Showing papers on "Receptor antagonist published in 1998"
TL;DR: The use of neutralizing anti-IL-1Ra antibodies has demonstrated that endogenous IL-1 Ra is an important natural antiinflammatory protein in arthritis, colitis, and granulomatous pulmonary disease and in patients with rheumatoid arthritis treated with IL- 1Ra for six months exhibited improvements in clinical parameters and in radiographic evidence of joint damage.
Abstract: ▪ Abstract The interleukin-1 receptor antagonist (IL-1Ra) is a member of the IL-1 family that binds to IL-1 receptors but does not induce any intracellular response. Two structural variants of IL-1Ra have previously been described: a 17-kDa form that is secreted from monocytes, macrophages, neutrophils, and other cells (sIL-1Ra) and an 18-kDa form that remains in the cytoplasm of keratinocytes and other epithelial cells, monocytes, and fibroblasts (icIL-1Ra). An additional 16-kDa intracellular isoform of IL-1Ra has recently been described in neutrophils, monocytes, and hepatic cells. Both of the major isoforms of IL-1Ra are transcribed from the same gene through the use of alternative first exons. The two promoters regulating transcription of the secreted and intracellular forms have been cloned, and some of the functional cis-acting DNA regions have been characterized. The production of IL-1Ra is stimulated by many substances including adherent IgG, other cytokines, and bacterial or viral components. The...
1,041 citations
TL;DR: There is growing evidence that the production and activity of IL-1, particularly IL- 1 beta, are tightly regulated events as if nature has placed specific "road blocks" to reduce the response toIL-1 during disease.
Abstract: IL-1 (IL-1 alpha or IL-1 beta) is the prototypic "multifunctional" cytokine. Unlike the lymphocyte and colony stimulating growth factors, IL-1 affects nearly every cell type, and often in concert with other cytokines or small mediator molecules. Although some lymphocyte and colony stimulating growth factors may be therapeutically useful, IL-1 is a highly inflammatory cytokine and the margin between clinical benefit and unacceptable toxicity in humans is exceedingly narrow. In contrast, agents that reduce the production and/or activity of IL-1 are likely to have an impact on clinical medicine. In support of this concept, there is growing evidence that the production and activity of IL-1, particularly IL-1 beta, are tightly regulated events as if nature has placed specific "road blocks" to reduce the response to IL-1 during disease. In addition to controlling gene expression, synthesis and secretion, this regulation extends to surface receptors, soluble receptors and a receptor antagonist. Investigators have studied how production of the different members of the IL-1 family is controlled, the various biological activities of IL-1, the distinct and various functions of the IL-1 receptor (IL-1R) family and the complexity of intracellular signaling. Mice deficient in IL-1 beta, IL-1 beta converting enzyme (ICE) and IL-1R type I have also been studied. Humans have been injected with IL-1 (either IL-1 alpha or IL-1 beta) for enhancing bone marrow recovery and for cancer treatment. The IL-1 specific receptor antagonist (IL-1Ra) has also been tested in clinical trials.
788 citations
TL;DR: It is suggested that changes in the production of the pro-inflammatory cytokines, TNF-alpha, IL-6 and IFN-gamma, and negative immunoregulatory cytokine,IL-10 and IL-4, take part in the homeostatic responses to psychological stress and that stress-induced anxiety is related to a T-helper-1-like response.
716 citations
TL;DR: It is concluded that trimers represent an essential element of P2X receptor structure and can aggregate to form larger complexes.
