thioperamide and Disease-Models--Animal

We established a novel dermatitis model in mice earlobes and analyzed the roles of histamine using specific antagonists for histamine receptors. After sensitization with picryl chloride (PiCl) by painting it on the earlobes of cyclophosphamide-treated mice, 12-O-tetradecanoylphorbol 13-acetate (TPA) was painted twice at the same site, and then allergic inflammation was induced by painting with PiCl. Histamine antagonists and cyclosporin A were administered i.v. The application of TPA shifted the PiCl-induced allergic inflammation from a delayed-type response to a biphasic response and increased the infiltration of eosinophils and mast cells at the inflammatory site. In this model, the PiCl-induced increase in the thickness of the earlobe in the immediate phase was suppressed by the histamine H₁ antagonist pyrilamine. In contrast, the increase in the swelling in the late phase and the infiltration of eosinophils were suppressed by the H₃/H₄ antagonist thioperamide. The inhibitory effect of the combined treatment with pyrilamine and thioperamide on TPA-modified contact dermatitis was as potent as that of cyclosporin A. Histamine plays significant roles in early-phase swelling via H₁ receptors and in late-phase swelling via H₃/H₄ receptors in this TPA-modified allergic dermatitis model.

Topics: Animals; Cyclosporine; Dermatitis, Atopic; Disease Models, Animal; Drug Therapy, Combination; Histamine; Histamine Antagonists; Humans; Mice; Picryl Chloride; Piperidines; Pyrilamine; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H3; Receptors, Histamine H4; Tetradecanoylphorbol Acetate

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

Unilateral labyrinthectomy (UL) causes the disappearance of ipsilateral medial vestibular nuclear (ipsi-MVe) activity and induces spontaneous nystagmus (SN), which disappears during the initial process of vestibular compensation (VC). Ipsi-MVe-activity restores in the late process of VC.. We evaluated the late process of VC after UL in rats and examined the effects of thioperamide (H3 antagonist) on VC.. MK801 (NMDA antagonist)-induced Fos-like immunoreactive (-LIR) neurons in contra-MVe, which had been suppressed by NMDA-mediated cerebellar inhibition in UL rats was used as an index.. The number of MK801-induced Fos-LIR neurons in contra-MVe gradually decreased to the same level as that of sham-operated rats 14 days after UL. Thioperamide moved the disappearance of the MK801-induced Fos-LIR neurons 2 days earlier. The number of MK801-induced Fos-LIR neurons in thioperamide-treated rats was significantly decreased, compared with that of vehicle rats on days 7 and 12 after UL. But, thioperamide did not influence the decline of SN frequency in UL rats.. These findings suggested that the number of MK801-induced Fos-LIR neurons in contra-MVe was decreased in concordance with the restoration of ipsi-MVe-activity during the late process of VC after UL and that thioperamide accelerated the late, but not the initial process of VC.

Topics: Adaptation, Physiological; Analysis of Variance; Animals; Biopsy, Needle; Disease Models, Animal; Functional Laterality; Immunohistochemistry; Male; Nystagmus, Pathologic; Otologic Surgical Procedures; Piperidines; Random Allocation; Rats; Rats, Wistar; Reference Values; Vestibular Function Tests; Vestibule, Labyrinth

Histamine receptors are known to participate in spinal cord nociceptive transmission, and previous studies have suggested that histaminergic receptors are involved in the analgesic effects of morphine. Herein, we investigated the effect of intrathecal injection of histaminergic agonists and antagonists in a model of acute articular inflammation and their interaction with morphine.. After carrageenan injection in the right knee joint, articular incapacitation was measured hourly, for up to 6 hours, by the paw elevation time during 1-minute periods of stimulated walking. Inflammatory edema was also assessed hourly by determining an increase in articular diameter. Spinal treatments were administered 20 minutes before knee-joint carrageenan injection and were compared with the saline-treated control group.. Intrathecally injected histamine increased incapacitation and articular edema, whereas the H1R antagonist, cetirizine, decreased both parameters. The H3R agonist, immepip, decreased both incapacitation and edema, but the H3R antagonist, thioperamide, increased both incapacitation and edema. Morphine inhibited both incapacitation and edema. Furthermore, combining a subeffective dose of morphine with cetirizine or immepip potentiated the analgesic and antiedematogenic effect.. Histamine seems to act at the spinal level via H1 and H3 receptors to modulate acute arthritis in rats. An H1R antagonist and H3R agonist were found to potentiate the analgesic and antiedematogenic effects of morphine, suggesting that histaminergic and opioid spinal systems may be explored for means of improving analgesia, as well as peripheral anti-inflammatory effects.

