共查询到20条相似文献,搜索用时 15 毫秒
1.
Neonatal brain hypoxic ischemia (HI) often results in long-term motor and cognitive impairments. Post-ischemic inflammation greatly effects outcome and adenosine receptor signaling modulates both HI and immune cell function. Here, we investigated the influence of adenosine A 1 receptor deficiency (A 1R ?/?) on key immune cell populations in a neonatal brain HI model. Ten-day-old mice were subjected to HI. Functional outcome was assessed by open locomotion and beam walking test and infarction size evaluated. Flow cytometry was performed on brain-infiltrating cells, and semi-automated analysis of flow cytometric data was applied. A 1R ?/? mice displayed larger infarctions (+33 %, p?<?0.05) and performed worse in beam walking tests (44 % more mistakes, p?<?0.05) than wild-type (WT) mice. Myeloid cell activation after injury was enhanced in A 1R ?/? versus WT brains. Activated B lymphocytes expressing IL-10 infiltrated the brain after HI in WT, but were less activated and did not increase in relative frequency in A 1R ?/?. Also, A 1R ?/? B lymphocytes expressed less IL-10 than their WT counterparts, the A 1R antagonist DPCPX decreased IL-10 expression whereas the A 1R agonist CPA increased it. CD4 + T lymphocytes including FoxP3 + T regulatory cells, were unaffected by genotype, whereas CD8 + T lymphocyte responses were smaller in A 1R ?/? mice. Using PCA to characterize the immune profile, we could discriminate the A 1R ?/? and WT genotypes as well as sham operated from HI-subjected animals. We conclude that A 1R signaling modulates IL-10 expression by immune cells, influences the activation of these cells in vivo, and affects outcome after HI. 相似文献
2.
Brain-derived neurotrophic factor (BDNF) and adenosine are widely recognized as neuromodulators of glutamatergic transmission in the adult brain. Most BDNF actions upon excitatory plasticity phenomena are under control of adenosine A 2A receptors (A 2ARs). Concerning gamma-aminobutyric acid (GABA)-mediated transmission, the available information refers to the control of GABA transporters. We now focused on the influence of BDNF and the interplay with adenosine on phasic GABAergic transmission. To assess this, we evaluated evoked and spontaneous synaptic currents recorded from CA1 pyramidal cells in acute hippocampal slices from adult rat brains (6 to 10 weeks old). BDNF (10–100 ng/mL) increased miniature inhibitory postsynaptic current (mIPSC) frequency, but not amplitude, as well as increased the amplitude of inhibitory postsynaptic currents (IPSCs) evoked by afferent stimulation. The facilitatory action of BDNF upon GABAergic transmission was lost in the presence of a Trk inhibitor (K252a, 200 nM), but not upon p75 NTR blockade (anti-p75 NTR IgG, 50 μg/mL). Moreover, the facilitatory action of BDNF onto GABAergic transmission was also prevented upon A 2AR antagonism (SCH 58261, 50 nM). We conclude that BDNF facilitates GABAergic signaling at the adult hippocampus via a presynaptic mechanism that depends on TrkB and adenosine A 2AR activation. 相似文献
3.
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
4.
Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named
A 1, A 2A, A 2B and A 3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A 2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding
of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A 2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective
agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview
of the recent advancements in identifying potent and selective A 2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine
ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N
6-, C 2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions.
Compounds 1-deoxy-1-{6-[ N′-(furan-2-carbonyl)-hydrazino]-9 H-purin-9-yl}-N-ethyl- β-D-ribofuranuronamide ( 19, hA 1
K
i = 1050 nM, hA 2A
K
i = 1550 nM, hA 2B EC 50 = 82 nM, hA 3
K
i > 5 μM) and its 2-chloro analogue 23 (hA 1
K
i = 3500 nM, hA 2A
K
i = 4950 nM, hA 2B EC 50 = 210 nM, hA 3
K
i > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay
in Chinese hamster ovary (CHO) cells expressing hA 2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide
( BAY-60–6583, hA 1, hA 2A, hA 3 EC 50 > 10 μM; hA 2B EC 50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis. 相似文献
5.
