys71 2.69-Cys159 45.43; II, Cys74 3.22-Cys146 45.30, and III, Cys77 3.25-Cys166 45.50). However, the A 2BAR subtype appears to require only disulfide bond III for proper function. In this study, each of the three disulfide bonds in the A 2AAR was disrupted by mutation of one of the cysteine residues to serine. The mutant receptors were stably expressed in Chinese hamster ovary cells and analyzed in cyclic adenosine monophosphate (cAMP) accumulation and radioligand binding studies using structurally diverse agonists: adenosine, NECA, CGS21680, and PSB-15826. Results were rationalized by molecular modeling. The observed effects were dependent on the investigated agonist. Loss of disulfide bond I led to a widening of the orthosteric binding pocket resulting in a strong reduction in the potency of adenosine, but not of NECA or 2-substituted nucleosides. Disruption of disulfide bond II led to a significant reduction in the agonists’ efficacy indicating its importance for receptor activation. Disulfide bond III disruption reduced potency and affinity of the small adenosine agonists and NECA, but not of the larger 2-substituted agonists. While all the three disulfide bonds were essential for high potency or efficacy of adenosine, structural modification of the nucleoside could rescue affinity or efficacy at the mutant receptors. At present, it cannot be excluded that formation of the extracellular disulfide bonds in the A 2AAR is dynamic. This might add another level of G protein-coupled receptor (GPCR) modulation, in particular for the cysteine-rich A 2A and A 2BARs. 相似文献
14.
Epilepsy is a chronic neurological disorder characterized by recurrent seizures. However, approximately one-third of epilepsy patients still suffer from uncontrolled seizures. Effective treatments for epilepsy are yet to be developed. N
6-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2) is a N 6-substitued adenosine analog. Here we describe an investigation of the effects and mechanisms of B2 on chemical convulsant-induced seizures. Seizures were induced in mice by administration of 4-aminopyridine (4-AP), pentylenetetrazol (PTZ), picrotoxin, kainite acid (KA), or strychnine. B2 has a dose-related anticonvulsant effect in these chemical-induced seizure models. The protective effects of B2 include increased latency of seizure onset, decreased seizure occurrence, shorter seizure duration and reduced mortality rate. Radioligand binding and cAMP accumulation assays indicated that B2 might be a functional ligand for both adenosine A 1 and A 2A receptors. Furthermore, DPCPX, a selective A 1 receptor antagonist, but not {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304"}}SCH58261, a selective A 2A receptor antagonist, blocked the anticonvulsant effect of B2 on PTZ-induced seizure. c-Fos is a cellular marker for neuronal activity. Immunohistochemical and western blot analyses indicated that B2 significantly reversed PTZ-induced c-Fos expression in the hippocampus. Together, these results indicate that B2 has significant anticonvulsant effects. The anticonvulsant effects of B2 may be attributed to adenosine A 1 receptor activation and reduced neuronal excitability in the hippocampus. These observations also support that the use of adenosine receptor agonist may be a promising approach for the treatment of epilepsy. 相似文献
15.
Benign prostatic hypertrophy has been related with glandular ischemia processes and adenosine is a potent vasodilator agent. This study investigates the mechanisms underlying the adenosine-induced vasorelaxation in pig prostatic small arteries. Adenosine receptors expression was determined by Western blot and immunohistochemistry, and rings were mounted in myographs for isometric force recording. A 2A and A 3 receptor expression was observed in the arterial wall and A 2A-immunoreactivity was identified in the adventitia–media junction and endothelium. A 1 and A 2B receptor expression was not obtained. On noradrenaline-precontracted rings, P1 receptor agonists produced concentration-dependent relaxations with the following order of potency: 5′- N-ethylcarboxamidoadenosine (NECA) = {"type":"entrez-protein","attrs":{"text":"CGS21680","term_id":"878113053","term_text":"CGS21680"}}CGS21680 > 2-Cl-IB-MECA = 2-Cl-cyclopentyladenosine = adenosine. Adenosine reuptake inhibition potentiated both NECA and adenosine relaxations. Endothelium removal and ZM241385, an A 2A antagonist, reduced NECA relaxations that were not modified by A 1, A 2B, and A 3 receptor antagonists. Neuronal voltage-gated Ca 2+ channels and nitric oxide (NO) synthase blockade, and adenylyl cyclase activation enhanced these responses, which were reduced by protein kinase A inhibition and by blockade of the intermediate (IK Ca)- and small (SK Ca)-conductance Ca 2+-activated K + channels. Inhibition of cyclooxygenase (COX), large-conductance Ca 2+-activated-, ATP-dependent-, and voltage-gated-K + channel failed to modify these responses. These results suggest that adenosine induces endothelium-dependent relaxations in the pig prostatic arteries via A 2A purinoceptors. The adenosine vasorelaxation, which is prejunctionally modulated, is produced via NO- and COX-independent mechanisms that involve activation of IK Ca and SK Ca channels and stimulation of adenylyl cyclase. Endothelium-derived NO playing a regulatory role under conditions in which EDHF is non-functional is also suggested. Adenosine-induced vasodilatation could be useful to prevent prostatic ischemia. 相似文献
16.