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Carrageenan; Cetirizine; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists, Non-Sedating; Histamine H3 Antagonists; Imidazoles; Injections, Spinal; Joints; Male; Morphine; Osteoarthritis; Piperidines; Rats, Wistar; Receptors, Histamine H1; Receptors, Histamine H3; Spinal Cord

Histamine, acting centrally as a neurotransmitter, evokes a reversal of hemorrhagic hypotension in rats due to the activation of the sympathetic and the renin-angiotensin systems as well as the release of arginine vasopressin and proopiomelanocortin-derived peptides. We demonstrated previously that central nicotinic cholinergic receptors are involved in the pressor effect of histamine. The aim of the present study was to examine influences of centrally administrated histamine on acetylcholine (ACh) release at the posterior hypothalamus-a region characterized by location of histaminergic and cholinergic neurons involved in the regulation of the sympathetic activity in the cardiovascular system-in hemorrhage-hypotensive anesthetized rats. Hemodynamic and microdialysis studies were carried out in Sprague-Dawley rats. Hemorrhagic hypotension was induced by withdrawal of a volume of 1.5 ml blood/100 g body weight over a period of 10 min. Acute hemorrhage led to a severe and long-lasting decrease in mean arterial pressure (MAP), heart rate (HR), and an increase in extracellular posterior hypothalamic ACh and choline (Ch) levels by 56% and 59%, respectively. Intracerebroventricularly (i.c.v.) administered histamine (50, 100, and 200 nmol) dose- and time-dependently increased MAP and HR and caused an additional rise in extracellular posterior hypothalamic ACh and Ch levels at the most by 102%, as compared to the control saline-treated group. Histamine H1 receptor antagonist chlorpheniramine (50 nmol; i.c.v.) completely blocked histamine-evoked hemodynamic and extracellular posterior hypothalamic ACh and Ch changes, whereas H2 and H3/H4 receptor blockers ranitidine (50 nmol; i.c.v.) and thioperamide (50 nmol; i.c.v.) had no effect. In conclusion, centrally administered histamine, acting via H1 receptors, increases ACh release at the posterior hypothalamus and causes a pressor and tachycardic response in hemorrhage-hypotensive anesthetized rats.

Topics: Acetylcholine; Animals; Blood Pressure; Chlorpheniramine; Choline; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Rate; Hemorrhage; Histamine; Histamine Agonists; Histamine Antagonists; Hypotension; Hypothalamus, Posterior; Male; Microdialysis; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors

Histamine is detected in high concentrations in the airways during an allergic asthma response. In a murine model of allergic asthma, the histamine H4 receptor (H4R)-selective ligand JNJ 7777120 reduces asthma-like symptoms. A sole antagonistic function of JNJ 7777120 at the murine H4R has, however, been questioned in the literature. Therefore, in the present study, we aimed at analyzing the effects of JNJ 7777120 in comparison to that of the H3/4R-selective antagonist thioperamide. Experimental murine asthma was induced by sensitization and provocation of BALB/c mice with ovalbumine (OVA). JNJ 7777120, thioperamide, or JNJ 5207852, an H3R-selective antagonist which was used to dissect H3R- and H4R-mediated activities of thioperamide, were injected subcutaneously during sensitization and effects were analyzed after provocation. Pharmacokinetic analyses revealed shortest t1/2 values in both plasma and lung tissue and lowest maximal concentration in lung tissue for JNJ 7777120 in comparison to thioperamide and JNJ 5207852. Nevertheless, JNJ 7777120 reduced serum titers of allergen-specific (anti-OVA) IgE, inflammatory infiltrations in lung tissue, and eosinophilia in bronchoalveolar lavage fluid. In contrast, thioperamide reduced only eosinophilia in bronchoalveolar lavage fluid, while anti-OVA IgE concentrations and lung infiltrations remained unaffected. JNJ 5207852 had no effect on these parameters. JNJ 7777120 provides beneficial effects in experimental murine asthma, which, however, could only partially be mimicked by thioperamide, despite more favorable pharmacokinetics. Thus, whether these effects of JNJ 7777120 are entirely attributable to an antagonistic activity at the murine H4R or whether an agonistic activity is also involved has to be reconsidered.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Count; Disease Models, Animal; Eosinophilia; Female; Histamine H3 Antagonists; Immunoglobulin E; Indoles; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Piperazines; Piperidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4