Subchronic treatment with MAP (4.6 mg/kg, i.p., once daily for 11 days) significantly decreased the K d, but not B max, values of [ 3H]1,3-dipropyl-8-cyclopentylxanthine ([ 3H]DPCPX) binding to adenosine A 1 receptors in the prefrontal cortex and hippocampus, but not striatum, of rat brain. However, subchronic treatment with PCP (10 mg/kg, i.p., once daily for 11 days) did not alter the K d and B max values of [ 3H]DPCPX binding to adenosine A 1 receptors in these three regions. Subchronic treatment with MAP or PCP did not alter the B max and K d values of [ 3H]2-p-(2-carboxyehyl)phenethylamino-5-N-ethylcarboxyamidoadenosine ([ 3H]CGS21680) binding to adenosine A 2A receptors in the striatum. Furthermore, subchronic treatment with MAP or PCP significantly decreased the specific binding of [ 3H]CGS21680 to adenosine A 2A receptors in the hippocampus, but not in the prefrontal cortex. Thus, these results suggest that MAP and PCP may produce differential effects on the adenosine A 2A receptors, but not adenosine A 1 receptors in rat brain. 相似文献
6.
In situations of hypoxia, glutamate excitotoxicity induces neuronal death. The release of extracellular adenosine is also triggered and is accompanied by an increase of the stress mediator, corticotrophin‐releasing factor (CRF). Adenosine A 2A receptors contribute to glutamate excitoxicity and their blockade is effective in stress‐induced neuronal deficits, but the involvement of CRF on this effect was never explored. We now evaluated the interaction between A 2A and CRF receptors (CRFR) function, upon glutamate insult. Primary rat cortical neuronal cultures (9 days in vitro) expressing both CRF 1R and CRF 2R were challenged with glutamate (20–1000 μM, 24 h). CRF 1R was found to co‐localize with neuronal markers and CRF 2R to be present in both neuronal and glial cells. The effects of the CRF and A 2A receptors ligands on cell viability were measured using propidium iodide and Syto‐13 fluorescence staining. Glutamate decreased cell viability in a concentration‐dependent manner. Urocortin (10 pM), an agonist of CRF receptors, increased cell survival in the presence of glutamate. This neuroprotective effect was abolished by blocking either CRF 1R or CRF 2R with antalarmin (10 nM) or anti‐Sauvagine‐30 (10 nM), respectively. The blockade of A 2A receptors with a selective antagonist SCH 58261 (50 nM) improved cell viability against the glutamate insult. This effect was dependent on CRF 2R, but not on CRF 1R activation. Overall, these data show a protective role of CRF in cortical neurons, against glutamate‐induced death. The neuroprotection achieved by A 2A receptors blockade requires CRF 2R activation. This interaction between the adenosine and CRF receptors can explain the beneficial effects of using A 2A receptor antagonists against stress‐induced noxious effects. 相似文献
7.
Effects of hyperthermia-induced seizures (HS) on GABA A and benzodiazepine (BDZ) receptor binding in immature rat brain were evaluated using in vitro autoradiography. HS were induced
in 10-days-old rats by a regulated stream of moderately heated air directed 50 cm above the animals. Rats were killed 30 min,
24 h or 20 days after HS and their brains were used for in vitro autoradiography experiments to determine GABA A and BDZ receptor binding. GABA A binding was significantly enhanced in all brain areas evaluated 30 min after HS, an effect that endures 24 h and 20 days
after seizures. Concerning BDZ receptor binding, a significant increase was detected in entorhinal and perirhinal cortices
and decreased in basolateral amygdala 30 min following HS. One day after HS, animals demonstrated enhanced BDZ binding in
the cingulate, frontal, posterior parietal, entorhinal, temporal and perirhinal cortices; striatum, accumbens, substantia
nigra pars compacta and amygdala nuclei. Twenty days after HS enhanced BDZ binding was restricted in the cingulated, frontal,
anterior and posterior parietal cortices, as well as in substantia nigra pars reticulata, whereas decreased values were found
in accumbens nucleus and substantia nigra pars compacta. Our data indicate differential effects of HS in GABA A and BDZ binding in immature brain. HS-induced GABA A and BDZ changes are different from those previously described in experimental models of temporal lobe epilepsy in adult animals. 相似文献
8.
