triprolidine and thioperamide

The central histaminergic neuron system inhibits epileptic seizures, which is suggested to occur mainly through histamine 1 (H1) and histamine 3 (H3) receptors. However, the importance of histaminergic neurons in seizure-induced cell damage is poorly known. In this study, we used an organotypic coculture system and confocal microscopy to examine whether histaminergic neurons, which were verified by immunohistochemistry, have any protective effect on kainic acid (KA)-induced neuronal damage in the developing hippocampus. Fluoro-Jade B, a specific marker for degenerating neurons, indicated that, after the 12 h KA (5 microM) treatment, neuronal damage was significantly attenuated in the hippocampus cultured together with the posterior hypothalamic slice containing histaminergic neurons [HI plus HY (POST)] when compared with the hippocampus cultured alone (HI) or with the anterior hypothalamus devoid of histaminergic neurons. Moreover, alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, eliminated the neuroprotective effect in KA-treated HI plus HY (POST), and extracellularly applied histamine (1 nM to 100 microM) significantly attenuated neuronal damage only at 1 nM concentration in HI. After the 6 h KA treatment, spontaneous electrical activity registered in the CA1 subregion contained significantly less burst activity in HI plus HY (POST) than in HI. Finally, in KA-treated slices, the H3 receptor antagonist thioperamide enhanced the neuroprotective effect of histaminergic neurons, whereas the H1 receptor antagonists triprolidine and mepyramine dose-dependently decreased the neuroprotection in HI plus HY (POST). Our results suggest that histaminergic neurons protect the developing hippocampus from KA-induced neuronal damage, with regulation of neuronal survival being at least partly mediated through H1 and H3 receptors.

Topics: Animals; Cell Death; Cells, Cultured; Coculture Techniques; Convulsants; Hippocampus; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Hypothalamus, Anterior; Hypothalamus, Posterior; Imidazoles; Kainic Acid; Methylhistidines; Microscopy, Confocal; Neurons; Neuroprotective Agents; Organ Culture Techniques; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Receptors, Histamine H3; Thiourea; Triprolidine

The effects of histaminergic ligands on both ACh spontaneous release from the hippocampus and the expression of c-fos in the medial septum-diagonal band (MSA-DB) of freely moving rats were investigated. Because the majority of cholinergic innervation to the hippocampus is provided by MSA-DB neurons, we used the dual-probe microdialysis technique to apply drugs to the MSA-DB and record the induced effects in the projection area. Perfusion of MSA-DB with high-KCl medium strongly stimulated hippocampal ACh release which, conversely, was significantly reduced by intra-MSA-DB administration of tetrodotoxin. Histamine or the H2 receptor agonist dimaprit, applied directly to the hippocampus, failed to alter ACh release. Conversely, perfusion of MSA-DB with these two compounds increased ACh release from the hippocampus. Also, thioperamide and ciproxifan, two H3 receptor antagonists, administered into MSA-DB, increased the release of hippocampal ACh, whereas R-alpha-methylhistamine, an H3 receptor agonist, produced the opposite effect. The blockade of MSA-DB H2 receptors, caused by local perfusion with the H2 receptor antagonist cimetidine, moderated the spontaneous release of hippocampal ACh and antagonized the facilitation produced by H3 receptor antagonists. Triprolidine, an H1 receptor antagonist, was without effect. Moreover, cells expressing c-fos immunoreactivity were significantly more numerous in ciproxifan- or thioperamide-treated rats than in controls, although no colocalization of anti-c-fos and anti-ChAT immunoreactivity was observed. These results indicate a role for endogenous histamine in modulating the cholinergic tone in the hippocampus.

Topics: Acetylcholine; Animals; Hippocampus; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Imidazoles; Male; Microdialysis; Neurons; Perfusion; Piperidines; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, Histamine H3; Septal Nuclei; Tetrodotoxin; Triprolidine

Histamine is one of the neurotransmitters suppressing appetite, but the interactions of histaminergic neurons with other neurons in satiety centers have not been clarified. Noradrenaline in the para-ventricular nucleus (PVN) has been shown to stimulate feeding. This study was designed to determine whether histamine modulates noradrenaline release via histamine H1-receptors in the PVN. Freely-fed rats were i.c.v. injected with an histamine H1-receptor antagonist, triprolidine (82 microg), and/or an alpha 2-adrenoceptor antagonist, rauwolscine (0, 20 and 40 microg), and food intake (n=8 each) over 2 h was measured. Food intake was significantly (p<0.01) increased in rats injected with triprolidine alone. The triprolidine-elicited increase in food intake was suppressed by rauwolscine at a dose of 40 microg. The noradrenaline content in perfusates collected by a microdialysis probe aimed at the PVN was significantly (p<0.05) increased by the presence of triprolidine in the perfusates. The noradrenaline concentrations in perfusates collected from the PVN were elevated after tyramine (a noradrenaline uptake inhibitor) administration, but not when both tyramine and histamine were given. In conclusion, these results suggest that histamine inhibits noradrenaline release from hypothalamic nerve terminals in the PVN, and thus suppresses feeding behavior.

