Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serotonin (5-HT) is one of the most extensively studied neurotransmitters of the central nervous system. 5-HT is, however, also present in a variety of peripheral tissues including in constituents of the immune system. The function of 5-HT in the immune system has received increasing attention since about 1984, but has been reviewed only once, in 1985. In recent years, modern techniques of molecular biology such as reverse-transcriptase polymerase chain reaction and targeted gene disruption have made it possible to study new important aspects of 5-HT in the immune system. In the first part of the review, we explore whether 5-HT is involved in interactions between the central nervous and immune systems. It emerges that 5-HT may mediate interactions of these two systems by four different pathways. In the second part, we dissect the functional roles of 5-HT in the immune system. We describe the distribution of 5-HT receptors and the 5-HT transporter on immune cells and estimate which levels 5-HT may attain in the extracellular space in physiological conditions and under pathological circumstances such as inflammation, thrombosis, and ischemia. At these 5-HT concentrations, four major functions for 5-HT emerge. These include T cell and natural killer cell activation, delayed-type hypersensitivity responses, production of chemotactic factors, and natural immunity delivered by macrophages. Finally, we discuss promising future avenues to further advance knowledge of the role of 5-HT in the immune system and in neuroimmune interactions.
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PMID:Role of serotonin in the immune system and in neuroimmune interactions. 1008 Aug 56

Sensory neurons that innervate the heart sense ischemia and mediate angina. To use patch-clamp methods to study ion channels on these cells, we fluorescently labeled cardiac sensory neurons (CSNs) in rats so that they could later be identified in dissociated primary culture of either nodose or dorsal root ganglia (DRG). Currents evoked by a variety of different agonists imply the importance of lowered pH (</=7.0) in signaling ischemia. Acidic pH evoked extremely large depolarizing current in almost all cardiac afferent neurons from the DRG (CDRGNs). In contrast, only about half of the unlabeled DRG neurons responded to acid, and their current amplitudes were much less than that in CDRGNs. In all respects tested--kinetics, selectivity, and pharmacology--the acid-evoked current was similar to that of previously described native and cloned acid-sensing ion channels. Cardiac afferents from the nodose ganglia differed from CDRGNs in having smaller acid-evoked currents but clearly larger currents evoked by ATP. Serotonin, acetylcholine, bradykinin, and adenosine elicited currents in fewer CSNs than did ATP or lowered pH, and the currents were relatively small. Capsaicin, an activator of small nociceptive sensory neurons that innervate skin, evoked only small and rare currents in CDRGNs. The extremely large amplitude and prevalent expression of acid-evoked current in CSNs imply a critical role for acidity in sensation associated with myocardial ischemia.
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PMID:Acid-evoked currents in cardiac sensory neurons: A possible mediator of myocardial ischemic sensation. 1022 39

We investigated the effect of an infusion of ramiprilat on the development of coronary endothelial dysfunction. In anesthetized dogs, the endothelium-dependent vasodilators acetylcholine (ACh, 5 and 10 microg x min(-1) for 1 min) and serotonin (5-HT, 50 and 100 microg x min(-1) for 1 min) and the endothelium-independent vasodilator nitroglycerin (NTG, 50 and 100 microg x min(-1) for 1 min) were given intracoronarily (i.c.) both prior to and after 60 min of ischemia (I) and 180 min of reperfusion (R) of a coronary artery. During I/R the dogs received i.c. either saline (N = 22) or ramiprilat (40 ng/kg x min(-1), N = 14). At the end of the experiment, a biopsy of the most distal coronary bed was processed for scanning electron microscopy (SEM). Prior to I/R all vasodilators induced a similar dose-related increase in coronary flow in both groups. Following I/R, in controls the responses to ACh and 5-HT were significantly blunted (ACh: -39% and -34%; 5-HT: -48% and -49%); those to NTG were unchanged. Ramiprilat significantly prevented the blunting of the responses to ACh (-5%, and -10%) and 5-HT (-11%, and -19%). SEM of control subepicardial arterioles showed adhesion of leukocytes to the endothelium and crater formation. No craters were seen in the ramiprilat-treated dogs. Thus, an acute infusion of ramiprilat significantly prevents the development of coronary endothelial dysfunction. Additionally, the appearance of crater-like changes on the endothelial surface can be taken as a morphological marker of endothelial dysfunction.
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PMID:Ramiprilat prevents the development of acute coronary endothelial dysfunction in the dog. 1050 23