Abstract: P2X receptors are cation channels gated by extracellular ATP The seven known P2X isoforms possess no sequence homology with other proteins Here we studied the quaternary structure of P2X receptors by chemical cross-linking and blue native PAGE P2X1 and P2X3 were N-terminally tagged with six histidine residues to allow for non-denaturing receptor isolation from cRNA-injected, [35S]methionine-labeled oocytes The His-tag did not change the electrophysiological properties of the P2X1 receptor His-P2X1 was found to carry four N-glycans per polypeptide chain, only one of which acquired Endo H resistance en route to the plasma membrane 3, 3'-Dithiobis(sulfosuccinimidylpropionate) (DTSSP) and two of three bifunctional analogues of the P2X receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) cross-linked digitonin-solubilized His-P2X1 and His-P2X3 quantitatively to homo-trimers Likewise, when analyzed by blue native PAGE, P2X receptors purified in digitonin or dodecyl-beta-D-maltoside migrated entirely as non-covalently linked homo-trimers, whereas the alpha2 beta gamma delta nicotinic acetylcholine receptor (used as a positive control) migrated as the expected pentamer P2X monomers remained undetected soon after synthesis, indicating that trimerization occurred in the endoplasmic reticulum The plasma membrane form of His-P2X1 was also identified as a homo-trimer If n-octylglucoside was used for P2X receptor solubilization, homo-hexamers were observed, suggesting that trimers can aggregate to form larger complexes We conclude that trimers represent an essential element of P2X receptor structure Keywords: blue native PAGE/cross-linking/P2X receptor/quaternary structure
552 citations
TL;DR: It is shown for the first time that the production of biologically significant amounts of IL-1β in the brain can be induced by a sustained increase in the activity of a discrete population of neurons and a physiological involvement of this cytokine in synaptic plasticity is suggested.
Abstract: It is widely accepted that interleukin-1β (IL-1β), a cytokine produced not only by immune cells but also by glial cells and certain neurons influences brain functions during infectious and inflammatory processes. It is still unclear, however, whether IL-1 production is triggered under nonpathological conditions during activation of a discrete neuronal population and whether this production has functional implications. Here, we show in vivo and in vitro that IL-1β gene expression is substantially increased during long-term potentiation of synaptic transmission, a process considered to underlie certain forms of learning and memory. The increase in gene expression was long lasting, specific to potentiation, and could be prevented by blockade of potentiation with the N-methyl-d-aspartate (NMDA) receptor antagonist, (±)-2-amino-5-phosphonopentanoic acid (AP-5). Furthermore, blockade of IL-1 receptors by the specific interleukin-1 receptor antagonist (IL-1ra) resulted in a reversible impairment of long-term potentiation maintenance without affecting its induction. These results show for the first time that the production of biologically significant amounts of IL-1β in the brain can be induced by a sustained increase in the activity of a discrete population of neurons and suggest a physiological involvement of this cytokine in synaptic plasticity.
469 citations
TL;DR: Selective ET(A) receptor antagonism causes vasodilatation of human forearm resistance vessels in vivo, which appears to result in major part from an increase in nitric oxide generation.
Abstract: Background —The role of endothelin (ET)-1 in maintenance of basal vascular tone has been demonstrated by local and systemic vasodilatation to endothelin receptor antagonists in humans. Although the constrictor effects mediated by the vascular smooth muscle ET A receptors are clear, the contribution from endothelial and vascular smooth muscle ET B receptors remains to be defined. The present study, in human forearm resistance vessels in vivo, was designed to further investigate the physiological function of ET A and ET B receptor subtypes in human blood vessels and determine the mechanism underlying the vasodilatation to the ET A -selective receptor antagonist BQ-123. Methods and Results —Two studies were performed, each in groups of eight healthy subjects. Brachial artery infusion of BQ-123 caused significant forearm vasodilatation in both studies. This vasodilatation was reduced by 95% ( P =.006) with inhibition of the endogenous generation of nitric oxide and by 38% ( P B receptor antagonist BQ-788. In contrast, inhibition of prostanoid generation did not affect the response to BQ-123. Infusion of BQ-788 alone produced a 20% reduction in forearm blood flow ( P Conclusions —Selective ET A receptor antagonism causes vasodilatation of human forearm resistance vessels in vivo. This response appears to result in major part from an increase in nitric oxide generation. ET B receptor antagonism either alone or on a background of ET A antagonism causes local vasoconstriction, indicating that ET B receptors in blood vessels respond to ET-1 predominantly by causing vasodilatation.