Topics: Adrenergic alpha-Antagonists; Animals; Eating; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Injections, Intraventricular; Male; Microdialysis; Norepinephrine; Paraventricular Hypothalamic Nucleus; Piperidines; Rats; Rats, Wistar; Triprolidine; Yohimbine

High levels of histamine can be found in the airways of asthma patients. This study describes the effects of histamine on anti-CD3-induced production of IL-4, IL-5, and IFN-gamma by T cell clones from subjects with allergic asthma and healthy subjects. T cell clones were obtained from bronchoalveolar lavage (BAL) fluid and blood. The number of clones tested, and the percentage of clones in which histamine inhibited or enhanced cytokine production by more than 25%, were as follows: IL-4, 47, 8.5%, and 4.3%; IL-5, 43, 14%, and 30%; and IFN-gamma, 52, 40%, and 15%. Inhibition of IL-5 and IFN-gamma production was reversed by IL-2. The enhancement of IFN-gamma production was associated with an enhancement of both IL-2 production and proliferation. In 21% of the clones a combined effect consisting of inhibition of IFN-gamma production and enhancement of IL-5 production was found. This response was reversed by H2-receptor antagonists and was significantly associated with a histamine-induced increase in intracellular levels of cAMP. The role of cAMP in mediating the histamine effects was supported by the observations that the beta2-agonist salbutamol had effects similar to histamine and that high concentrations of PGE2 mimicked the inhibitory effects of histamine. Clones from BAL fluid and blood showed similar responses, as did clones from patients with asthma and from control subjects. The enhancement of IFN-gamma production by histamine, however, was found only in clones from healthy subjects. The results warrant further investigations on the role of cAMP in the regulation of cytokine production.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Albuterol; Asthma; Bronchoalveolar Lavage Fluid; Clone Cells; Cyclic AMP; Dinoprostone; Enzyme Activation; Famotidine; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Impromidine; Interferon-gamma; Interleukin-2; Interleukin-4; Interleukin-5; Lung; Methylhistamines; Piperidines; Pyridines; Ranitidine; T-Lymphocytes; Triprolidine

Dispase-dissociated primary cultures of human conjunctival epithelial (HCE) cells were stimulated with histamine and the generation of inositol phosphates ([3H]IPs) from [3H]phosphoinositide (PI) hydrolysis and the mobilization of intracellular calcium ([Ca2+]i) were studied using ion exchange chromatography and Fura-2 fluorescence techniques, respectively. Histamine (100 microM) maximally stimulated PI turnover in HCE cells by 210 +/- 10% (n = 21) above basal levels and with a potency (EC50) of 3.3 microM (n = 4). Histamine (EC50 = 5.8 microM, n = 3) rapidly mobilized [Ca2+]i which peaked within 10 sec but which was still significantly elevated 20 min after stimulation. The histamine-induced [Ca2+]i responses did not desensitize upon repeated applications of histamine. The effects of histamine (100 microM) on PI turnover and [Ca2+]i were potently antagonized by the H1-antagonists, emedastine (IC50 = 1.6-2.9 nM), triprolidine (IC50 = 3.1 nM) and levocabastine (IC50 = 8 nM), but weakly by the H2-(ranitidine/cimetidine) and H3-(thioperamide) antagonists (IC50s = 10-100 microM). In conclusion, HCE cells have been shown to possess functional H1-histamine receptors that couple to inositol phosphates generation which then mobilize intracellular calcium. These intracellular signaling mechanisms may be intimately linked with the process of inflammatory cytokine secretion from the HCE cells after stimulation by histamine released from the conjunctival mast cells. The current results strongly suggest that the HCE cells are active participants in mediating, and perhaps amplifying, the pro-inflammatory and allergic effects of histamine which is released from conjunctival mast cells during ocular allergic and inflammatory reactions.

Topics: Benzimidazoles; Calcium; Cells, Cultured; Chromatography, Ion Exchange; Conjunctiva; Cytokines; Epithelium; Eye Diseases; Histamine; Histamine Antagonists; Humans; Hypersensitivity; Inflammation; Phosphatidylinositols; Piperidines; Receptors, Histamine H1; Stimulation, Chemical; Triprolidine

Histamine 0.1 microM-0.1 mM increased adenylate cyclase activity five- to ten-fold in human fundic membranes, with a potency Ka = 3 microM. The histamine dose-response curve was mimicked by the H3 receptor agonist (R) alpha-MeHA, but at 100 times lower potency, Ka = 0.3 mM. Histamine-induced adenylate cyclase activation was abolished by H2, H1 and H3 receptor antagonists, according to the following order of potency IC50: famotidine (0.3 microM) greater than triprolidine (0.1 mM) thioperamide (2 mM), respectively. Famotidine has no action on membrane components activating the adenylate cyclase system, including the Gs subunit of the enzyme stimulated by forskolin and cell surface receptors sensitive to isoproterenol (beta 2-type), PGE2 and VIP. The Schild plot was linear for famotidine (P less than 0.01) with a regression coefficient r = 0.678. The slope of the regression line was 0.64 and differs from unity. Accordingly, famotidine showed a slow onset of inhibition and dissociation from the H2 receptor in human cancerous HGT-1 cells. The results demonstrate that famotidine is a potent and selective H2 receptor antagonist with uncompetitive actions in human gastric mucosa. Consequently, famotidine might be a suitable drug with long-lasting actions in the treatment of Zollinger-Ellison syndrome. The results also confirm and extend the previous observations that (R) alpha-MeHA and thioperamide are two selective ligands at histamine H3 receptor sites. In the human gastric mucosa, these drugs are respectively 330 and 6700 times less potent than histamine and famotidine on the adenylate cyclase system. The possible involvement of histamine H3 receptors in the regulation of gastric secretion is proposed.

Topics: Adenylyl Cyclases; Cyclic AMP; Famotidine; Gastric Fundus; Histamine; Histamine H2 Antagonists; Humans; In Vitro Techniques; Methylhistamines; Piperidines; Ranitidine; Receptors, Histamine; Stomach Neoplasms; Thiazoles; Triprolidine