The aim of this study was to assess whether cyclooxygenase (COX) inhibitors protect the endothelial function against the deleterious effect of ischemia and reperfusion. Isolated rat hearts perfused under constant-flow conditions were exposed to 30 min of partial ischemia (flow, 1 ml/min) followed by 20 min of reperfusion, after which coronaries were precontracted with U-46619, and the response to the endothelium-dependent vasodilator, serotonin (5-HT), was compared with that of the endothelium-independent vasodilator, sodium nitroprusside (SNP). In untreated hearts, ischemia diminished selectively 5-HT-induced vasodilation, compared with sham hearts (without ischemia). The vasodilation to SNP was unaffected in all groups. Pretreatment with 6-MNA, 30 microM, a COX-2 inhibitor with some activity on COX 1, diclofenac, 1 microM (COX-1 and -2), or 1-(7-carboxyheptyl) imidazole, 10 microM [thromboxane (TX) synthase inhibitor] but not indomethacin, 10 microM (COX-1 inhibitor) preserved the vasodilation induced by 5-HT after ischemia. Enzyme immunoassays indicated that all COX inhibitors decreased the concentration of TXB2 and 6-keto-PGF1alpha [stable metabolites of TXA2 and prostacyclin (PGI2), respectively] in coronary effluent during ischemia. Furthermore, indomethacin was the only one to abolish the concentration of PGE2 during ischemia and early reperfusion. No clear trend on ventricular postischemic recovery could be observed between treated and untreated groups under our experimental protocols. These data suggest that, under our conditions, 6-MNA, diclofenac, and 1-7-CHI, but not indomethacin, protect the endothelial function via a reduction in TX concentration. Disparities between COX inhibitors may be due to the complete abolition of PGE2 concentration during ischemia and reperfusion in the indomethacin group.
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PMID:Mechanisms of protection afforded by cyclooxygenase inhibitors to endothelial function against ischemic injury in rat isolated hearts. 1054 94

The aim of this study was to investigate the effect of 30 min forebrain ischemia, followed by 120 min reperfusion on extracellular fluid (ECF) levels of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum of gerbils, so as to obtain further information on the mechanism of Radix Salviae Miltiorrhizae (RSM)-induced neuroprotection. Microdialysis was used to sample the extracellular space. Dialysate was measured by high performance liquid chromatography with electrochemical detector (HPLC-ED). ECF DA, NE levels increased from basal levels by 282, 227 and 221 folds, by 9.14, 8.51 and 8.25 folds, respectively for the three ischemic duration (0-10; 11-20; 21-30 min). ECF DA, NE, 5-HT levels in the RSM-treated group were significantly decreased as compared with those in the control group during ischemia (P < 0.01). The results suggested that monoamine neurotransmitters were involved in ischemic neuron damage directly or indirectly; and that RSM plays a protective role during cerebral ischemia by attenuating the dysfunctions of monoamine neurotransmitters.
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PMID:Effects of transient forebrain ischemia and radix Salviae miltiorrhizae (RSM) on extracellular levels of monoamine neurotransmitters and metabolites in the gerbil striatum--an in vivo microdialysis study. 1068 74

1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed. 2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved. 3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions. 4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling). 5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized. 6. Bradykinin (Bk) increases blood-brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with evidence that IL-1 beta potentiates the actions of Bk in ischemia. 7. Serotonin (5HT) has been reported to increase blood-brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase. 8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H2 receptors and elevation of [Ca2+]i and an H1 receptor-mediated reduction in permeability coupled to an elevation of cAMP. 9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood-brain barrier permeability. The effects are mediated predominantly via a P2U (P2Y2) G-protein-coupled receptor causing an elevation of [Ca2+]i; a P2Y1 receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations. 10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood-brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways. 11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood-brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood-brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.
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PMID:Inflammatory mediators and modulation of blood-brain barrier permeability. 1069 6