466 citations
TL;DR: Data indicate that such antidepressant treatments, acting on entirely different primary targets, might alleviate depression by enhancing the tonic activation of forebrain postsynaptic 5-HT1Areceptors.
Abstract: We report here the first direct functional evidence of an increase in the tonic activation of postsynaptic 5-HT1A receptors by antidepressant treatments. Because 5-HT1A receptor activation hyperpolarizes and inhibits CA3 pyramidal neurons in the dorsal hippocampus, we determined, using in vivo extracellular recording, whether the selective 5-HT1A receptor antagonist WAY 100635 could disinhibit these neurons. Unexpectedly, no disinhibition could be detected in controls. However, after long-term treatment with the tricyclic antidepressant imipramine, the selective 5-HT reuptake inhibitor paroxetine, the reversible monoamine oxidase-A inhibitor befloxatone, the alpha2-adrenergic antagonist mirtazapine, or the 5-HT1A receptor agonist gepirone or multiple electroconvulsive shock (ECS) administration, WAY 100635 markedly increased (60-200%) the firing activity of CA3 pyramidal neurons. Such a disinhibition was absent in rats treated with the nonantidepressant drug chlorpromazine, in rats receiving only one ECS, or in rats receiving multiple ECSs in combination with an intrahippocampal pertussis toxin treatment to inactivate Gi/o-coupled 5-HT1A receptors. These data indicate that such antidepressant treatments, acting on entirely different primary targets, might alleviate depression by enhancing the tonic activation of forebrain postsynaptic 5-HT1A receptors.
352 citations
Journal Article•
TL;DR: The results suggest that 5-HT2C receptor agonism is associated with therapeutic potential in obsessive compulsive disorder and depression.
Abstract: In vitro, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 and (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1, 2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 exhibited high-affinity binding to the serotonin2C (5HT2C) receptors and stimulated turnover of inositol 1,4,5-triphosphate. Affinity to several of the other 5-HT receptor subtypes and to numerous nonserotonergic receptors was much lower. In rats, both compounds elicited behavioral signs of 5-HT2C receptor agonism but not 5-HT2A receptor agonism. Hypomotility induced in rats by high doses of these compounds was reversed by the 5-HT2C receptor antagonist N-(2-naphthyl)-N'-(3-pyridyl)-urea 1:1 HCI. In addition, these compounds were active in tests used to demonstrate anticompulsive effects: reducing schedule-induced polydipsia in rats (prevented by the 5-HT2C/2B receptor antagonist N-(1-methyl-5'-indolyl)-(3-pyridyl)urea 1:1 HCl, reversing increased scratching induced with 8-hydroxy-dipropylaminotetralin 1:1 HCl in squirrel monkeys (no tolerance developed), decreasing responding in the marble-burying task in mice, and decreasing excessive eating of palatable food in rats. In contrast to these compounds, fluoxetine was much less potent, and in some tasks less efficacious, in reducing excessive behavior in these models. These two 5-HT2C receptor agonists do not show anxiogenic effects in the plus-maze in rats. (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1, 2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 reduced the olfactory bulbectomy-induced passive avoidance impairment in rats, a result that indicates antidepressant potential. Similarly, in the differential-reinforcement-of-low rate 72-s operant schedule task in rats, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 increased (and (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1, 2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 showed a tendency to increase) total reinforcements received, which is suggestive of antidepressant activity. The electroencephalography defined sleep-waking pattern in rats produced by these two 5-HT2C agonists, as well as fluoxetine, included increased quiet-waking and decreased rapid-eye-movement sleep, which is characteristic of antidepressant drugs. These results suggest that 5-HT2C receptor agonism is associated with therapeutic potential in obsessive compulsive disorder and depression.
351 citations
TL;DR: Based upon structure-function studies and a mechanism in which receptor dimerization is critical for signaling, a receptor antagonist in the form of a heterodimer of VEGF that contained one functional and one non-functional site is constructed to establish a functional foundation for the design of V EGF analogs, mimics, and antagonists.