The structure of the human A 2A adenosine receptor has been elucidated by X-ray crystallography with a high affinity non-xanthine antagonist, ZM241385, bound to it. This template molecule served as a starting point for the incorporation of reactive moieties that cause the ligand to covalently bind to the receptor. In particular, we incorporated a fluorosulfonyl moiety onto ZM241385, which yielded LUF7445 (4-((3-((7-amino-2-(furan-2-yl)-[ 1, 2, 4]triazolo[1,5- a][ 1, 3, 5]triazin-5-yl)amino)propyl)carbamoyl)benzene sulfonyl fluoride). In a radioligand binding assay, LUF7445 acted as a potent antagonist, with an apparent affinity for the hA 2A receptor in the nanomolar range. Its apparent affinity increased with longer incubation time, suggesting an increasing level of covalent binding over time. An in silico A 2A-structure-based docking model was used to study the binding mode of LUF7445. This led us to perform site-directed mutagenesis of the A 2A receptor to probe and validate the target lysine amino acid K153 for covalent binding. Meanwhile, a functional assay combined with wash-out experiments was set up to investigate the efficacy of covalent binding of LUF7445. All these experiments led us to conclude LUF7445 is a valuable molecular tool for further investigating covalent interactions at this receptor. It may also serve as a prototype for a therapeutic approach in which a covalent antagonist may be needed to counteract prolonged and persistent presence of the endogenous ligand adenosine. 相似文献
9.
Angiotensin II (Ang II) plays an important role on the pathogenesis of cardiac fibrosis. Prolong and overstimulation of angiotensin II type 1 receptor with Ang II-induced collagen synthesis and myofibroblast differentiation in cardiac fibroblasts, leading to cardiac fibrosis. Although adenosine and its analogues are known to have cardioprotective effects, the mechanistic by which adenosine A 2 receptors (A 2Rs) inhibit Ang II-induced cardiac fibrosis is not clearly understood. In the present study, we examined the effects of exogenous adenosine and endogenous adenosine on Ang II-induced collagen and myofibroblast differentiation determined by α-smooth muscle action (α-SMA) overexpression and their underlying signal transduction. Elevation of endogenous adenosine levels resulted in the inhibition of Ang II-induced collagen type I and III and α-SMA synthesis in cardiac fibroblasts. Moreover, treatment with exogenous adenosine which selectively stimulated A 2Rs also suppressed Ang II-induced collagen synthesis and α-SMA production. These antifibrotic effects of both endogenous and exogenous adenosines are mediated through the A 2B receptor (A 2BR) subtype. Stimulation of A 2BR exhibited antifibrotic effects via the cAMP-dependent and Epac-dependent pathways. Our results provide new mechanistic insights regarding the role for cAMP and Epac on A 2BR-mediated antifibrotic effects. Thus, A 2BR is one of the potential therapeutic targets against cardiac fibrosis. 相似文献
10.
Summary Effects of hyperthermia-induced seizures (HS) on GABA A and benzodiazepine (BDZ) receptor binding in immature rat brain were evaluated using in vitro autoradiography. HS were induced in 10-day-old rats by a regulated stream of moderately heated air directed 50 cm above the
animals. Rats were killed 30 min, 24 h, or 20 days after HS and their brains were used for in vitro autoradiography experiments to determine GABA A and BDZ receptor binding. GABA A binding was significantly enhanced in all brain areas evaluated 30 min after HS, an effect that endures 24 h and 20 days
after seizures. Concerning BDZ receptor binding, a significant increase was detected in entorhinal and perirhinal cortices
and decreased in basolateral amygdala 30 min following HS. One day after HS, animals demonstrated enhanced BDZ binding in
the cingulate, frontal, posterior parietal, entorhinal, temporal, and perirhinal cortices; striatum, accumbens, substantia
nigra pars compacta, and amygdala nuclei. Twenty days after HS enhanced BDZ binding was restricted in the cingulated, frontal,
anterior and posterior parietal cortices, as well as in substantia nigra pars reticulata, whereas decreased values were found
in accumbens nucleus and substantia nigra pars compacta. Our data indicate differential effects of HS in GABA A and BDZ binding in immature brain. HS-induced GABA A and BDZ changes are different from those previously described in experimental models of temporal lobe epilepsy in adult animals. 相似文献
11.