Abstract A variety of adenosine analogues have been recently evaluated in order Lo find more potent and selective agonists on adenosine receptors. The most potent adenosine analogues acting on A 1 receptor, a high affinity receptor inhibitory to adenylate cyclase, are N 6-substituted compounds. So 6-cyclohexyladenosine (CHA) and 6-L-phenylisopropyladenosine (L-PIA) are extremely potent agonists on A 2 receptor, whereas they are relatively weak agonists on A receptor, a lower affinity receptor which is stirnulatory to cyclase, and they have no effect on the adenosine P site. 相似文献
17.
Background Caffeine, a nonselective adenosine A 1 and A 2A receptor antagonist, is the most widely used psychoactive substance in the world. Evidence demonstrates that caffeine and
selective adenosine A 2A antagonists interact with the neuronal systems involved in drug reinforcement, locomotor sensitization, and therapeutic effect
in Parkinson's disease (PD). Evidence also indicates that low doses of caffeine and a selective adenosine A 2A antagonist SCH58261 elicit locomotor stimulation whereas high doses of these drugs exert locomotor inhibition. Since these
behavioral and therapeutic effects are mediated by the mesolimbic and nigrostriatal dopaminergic pathways which project to
the striatum, we hypothesize that low doses of caffeine and SCH58261 may modulate the functions of dopaminergic neurons in
the striatum. 相似文献
18.
A series of 2-phenylethynyladenosine (PEAdo) derivatives substituted in the N 6- and 4′-position was synthesised and the new derivatives were tested at the four human adenosine receptors stably transfected into Chinese hamster ovary (CHO) cells, using radioligand binding studies (A 1, A 2A, A 3) or adenylyl cyclase activity assay (A 2B). Binding studies showed that the presence of a phenyl ethynyl group in the 2 position of adenosine favoured the interaction with A 3 receptors, resulting in compounds endowed with high affinity and selectivity for the A 3 subtype. Additional substitution of the N 6- and 4′-position increases both A 3 affinity and selectivity. The results showed that the new compounds have a good affinity for the A 3 receptor and in particular, the N 6-methoxy-2-phenylethynyl-5′-N-methylcarboxamidoadenosine, with a K i at A 3 of 1.9 nM and a selectivity A 1/A 3 and A 2A/A 3 of 4,800- and 8,600-fold, respectively. Therefore, it is one of the most potent and selective agonists at the human A 3 adenosine receptor subtype reported so far. Furthermore, functional assays of inhibition of 10 μM forskolin-stimulated cAMP production via the adenosine A 3 receptor revealed that the new trisubstituted adenosine derivatives behave as full agonist of this receptor subtype. Docking analysis of these compounds was performed at a homology model of the human A 3 receptor based on the bovine rhodopsin crystal structure as template, and the results are in accordance with the biological data.An erratum to this article can be found at 相似文献
19.
Adenosine receptor activation has been shown to be associated with diminution of cardiac hypertrophy and it has been suggested that endogenously produced adenosine may serve to blunt pro-hypertrophic processes. In the present study, we determined the effects of two pro-hypertrophic stimuli, angiotensin II (Ang II, 100 nM) and endothelin-1 (ET-1, 10 nM) on Ras homolog gene family, member A (RhoA)/Rho-associated, coiled-coil containing protein kinase (ROCK) activation in cultured neonatal rat ventricular myocytes and whether the latter serves as a target for the anti-hypertrophic effect of adenosine receptor activation. Both hypertrophic stimuli potently increased RhoA activity with peak activation occurring 15–30 min following agonist addition. These effects were associated with significantly increased phosphorylation (inactivation) of cofilin, a downstream mediator of RhoA, an increase in actin polymerization, and increased activation and nuclear import of p38 mitogen activated protein kinase. The ability of both Ang II and ET-1 to activate the RhoA pathway was completely prevented by the adenosine A 1 receptor agonist N 6-cyclopentyladenosine, the A 2a receptor agonist 2- p-(2-carboxyethyl)-phenethylamino-5′- N-ethylcarboxamidoadenosine, the A 3 receptor agonist N 6-(3-iodobenzyl)adenosine-5′-methyluronamide as well as the nonspecific adenosine analog 2-chloro adenosine. All effects of specific receptor agonists were prevented by their respective receptor antagonists. Moreover, all adenosine agonists prevented either Ang II- or ET-1-induced hypertrophy, a property shared by the RhoA inhibitor Clostridium botulinum C3 exoenzyme, the ROCK inhibitor Y-27632 or the actin depolymerizing agent latrunculin B. Our study therefore demonstrates that both Ang II and ET-1 can activate the RhoA pathway and that prevention of the hypertrophic response to both agonists by adenosine receptor activation is mediated by prevention of RhoA stimulation and actin polymerization. 相似文献
20.
腺苷作为神经调质,调节多种神经生物学功能.随觉醒时间延长,动物脑内腺苷水平逐渐增高,在睡眠期显著降低.因此,腺苷被认为是调节睡眠的内稳态因子之一.腺苷受体(receptor,R)有A1R、A2AR、A2BR和A3R四种亚型,其中A1R和A2AR与诱导睡眠相关.激活A1R可抑制促觉醒神经元诱导睡眠,也可抑制促眠神经元导致... 相似文献
|