309 citations
TL;DR: The data suggest that 5-HT2C receptors exert a tonic, inhibitory influence upon frontocortical dopaminergic and adrenergic, but not serotonergic, transmission.
299 citations
TL;DR: The results demonstrate that the anti-amnesic effect of sigma 1 receptor agonists may be of therapeutic relevance in pathological states affecting the cholinergic and/or glutamatergic systems, such as in pathological aging.
TL;DR: It is suggested that cannabimimetic drugs may slow the progression of neurodegenerative diseases by providing significant protection from excitotoxicity.
Abstract: Cannabinoid receptor agonists act presynaptically to inhibit the release of glutamate. Because other drugs with this action are known to reduce excitotoxicity, we tested several cannabimimetics in a model of synaptically mediated neuronal death. Reduction of the extracellular Mg2+ concentration to 0.1 mm evoked a repetitive pattern of intracellular Ca2+ concentration ([Ca2+]i) spiking that, when maintained for 24 hr, resulted in significant neuronal death. The [Ca2+]i spiking and cell death in this model result from excessive activation of N -methyl-d-aspartate receptors, as indicated by the inhibition of both [Ca2+]i spiking and neuronal death by the N -methyl-d-aspartate receptor antagonist CGS19755 (10 μm). The cannabimimetic drug Win55212–2 (100 nm) completely blocked [Ca2+]i spiking and prevented neuronal death induced by low extracellular Mg2+ concentrations. These effects on [Ca2+]i spiking and viability were stereoselective and were prevented by the CB1 receptor antagonist SR141716 (100 nm). The partial agonist CP55940 (100 nm) also afforded significant protection from excitotoxicity. Cannabimimetic drugs did not protect cells from the direct application of glutamate (30 μm). These data suggest that cannabimimetic drugs may slow the progression of neurodegenerative diseases.
TL;DR: The purpose of the present study was to test the hypothesis that ischemic preconditioning is mediated through stimulation of one or both δ-opioid receptor subtypes, and to test for a role of μ-OPioid receptors in the heart.
Abstract: Background—Our laboratory has previously shown that δ-opioid receptors are involved in the cardioprotective effect of ischemic preconditioning in the rat heart. However, this class of receptors consists of two subtypes, δ1 and δ2, and μ- or κ-opioid receptors may also exist in the heart. Therefore, the purpose of the present study was to test the hypothesis that ischemic preconditioning is mediated through stimulation of one or both δ-opioid receptor subtypes. Methods and Results—Anesthetized, open chest, male Wistar rats were assigned to 1 of 14 groups. All animals were subjected to 30 minutes of occlusion and 2 hours of reperfusion. Ischemic preconditioning was elicited by three 5-minute occlusion periods interspersed with 5 minutes of reperfusion. Two doses of 7-benzylidenenaltrexone (BNTX; 1 and 3 mg/kg IV), a selective δ1-opioid receptor antagonist, or naltriben (NTB; 1 and 3 mg/kg IV), a selective δ2-opioid receptor antagonist, were given before ischemic preconditioning. To test for a role of μ-opio...
TL;DR: Rat cerebellar tissue slices indicate that glutamate specifically modulates oligodendrocyte but not astrocytes development through selective activation of alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and cell depolarization and blockage of voltage-dependent K+ channels is likely to be the triggering mechanism.