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
12.
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, enhances synaptic transmission and regulates
neuronal proliferation and survival. Functional interactions between adenosine A 2A receptors (A 2ARs) and BDNF have been recently reported. In this article, we report some recent findings from our group showing that A 2ARs regulate both BDNF functions and levels in the brain. Whereas BDNF (10 ng/ml) increased the slope of excitatory postsynaptic
field potentials (fEPSPs) in hippocampal slices from wild-type (WT) mice, it was completely ineffective in slices taken from
A 2AR knock-out (KO) mice. Furthermore, enzyme immunoassay studies showed a significant reduction in hippocampal BDNF levels in
A 2AR KO vs. WT mice. Having found an even marked reduction in the striatum of A 2AR KO mice, and as both BDNF and A 2ARs have been implicated in the pathogenesis of Huntington’s disease (HD), an inherited striatal neurodegenerative disease,
we then evaluated whether the pharmacological blockade of A 2ARs could influence striatal levels of BDNF in an experimental model of HD-like striatal degeneration (quinolinic acid-lesioned
rats) and in a transgenic mice model of HD (R6/2 mice). In both QA-lesioned rats and early symptomatic R6/2 mice (8 weeks),
the systemic administration of the A 2AR antagonist SCH58261 significantly reduced striatal BDNF levels. These results indicate that the presence and the tonic activation
of A 2ARs are necessary to allow BDNF-induced potentiation of synaptic transmission and to sustain a normal BDNF tone. The possible
functional consequences of reducing striatal BDNF levels in HD models need further investigation. 相似文献
13.
The aim of the present paper was to examine, in a comparative way, the occurrence and the mechanisms of the interactions between adenosine A 2A receptors (A 2ARs) and metabotropic glutamate 5 receptors (mGlu5Rs) in the hippocampus and the striatum. In rat hippocampal and corticostriatal slices, combined ineffective doses of the mGlu5R agonist 2-chloro-5-hydroxyphenylglycine (CHPG) and the A 2AR agonist CGS 21680 synergistically reduced the slope of excitatory postsynaptic field potentials (fEPSPs) recorded in CA1 and the amplitude of field potentials (FPs) recorded in the dorsomedial striatum. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway appeared to be involved in the effects of CGS 21680 in corticostriatal but not in hippocampal slices. In both areas, a postsynaptic locus of interaction appeared more likely. N-methyl- D-aspartate (NMDA) reduced the fEPSP slope and FP amplitude in hippocampal and corticostriatal slices, respectively. Such an effect was significantly potentiated by CHPG in both areas. Interestingly, the A 2AR antagonist ZM 241385 significantly reduced the NMDA-potentiating effect of CHPG. In primary cultures of rat hippocampal and striatal neurons (ED 17, DIV 14), CHPG significantly potentiated NMDA-induced lactate dehydrogenase (LDH) release. Again, such an effect was prevented by ZM 241385. Our results show that A 2A and mGlu5 receptors functionally interact both in the hippocampus and in the striatum, even though different mechanisms seem to be involved in the two areas. The ability of A 2ARs to control mGlu5R-dependent effects may thus be a general feature of A 2ARs in different brain regions (irrespective of their density) and may represent an additional target for the development of therapeutic strategies against neurological disorders. 相似文献
14.
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
15.