The serotonin (5-HT)(1A) receptor agonists have already been shown to protect cultured neurons from excitotoxic as well as from apoptotic damage [B. Ahlemeyer, J. Krieglstein, Stimulation of 5-HT(1A) receptors inhibits apoptosis induced by serum deprivation in cultured neurons from chick embryo, Brain Res. 777 (1997) 179-186. ; B. Ahlemeyer, A. Glaser, C. Schaper, I. Semkova, J. Krieglstein, The 5-HT(1A) receptor agonist, Bay x 3702, inhibited apoptosis induced by serum deprivation in cultured neurons, Eur. J. Pharmacol. 370 (1999) 211-216.; J.H.M. Prehn, M. Welsch, C. Backhauss, J. Nuglisch, F. Ausmeier, C. Karkoutly, J. Krieglstein, Effects of serotonergic drugs in experimental brain ischemia: evidence for a protective role of serotonin in cerebral ischemia, Brain Res. 630 (1993) 110-120.; I. Semkova, P. Wolz, J. Krieglstein, Neuroprotective effect of 5-HT(1A) receptor agonist, Bay x 3702, demonstrated in vitro and in vivo, Eur. J. Pharmacol. 359 (1998) 251-260.; B. Suchanek, H. Struppeck, T. Fahrig, The 5-HT(1A) receptor agonist, Bay x 3702, prevents staurosporine-induced apoptosis, Eur. J. Pharmacol. 355 (1998) 95-101.] and to increase the release of the neurotrophic protein, S-100beta [P.M. Whitaker-Azmitia, R. Murphy, E.C. Azmitia, Stimulation of astroglial 5-HT(1A) receptors releases the serotonergic growth factor, protein S-100, and alters astroglial morphology, Brain Res. 497 (1989) 80-86. ; P.M. Whitaker-Azmitia, R. Murphy, E.C. Azmitia, S-100 protein is released from astroglial cells by stimulation of 5-HT(1A) receptors, Brain Res. 528 (1990) 155-158.]. In this study, we tried to find out whether S-100beta can protect cultured neurons from glutamate- and staurosporine-induced damage and whether the neuroprotective activity of the highly selective 5-HT(1A) receptor agonist, Bay x 3702, is mediated by an induction of S-100beta. Extracellularly added S-100beta (1-10 ng/ml) reduced staurosporine-induced damage in pure neuronal cultures from chick embryo telencephalon as well as in mixed neuronal/glial cultures from neonatal rat hippocampus. In addition, S-100beta (1 ng/ml) reduced neuronal death induced by exposure to glutamate (0.25 mM, 30 min) in mixed neuronal/glial cultures from neonatal rat hippocampus. In cultured rat cortical astrocytes, a 24 h-treatment with Bay x 3702 (1 nM) increased the S-100beta content in the culture medium from 2.2+/-0.3 (controls) to 6.2+/-0.7 ng/ml. In the adult rat, a 4 h-infusion of 4 microg/kg Bay x 3702 (i.v.) was found to increase the S-100beta content in the striatum 6 h after the beginning of the infusion to 153+/-37 microg/g compared with 60+/-20 microg/g in vehicle-treated rats. Bay x 3702 had no effect on the S-100beta content in the rat hippocampus. Finally, we tried to block the protective effect of Bay x 3702 against staurosporine-induced damage in mixed neuronal/glial cultures from rat neonatal hippocampus by anti-S-100beta antibodies. We found only a partial blockade, although the antibodies fully blocked the antiapoptotic effect of S-100beta itself demonstrating that the antibody was effective in blocking neuroprotection by S-100beta. Thus, we conclude that S-100beta was able to protect cultured neurons against glutamate- and staurosporine-induced damage. Furthermore, S-100beta mediated partially the protective effect of the 5-HT(1A) receptor agonist, Bay x 3702, against staurosporine-induced apoptosis in mixed neuronal/glial cultures from neonatal rat hippocampus.
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PMID:S-100beta protects cultured neurons against glutamate- and staurosporine-induced damage and is involved in the antiapoptotic action of the 5 HT(1A)-receptor agonist, Bay x 3702. 1070 Jun 4