Abstract: We tested the hypothesis that the neurotransmitter glutamate would influence glial proliferation and differentiation in a cytoarchitecturally intact system. Postnatal day 6 cerebellar slices were maintained in organotypic culture and treated with glutamate receptor agonists or antagonists. After dissociation, cells were stained with antibodies for different oligodendrocyte developmentally regulated antigens. Treatment of the slices with the glutamate receptor agonists kainate or alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid significantly decreased the percentage of LB1(+), NG2(+) and O4(+) cells, and their bromodeoxyuridine labeling index. The non-N-methyl-D-aspartate glutamate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione increased the percentage and bromodeoxyuridine labeling of LB1(+), NG2(+) and O4(+) cells. In intact slices, RNA levels of the oligodendrocyte gene for 2′,3′-cyclic nucleotide 3′-phosphodiesterase were decreased by kainate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and increased by 6,7-dinitroquinoxaline-2,3-dione. The percentage of astrocytes was not modified by kainate, alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or 6, 7-dinitroquinoxaline-2,3-dione. Treatment with the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid did not alter the percentage of O4(+) cells, nor their proliferation. Incubation with the gamma-aminobutyric acid receptor antagonist bicuculline did not modify the percentage of LB1(+), A2B5(+) and O4(+) cells. In purified cerebellar oligodendrocyte progenitor cells, glutamate receptor agonists blocked K+ currents, and inhibited cell proliferation and lineage progression. The K+ channel blocker tetraethylammonium also inhibited oligodendrocyte progenitor cell proliferation. These findings indicate that in rat cerebellar tissue slices: (i) glutamate specifically modulates oligodendrocyte but not astrocyte development through selective activation of alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and (ii) cell depolarization and blockage of voltage-dependent K+ channels is likely to be the triggering mechanism.
TL;DR: Results show that activation of CB1 cannabinoid receptors reduces GABAergic inhibitory postsynaptic currents in medium spiny neurons of the corpus striatum: the likely mechanism is presynaptic inhibition of GABA release from terminals of recurrent axons of the medium spini neurons themselves.
TL;DR: The ArrayScanTM technology provides a rapid, sensitive, quantitative technique for measuring early events in the signal transduction of NF-kappaB, indicating that subtle functional responses to complex agonist and antagonist stimuli could be measured.
TL;DR: It is reported that ANG II via its ANG II type 2 (AT2) receptor promotes the axonal elongation of postnatal rat retinal explants and dorsal root ganglia neurons in vitro, and, moreover, axonal regeneration of retinal ganglion cells after optic nerve crush in vivo.
Abstract: The renin-angiotensin system (RAS) has been traditionally linked to blood pressure and volume regulation mediated through the angiotensin II (ANG II) type 1 (AT1) receptor. Here we report that ANG II via its ANG II type 2 (AT2) receptor promotes the axonal elongation of postnatal rat retinal explants (postnatal day 11) and dorsal root ganglia neurons in vitro, and, moreover, axonal regeneration of retinal ganglion cells after optic nerve crush in vivo. In retinal explants, ANG II (10−7–10−5 M) induced neurite elongation via its AT2 receptor, since the effects were mimicked by the AT2 receptor agonist CGP 42112 (10−5 M) and were entirely abolished by costimulation with the AT2 receptor antagonist PD 123177 (10−5 M), but not by the AT1 receptor antagonist losartan (10−5 M). To investigate whether ANG II is able to promote axonal regeneration in vivo, we performed optic nerve crush experiments in the adult rats. After ANG II treatment (0.6 nmol), an increased number of growth-associated protein (GAP)-43–positive fibers was detected and the regenerating fibers regularly crossed the lesion site (1.6 mm). Cotreatment with the AT2 receptor antagonist PD 123177 (6 nmol), but not with the AT1 receptor antagonist losartan (6 nmol), completely abolished the ANG II–induced axonal regeneration, providing for the first time direct evidence for receptor-specific neurotrophic action of ANG II in the central nervous system of adult mammals and revealing a hitherto unknown function of the RAS.
TL;DR: There is a complex pattern of reciprocal autoreceptor and heteroceptor control of monoamine release in the frontal cortex of freely-moving rats using a novel and exceptionally sensitive method of high-performance liquid chromatography coupled to coulometric detection.
TL;DR: In isolated rat caudal artery segments, denuded of endothelium, melatonin potentiated phenylephrine-induced contractions in a concentration-dependent manner, but at higher melatonin concentrations the potentiating effect was attenuated.
TL;DR: IL-1 plays a crucial role in the initial step of the atherosclerotic process in this animal model, and blocking the activity of this cytokine should be considered as a therapeutic possibility.