In atopic dermatitis, inflammation induced by antigen-nonspecific stimuli further enhances the allergic inflammation. However, there is no experimental model in which allergic dermatitis is evoked where the inflammation has been induced by antigen-nonspecific stimuli. Here, we established a novel dermatitis model in mice and analyzed the role of histamine.. After sensitization with picryl chloride (PiCl) by painting on ear lobes of cyclophosphamide-treated mice, 12-O-tetradecanoylphorbol 13-acetate (TPA) was painted twice at the same site, and then allergic inflammation was induced by painting PiCl. Histamine antagonists and cyclosporine A (CsA) were administered intravenously.. The application of TPA shifted the PiCl-induced allergic inflammation from a delayed-type response to a biphasic response, increased the infiltration of eosinophils and mast cells at the inflammatory site, shifted the cytokine milieu from Th1 to Th2 and induced the expression of thymic stromal lymphopoietin in the ear lobes. The PiCl-induced increase in the thickness of the ear lobe in the immediate phase was suppressed by the H1 antagonist pyrilamine. In contrast, the increase in the swelling in the late phase and the infiltration of eosinophils were suppressed by the H3/H4 antagonist thioperamide. The inhibitory effect of the combined treatment with pyrilamine and thioperamide on the TPA-modified contact dermatitis was as potent as that of CsA.. Induction of the antigen-nonspecific inflammation by TPA enhanced the PiCl-induced allergic inflammation. Histamine plays significant roles in the early-phase swelling via H1 receptors, and the late-phase swelling via H3/H4 receptors in this TPA-modified allergic dermatitis model.

Topics: Animals; Cell Count; Cimetidine; Cyclophosphamide; Cyclosporine; Cytokines; Dermatitis, Allergic Contact; Disease Models, Animal; Ear Auricle; Eosinophil Peroxidase; Eosinophils; Gene Expression; Histamine; Histamine Antagonists; Immunoglobulin E; Interferon-gamma; Interleukin-4; Male; Mast Cells; Mice; Mice, Inbred BALB C; Picryl Chloride; Piperidines; Pyrilamine; Tetradecanoylphorbol Acetate; Thymic Stromal Lymphopoietin

Siberian hamsters develop hypophagia and increase catabolism of fat reserves in response to short photoperiods resulting in a natural loss of body weight in winter. We previously found that histamine 3 receptor (H3R) mRNA in the posterior hypothalamus is significantly decreased in short photoperiods. We hypothesized that this lower expression of H3R might contribute to the winter hypophagic state, therefore we examined the effects of the H3R agonist imetit and inverse agonists clobenpropit and thioperamide on food intake. We expressed the Siberian hamster H3R receptor in vitro and confirmed that imetit, clobenpropit and thioperamide are bound specifically, thus validating them as tools to investigate the role of H3R in vivo. Intracerebroventricular administration of histamine decreased food intake in hamsters in the fat summer state. Administration of imetit to hamsters in the lean state increased food intake, whereas administration of inverse agonists decreased food intake, though this was associated with decreased locomotor activity. Both H3R inverse agonists prevented the nocturnal rise in body temperature indicating additional effects on energy expenditure. In summary, our results suggest that increased availability of central histamine or the reduction of H3R activity decrease food intake. These effects are similar to those observed in hamsters in short photoperiods.

Topics: Animals; Body Temperature; Cell Line, Transformed; Cricetinae; Disease Models, Animal; Eating; Histamine; Imidazoles; Injections, Intraventricular; Motor Activity; Obesity; Phodopus; Photoperiod; Piperidines; Receptors, Histamine H3; Seasons; Thiourea; Transfection

In view of the recent evidence for the involvement of histamine in cerebral ischemia, the present study evaluated the effect of thioperamide (THP), a selective histamine H3-receptor antagonist, on middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia in rats. The rats were subjected to 2 h of MCAO followed by 22 h reperfusion after which the grip strength, locomotor activity and spontaneous alternation performance were assessed. Animals were then killed and oxidative stress markers were estimated in the whole brain. An elevation of thiobarbituric acid reactive substance (TBARS) and a reduction in glutathione (GSH) and antioxidant enzymes, such as glutathione-S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD), was observed following MCAO, the last two being statistically insignificant. Pretreatment with THP (5.5 mg/kg i.p. and 11 mg/kg i.p.) significantly reversed the MCAO-induced increase in TBARS, but could not reverse the other parameters. Paradoxically, it further reduced the levels of GPx, GR and SOD. No significant changes were observed in the catalase levels and in the grip strength and spontaneous alternation behavior of rats. Locomotor activity was reduced slightly, but reversed on pretreatment with THP. The dual effect of THP on oxidative stress requires further investigation and raises doubts on its possible use in cerebral ischemia.