Mast cell degranulation triggers hypersensitivity reactions at the body–environment interface. Adenosine modulates degranulation, but enhancement and inhibition have both been reported. Which of four adenosine receptors (ARs) mediate modulation, and how, remains uncertain. Also uncertain is whether adenosine reaches mast cell ARs by autocrine ATP release and ecto-enzymatic conversion. Uncertainties partly reflect species and cell heterogeneity, circumvented here by focusing on homogeneous human LAD2 cells. Quantitative PCR detected expression of A 2A, A 2B, and A 3, but not A 1, ARs. Nonselective activation of ARs with increasing NECA monotonically enhanced immunologically or C3a-stimulated degranulation. NECA alone stimulated degranulation slightly. Selective AR antagonists did not affect C3a-stimulated degranulation. NECA''s enhancement of C3a-triggered degranulation was partially inhibited by separate application of each selective antagonist, and abolished by simultaneous addition of antagonists to the three ARs. Only the A 2A antagonist separately inhibited NECA''s enhancement of immunologically stimulated degranulation, which was abolished by simultaneous addition of the three selective antagonists. Immunological or C3a activation did not stimulate ATP release. NECA also enhanced immunologically triggered degranulation of mouse bone marrow derived mast cells (BMMCs), which was partially reduced only by simultaneous addition of the three antagonists or by the nonselective antagonist {"type":"entrez-protein","attrs":{"text":"CGS15943","term_id":"875345334"}}CGS15943. BMMCs also expressed A 2A, A 2B, and A 3 ARs. but not A 1AR detectably. We conclude that (a) A 1AR is unnecessary for LAD2 degranulation or AR enhancement; (b) A 2A, A 2B, and A 3 ARs all contribute to pharmacologic AR enhancement of LAD2 and BMMC degranulation; and (c) LAD2 cells depend on microenvironmental adenosine to trigger AR modulation. 相似文献
16.
Adenosine can show anti-inflammatory as well as pro-inflammatory activities. The contribution of the specific adenosine receptor
subtypes in various cells, tissues and organs is complex. In this study, we examined the effect of the adenosine A 2A receptor agonist CGS 21680 and the A 2BR antagonist PSB-1115 on acute inflammation induced experimentally by 2,4,6-trinitrobenzenesulfonic acid (TNBS) on rat ileum/jejunum
preparations. Pre-incubation of the ileum/jejunum segments with TNBS for 30 min resulted in a concentration-dependent inhibition
of acetylcholine (ACh)-induced contractions. Pharmacological activation of the A 2AR with CGS 21680 (0.1–10 μM) pre-incubated simultaneously with TNBS (10 mM) prevented concentration-dependently the TNBS-induced
inhibition of the ACh contractions. Stimulation of A 2BR with the selective agonist BAY 60-6583 (10 μM) did neither result in an increase nor in a further decrease of ACh-induced
contractions compared to the TNBS-induced inhibition. The simultaneous pre-incubation of the ileum/jejunum segments with TNBS
(10 mM) and the selective A 2BR antagonist PSB-1115 (100 μM) inhibited the contraction-decreasing effect of TNBS. The effects of the A 2AR agonist and the A 2BR antagonist were in the same range as the effect induced by 1 μM methotrexate. The combination of the A 2AR agonist CGS 21680 and the A 2BR antagonist PSB-1115 at subthreshold concentrations of both agents found a significant amelioration of the TNBS-diminished
contractility. Our results demonstrate that the activation of A 2A receptors or the blockade of the A 2B receptors can prevent the inflammation-induced disturbance of the ACh-induced contraction in TNBS pre-treated small intestinal
preparations. The combination of both may be useful for the treatment of inflammatory bowel diseases. 相似文献
17.