Abstract: Background—The cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF) are secreted by the different cell populations of the vascular wall and have been suggested to promote atherosclerosis. Methods and Results—Their respective roles in fatty-streak formation in apolipoprotein E–deficient mice were investigated by use of IL-1 receptor antagonist and TNF binding protein. Estradiol-17β was used as a positive control. Blocking TNF seemed to be active in female animals but not in males. IL-1 receptor antagonist was as effective as or more effective than estradiol in both sexes. Conclusions—IL-1 plays a crucial role in the initial step of the atherosclerotic process in this animal model, and blocking the activity of this cytokine should be considered as a therapeutic possibility.
TL;DR: In this article, the effects of α4β2 nicotinic receptor agonists against β amyloid (Aβ) cytotoxicity to rat cortical neurons were examined.
TL;DR: It is proposed in the present paper that infantile autism is a hypoglutamatergic disorder and possible future pharmacological interventions in autism are discussed in the light of the intimate interplay between central glutamate and serotonin.
Abstract: Based on 1) neuroanatomical and neuroimaging studies indicating aberrations in brain regions that are rich in glutamate neurons and 2) similarities between symptoms produced by N-methyl-D-aspartate (NMDA) antagonists in healthy subjects and those seen in autism, it is proposed in the present paper that infantile autism is a hypoglutamatergic disorder. Possible future pharmacological interventions in autism are discussed in the light of the intimate interplay between central glutamate and serotonin, notably the serotonin (5-HT) 2A receptor. The possible benefit of treatment with glutamate agonists [e.g. agents acting on the modulatory glycine site of the NMDA receptor, or so-called ampakines acting on the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor] is discussed, as well as the potential usefulness of a selective 5-HT2A receptor antagonist.
TL;DR: The activity of 17 at extended time points in these preclinical animal models sets it apart from earlier morpholine antagonists (such as 4), and the piperidine antagonists 2 and 3 and could prove to be an advantage in the treatment of chronic disorders related to the actions of Substance P.
Abstract: Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-ox o-1 ,2,4-triazol-5-yl)methyl morpholine (17) This modified compound is a potent, long-acting hNK-1 receptor antagonist as evidenced by its ability to displace [125I]Substance P from hNK-1 receptors stably expressed in CHO cells (IC50 = 009 +/- 006 nM) and by the measurement of the rates of association (k1 = 28 +/- 11 x 10(8) M-1 min-1) and dissociation (k-1 = 00054 +/- 0003 min-1) of 17 from hNK-1 expressed in Sf9 membranes which yields Kd = 19 +/- 12 pM and a t1/2 for receptor occupancy equal to 154 +/- 75 min Inflammation in the guinea pig induced by a resiniferatoxin challenge (with NK-1 receptor activation mediating the subsequent increase in vascular permeability) is inhibited in a dose-dependent manner by the oral preadmininstration of 17 (IC50 (1 h) = 0008 mg/kg; IC90 (24 h) = 18 mg/kg), indicating that this compound has good oral bioavailbility and peripheral duration of action Central hNK-1 receptor stimulation is also inhibited by the systemic preadministration of 17 as shown by its ability to block an NK-1 agonist-induced foot tapping response in gerbils (IC50 (4 h) = 004 +/- 0006 mg/kg; IC50 (24 h) = 033 +/- 0017 mg/kg) and by its antiemetic actions in the ferret against cisplatin challenge The activity of 17 at extended time points in these preclinical animal models sets it apart from earlier morpholine antagonists (such as 4), and the piperidine antagonists 2 and 3 and could prove to be an advantage in the treatment of chronic disorders related to the actions of Substance P In part on the basis of these data, 17 has been identified as a potential clinical candidate for the treatment of peripheral pain, migraine, chemotherapy-induced emesis, and various psychiatric disorders
Journal Article•
TL;DR: These data show that Ang-(1-7) and Ang II stimulate AA release and prostacyclin synthesis via activation of distinct types of AT receptors.