The effects of ecabapide, a novel substituted benzamide compound (3-[2-(3,4-dimethoxyphenyl)ethylcarbamoylmethyl]amino-N-methylb enzamide) that has gastrointestinal prokinetic action, were examined on the discharge of extrinsic afferent nerves supplying the stomach and jejunum in anaesthetized rats. Ecabapide (60 and 180 microg kg(-1), i.v.) had no effect on the baseline discharge of vagal gastric distension-sensitive afferents or the stimulus-response profile to gastric distension. Ecabapide also had no effect on either spontaneous jejunal mesenteric afferent nerve discharge or responses to intestinal distension. Ecabapide (180 microg kg(-1)) significantly inhibited the maximum discharge of jejunal afferents induced by cholecystokinin (CCK8; 50 pmol, i.v.), whereas it failed to inhibit the excitatory action of 2-methyl-5-hydroxytryptamine (2Me-5-HT; 10 microg, i.v.), a selective 5-HT3 receptor agonist. A model of acute focal intestinal ischaemia was used to evaluate the actions of ecabapide on the discharge of activated jejunal afferents. Ischaemia produced a substantial increase in afferent discharge which was reproducible when the duration of ischaemia was limited to less than 10 min and repeated every 15 min. Ecabapide at doses of 60 and 180 microg kg(-1) significantly reduced ischaemia-induced increases in afferent discharge. In addition to its therapeutic efficacy as a gastrointestinal prokinetic agent, these findings show also that ecabapide may also have an inhibitory action on the discharge of intestinal afferents activated by ischaemia.
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PMID:Modulation of gastrointestinal afferent sensitivity by a novel substituted benzamide (ecabapide). 1078 88

It has recently been shown that 5-HT(1A) receptor stimulation reduced the infarct volume after occlusion of the middle cerebral artery in rats. Since there is increasing evidence that apoptosis is involved in neurodegenerative diseases and stroke, we investigated whether the 5-HT(1A) agonist Bay x 3702 could protect neurons against apoptotic damage in a rat model of transient forebrain cerebral ischemia. Bay x 3702 (4 microg/kg i.v.) caused a 10% reduction of neuronal damage in the hippocampal CA1 subfield. Higher doses of Bay x 3702 (40 and 12 microg/kg i.v.) did not cause any neuroprotective effect, most likely because of the strong reduction of mean arterial blood pressure during the period of Bay x 3702 infusion. Bay x 3702 (4 microg/kg i.v.) diminished DNA laddering in the hippocampus and striatum 4 days after 10 min forebrain ischemia. These results were confirmed by TUNEL-staining. The anti-apoptotic effect was abolished by additional treatment with the 5-HT(1A) receptor antagonist WAY 100635 (1 mg/kg). Taken together, the results suggest that Bay x 3702 can rescue hippocampal as well as striatal neurons from apoptotic cell death in vivo via stimulation of 5-HT(1A) receptors.
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PMID:Stimulation of 5-HT(1A) receptors reduces apoptosis after transient forebrain ischemia in the rat. 1106 86

Brain ischemia provoked by stroke or traumatic brain injury induces a massive increase in neurotransmitter release, in particular of the excitotoxin glutamate. Glutamate triggers a cascade of events finally leading to widespread neuronal cell damage and death. The aminomethylchroman derivative BAY x 3702 is a novel neuroprotectant which shows pronounced beneficial effects in various animal models of ischemic brain injury. As shown previously BAY x 3702 binds to 5-HT(1A) receptors of different species in subnanomolar range and is characterized as a full receptor agonist. In this study we investigated the influence of BAY x 3702 on potassium-evoked glutamate release in vitro and ischemia-induced glutamate release in vivo. In rat hippocampal slices BAY x 3702 inhibited evoked glutamate release in a dose-dependent manner (IC(50)=1 microM). This effect was blocked by the selective 5-HT(1A) receptor antagonist WAY 100635, indicating that BAY x 3702 specifically acts via 5-HT(1A) receptors. In vivo, release of endogenous aspartate and glutamate was measured in the cortex of rats by microdialysis before and after onset of permanent middle cerebral artery occlusion. Single dose administration of BAY x 3702 (1 microg/kg or 10 microg/kg i.v.) immediately after occlusion reduced the increase and total release of extracellular glutamate by about 50% compared to non-treated animals, whereas the extracellular aspartate levels were not significantly affected. Inhibition of glutamate release may therefore contribute to the pronounced neuroprotective efficacy of BAY x 3702 in various animal models of ischemic brain damage.
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PMID:Inhibition of evoked glutamate release by the neuroprotective 5-HT(1A) receptor agonist BAY x 3702 in vitro and in vivo. 1114 61


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