Sepsis is a generalized infection accompanied by response of the body that manifests in a clinical and laboratory syndrome, namely, in the systemic inflammatory response syndrome (SIRS) from the organism to the infection. Although sepsis is a widespread and life-threatening disease, the assortment of drugs for its treatment is mostly limited by antibiotics. Therefore, the search for new cellular targets for drug therapy of sepsis is an urgent task of modern medicine and pharmacology. One of the most promising targets is the adenosine A 2A receptor (A 2AAR). The activation of this receptor, which is mediated by extracellular adenosine, manifests in almost all types of immune cells (lymphocytes, monocytes, macrophages, and dendritic cells) and results in reducing the severity of inflammation and reperfusion injury in various tissues. The activation of adenosine A 2A receptor inhibits the proliferation of T cells and production of proinflammatory cytokines, which contributes to the activation of the synthesis of anti-inflammatory cytokines, thereby suppressing the systemic response. For this reason, various selective A 2AAR agonists and antagonists may be considered to be drug candidates for sepsis pharmacotherapy. Nevertheless, they remain only efficient ligands and objects of pre-clinical and clinical trials. This review examines the molecular mechanisms of inflammatory response in sepsis and the structure and functions of A 2AAR and its role in the pathogenesis of sepsis, as well as examples of using agonists and antagonists of this receptor for the treatment of SIRS and sepsis. 相似文献
18.
We studied expression of the 5-HT 1A receptor in cortical and limbic areas of the brain of the tree shrew. In situ hybridization with a receptor-specific probe and immunocytochemistry with various antibodies was used to identify distinct neurons expressing the receptor. In vitro receptor autoradiography with 3H-8-OH-DPAT ( 3H-8-hydroxy-2-[di-n-propylamino]tetralin) was performed to visualize receptor-binding sites. In the prefrontal, insular, and occipital cortex, 5-HT 1A receptor mRNA was expressed in pyramidal neurons of layer 2, whereas 3H-8-OH-DPAT labeled layers 1 and 2 generating a columnar-like pattern in the prefrontal and occipital cortex. In the striate and ventral occipital cortex, receptor mRNA was present within layers 5 and 6 in pyramidal neurons and Meynert cells. Pyramid-like neurons in the claustrum and anterior olfactory nucleus also expressed the receptor. Principal neurons in hippocampal region CA1 expressed 5-HT 1A receptor mRNA, and 3H-8-OH-DPAT labeled both the stratum oriens and stratum radiatum. CA3 pyramidal neurons displayed low 5-HT 1A receptor expression, whereas granule neurons in the dentate gyrus revealed moderate expression of this receptor. In the amygdala, large pyramid-like neurons in the basal magnocellular nucleus strongly expressed the receptor. Immunocytochemistry with antibodies against parvalbumin, calbindin, and gamma aminobutyric acid (GABA) provided no evidence for 5-HT 1A receptor expression in GABAergic neurons in cortical and limbic brain areas. Our data agree with previous findings showing that the 5-HT 1A receptor mediates the modulation of glutamatergic neurons. Expression in the limbic and cortical areas suggested an involvement of 5-HT 1A receptors in emotional and cognitive processes.This work was supported by the German Science Foundation (SFB 406; C4 to G.F.). 相似文献
19.
Adenosine has been found to be cardioprotective during episodes of cardiac ischemia/reperfusion through activation of the A 1 and possibly A 3 receptors. Therefore, we have investigated whether activation of these receptors can protect also against apoptotic death induced by angiotensin II (Ang II) in neonatal rat cardiomyocyte cultures. Exposure to Ang II (10 nM) resulted in a 3-fold increase in programmed cell death (p < 0.05). Pretreatment with the A 1 adenosine receptor agonist 2-chloro-N 6-cyclopentyladenosine (CCPA, 1 M), abolished the effects of Ang II on programmed cardiomyocyte death. Moreover, exposure of cells to the A 1 adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX) before pretreatment with CCPA, prevented the protective effect of the latter. Pretreatment with the A 3 adenosine receptor agonist N 6-(3-iodobenzyl) adenosine-5-N-methyluronamide (IB-MECA, 0.1 M), led to a partial decrease in apoptotic rate induced by Ang II. Exposure of myocytes to Ang II caused an immediate increase in the concentration of intracellular free Ca 2+ that lasted 40–60 sec. Pre-treatment of cells with CCPA or IB-MECA did not block Ang II-induced Ca 2+ elevation. In conclusion, activation of adenosine A 1 receptors can protect the cardiac cells from apoptosis induced by Ang II, while activation of the adenosine A 3 receptors confers partial cardioprotection. 相似文献
20.
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
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