Abstract: This study investigated the signal transduction mechanisms of angiotensin-(1-7) [Ang-(1-7)]- and Ang II-stimulated arachidonic acid (AA) release for prostaglandin (PG) production in rabbit aortic vascular smooth muscle cells. Ang II and Ang-(1-7) enhanced AA release in cells prelabeled with [3H]AA. However, 6-keto-PGF1 alpha synthesis produced by Ang II was much less than that caused by Ang-(1-7). In the presence of the lipoxygenase inhibitor baicalein, Ang II enhanced production of 6-keto-PGF1 alpha to a greater degree than Ang-(1-7). Angiotensin type (AT)1 receptor antagonist DUP-753 inhibited only Ang II-induced [3H]AA release, whereas the AT2 receptor antagonist PD-123319 inhibited both Ang II- and Ang-(1-7)-induced [3H]AA release. Ang-(1-7), receptor antagonist D-Ala7-Ang-(1-7) inhibited the effect of Ang-(1-7), but not of Ang II. In cells transiently transfected with cytosolic phospholipase A2 (cPLA2), mitogen-activated protein (MAP) kinase or Ca(++)-/cal-modulin-dependent protein (CAM) kinase II antisense oligonucleotides, Ang-(1-7)- and Ang II-induced [3H]AA release was attenuated. The CaM kinase II inhibitor KN-93 and the MAP kinase kinase inhibitor PD-98059 attenuated both Ang-(1-7)- and Ang II-induced cPLA2 activity and [3H]AA release. Ang-(1-7) and Ang II also increased CaM kinase II and MAP kinase activities. Although KN-93 attenuated MAP kinase activity, PD-98059 did not affect CaM kinase II activity. Both Ang II and Ang-(1-7) caused translocation of cytosolic PLA2 to the nuclear envelope. These data show that Ang-(1-7) and Ang II stimulate AA release and prostacyclin synthesis via activation of distinct types of AT receptors. Both peptides appear to stimulate CaM kinase II, which in turn, via MAP kinase activation, enhances cPLA2 activity and release of AA for PG synthesis.
TL;DR: Findings indicate that 5-HT1B receptor stimulation facilitates the reinforcing properties of cocaine and may have important ontogenic implications in the area of drug abuse research.
Abstract: The effects of serotonin1B[5-hydroxytryptamine1B (5-HT1B)] receptor activation on cocaine reinforcement were investigated using intravenous cocaine self-administration by rats. The 5-HT1Breceptor agonists 5-methoxy-3-1,2,3,6-tetrahydro-4-pyridinyl-1H-indole (RU 24969) (0.3–3 mg/kg), 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94,253) (0.3–3 mg/kg), and 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyridine (CP 93,129) (3 and 10 μg, i.c.v.) each dose-dependently reduced the self-administration of a cocaine dose on the descending limb of the fixed-ratio 5 (FR-5) cocaine dose–effect function, in a manner similar to the effect produced by increasing the unit dose of cocaine. In addition, each of these 5-HT1B agonists lowered the threshold dose of cocaine that supported self-administration. These results are consistent with a 5-HT1B agonist-induced potentiation of cocaine reinforcement. On a progressive ratio schedule of reinforcement, RU 24969 and CP 94,253 dose-dependently (0.3–3 mg/kg) increased the highest completed ratio for cocaine self-administration, again by producing behavioral alterations similar to those induced by increasing the unit dose of cocaine. The effect of CP 94,253 was dose-dependently blocked by the 5-HT1B/1D receptor partial agonist 2′-methyl-4′-(5-methyl[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid[4-methodoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127,935) (0.3–10 mg/kg) but was unaffected by the 5-HT1A receptor antagonist 4-iodo- N -[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]- N -2-pyridinyl- benzamide (p-MPPI; 1–10 mg/kg). Self-administration behavior was not maintained when either RU 24969 or CP 94,253 was substituted for cocaine, indicating that these 5-HT1B agonists do not produce significant reinforcing effects alone. Together, these findings indicate that 5-HT1B receptor stimulation facilitates the reinforcing properties of cocaine. These results are in opposition to recent findings with 5-HT1B receptor knock-out mice and may have important ontogenic implications in the area of drug abuse research.
TL;DR: Novel actions of IL‐1 in the Striatum are revealed which markedly exacerbate cortical neuronal damage elicited by local excitotoxins in the striatum or cortex.
Abstract: The cytokine interleukin-1 (IL-1) has been implicated in ischaemic, traumatic and excitotoxic brain damage. The results presented here reveal novel actions of IL-1 in the striatum which markedly exacerbate cortical neuronal damage elicited by local excitotoxins in the striatum or cortex. Intrastriatal infusion of IL-1 receptor antagonist, IL-1ra, markedly inhibited striatal neuronal damage caused by N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor activation in the rat. In contrast, intracortical infusion of IL-1ra failed to inhibit NMDA or AMPA receptor-induced damage in the cortex. Intrastriatal co-infusion of IL-1 with the NMDA or AMPA receptor agonist did not affect local striatal damage induced by activation of either glutamate receptor subtype, but caused extensive cortical damage when administered into the striatum with AMPA. This secondary damage was significantly reduced by pretreatment with the NMDA receptor antagonist (MK-801), which did not affect local (striatal) damage caused by AMPA. Infusion of IL-1beta into the striatum (but not the cortex) markedly enhanced cortical damage caused by infusion of an NMDA or AMPA receptor agonist into the cortex. These data reveal selective actions of IL-1 and IL-1ra in the striatum, which influence cortical neuronal loss and suggest that IL-1 selectively enhances damage caused by AMPA receptor activation.
TL;DR: HS024 increased the food intake of free feeding rats to levels comparable to those in food-deprived rats, indicating that blockade of the MC4 receptor is a highly effective way to increase feeding.
Abstract: Several novel cyclic MSH analogs were synthesized, and their binding properties were tested on cells transiently expressing the human melanocortin-1 (MC1), MC3, MC4, and MC5 receptors. We discovered a novel substance (HS024) that showed about 20-fold selectivity and very high affinity (Ki = 0.29 nM) for the MC4 receptor. HS024 (cyclic [AcCys3,Nle4,Arg5,D-Nal7,Cys-NH2(11)]alpha-MSH-(3-11)) has a 29-membered atom ring structure that includes an Arg in position 5. HS024 was found to antagonize an alphaMSH-induced cAMP response in cells expressing the human MC1, MC3, MC4, and MC5 receptor DNAs. HS024 also caused a dose-dependent increase in food intake, with a maximum response (4-fold increase) at a 1-nmol dose injected intracerebroventricularly in free feeding rats. We also tested SHU9119, a previously described nonselective MC receptor antagonist, and found HS024 and SHU9119 to have similar potencies for increasing food intake, although SHU9119 appeared to induce more serious side-effects. HS024 increased the food intake of free feeding rats to levels comparable to those in food-deprived rats, indicating that blockade of the MC4 receptor is a highly effective way to increase feeding. Moreover, we tested the effects of intracerebroventricular injections of HS024 in elevated plus-maze and open-field experiments on rats. In these tests, HS024 did not appear to affect emotionality or locomotor activity, suggesting that the MC4 receptor does not mediate the anxiogenic-like and locomotor effects related to the melanocortic peptides.
TL;DR: The mGlu receptor antagonist activity of LY341495 is further characterised and this compound is used to investigate roles of mGLU receptors in hippocampal long-term potentiation (LTP) and long- term depression (LTD).
TL;DR: It is shown here that L-CCG-I is a general mGlu receptor agonist activating all cloned receptors, and it is confirmed that DCG-IV, which corresponds to L- CCG- I with an additional carboxylic group, is a selective group-II agonist.
TL;DR: Catecholamines (norepinephrine, epinephrine, and dopamine) increase the vulnerability of cultured hippocampal neurons to A beta toxicity and suggest roles for oxidative stress induced by catecholamine in several different neurodegenerative conditions.