Topics: Animals; Biomarkers; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Histamine H3 Antagonists; Infarction, Middle Cerebral Artery; Lipid Peroxidation; Male; Maze Learning; Middle Cerebral Artery; Motor Activity; Muscle Strength; Oxidative Stress; Oxidoreductases; Piperidines; Rats; Rats, Wistar; Reperfusion Injury; Thiobarbituric Acid Reactive Substances

Histamine regulates many functions by binding to four histamine G-coupled receptor proteins (H1R, H2R, H3R and H4R). As H3R exerts their effects by coupling to Galpha(i/o) proteins reducing adenosine 3', 5'-monophosphate (cAMP) levels (a key player in the modulation of cholangiocyte hyperplasia/damage), we evaluated the role of H3R in the regulation of biliary growth. We posed the following questions: (1) Do cholangiocytes express H3R? (2) Does in vivo administration of (R)-(alpha)-(-)-methylhistamine dihydrobromide (RAMH) (H3R agonist), thioperamide maleate (H3R antagonist) or histamine, in the absence/presence of thioperamide maleate, to bile duct ligated (BDL) rats regulate cholangiocyte proliferation? and (3) Does RAMH inhibit cholangiocyte proliferation by downregulation of cAMP-dependent phosphorylation of protein kinase A (PKA)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ets-like gene-1 (Elk-1)? The expression of H3R was evaluated in liver sections by immunohistochemistry and immunofluorescence, and by real-time PCR in cholangiocyte RNA from normal and BDL rats. BDL rats (immediately after BDL) were treated daily with RAMH, thioperamide maleate or histamine in the absence/presence of thioperamide maleate for 1 week. Following in vivo treatment of BDL rats with RAMH for 1 week, and in vitro stimulation of BDL cholangiocytes with RAMH, we evaluated cholangiocyte proliferation, cAMP levels and PKA, ERK1/2 and Elk-1 phosphorylation. Cholangiocytes from normal and BDL rats express H3R. The expression of H3R mRNA increased in BDL compared to normal cholangiocytes. Histamine decreased cholangiocyte growth of BDL rats to a lower extent than that observed in BDL RAMH-treated rats; histamine-induced inhibition of cholangiocyte growth was partly blocked by thioperamide maleate. In BDL rats treated with thioperamide maleate, cholangiocyte hyperplasia was slightly higher than that of BDL rats. In vitro, RAMH inhibited the proliferation of BDL cholangiocytes. RAMH inhibition of cholangiocyte growth was associated with decreased cAMP levels and PKA/ERK1/2/Elk-1 phosphorylation. Downregulation of cAMP-dependent PKA/ERK1/2/Elk-1 phosphorylation (by activation of H3R) is important in the inhibition of cholangiocyte growth in liver diseases.

Topics: Animals; Bile Ducts; Bile Ducts, Intrahepatic; Cell Proliferation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Down-Regulation; Drug Therapy, Combination; Gene Expression Regulation, Enzymologic; Histamine; Histamine Agonists; Hyperplasia; Ligation; Liver; Male; MAP Kinase Signaling System; Methylhistamines; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Phosphorylation; Piperidines; Protein Serine-Threonine Kinases; Rats; Rats, Inbred F344; Receptor, EphA8; Receptors, Histamine H3

Using a cyanide model to induce neurotoxic effects in rat brain homogenates, we examined the neuroprotective properties of three H3 antagonists, namely clobenpropit, thioperamide and impentamine, and compared them to aspirin, a known neuroprotective agent. Superoxide anion levels and malondialdehyde concentration were assessed using the nitroblue tetrazolium and lipid peroxidation assays. Clobenpropit and thioperamide significantly reduced superoxide anion generation and lipid peroxidation. Impentamine reduced lipid peroxidation at all concentrations used, but only reduced superoxide anion generation at a concentration of 1 mM. In the lipid peroxidation assay, all the drugs compared favourably to aspirin. This study demonstrates the potential of these agents to be neuroprotective by exerting antioxidant effects.

Topics: Animals; Antioxidants; Aspirin; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Histamine Agonists; Imidazoles; In Vitro Techniques; Lipid Peroxidation; Male; Malondialdehyde; Neuroprotective Agents; Neurotoxicity Syndromes; Piperidines; Potassium Cyanide; Rats; Rats, Wistar; Receptors, Histamine H3; Superoxides; Thiourea

The effects of histamine H3 antagonists on amygdaloid kindled and maximal electroshock seizures in rats were studied to determine their potential as new antiepileptic drugs. Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus and a stainless steel guide cannula for drug administration was implanted into the lateral ventricle. In amygdaloid kindled seizures, electrodes were implanted into the right amygdala and electroencephalogram was recorded bipolarly; stimulation was applied bipolarly every day by a constant current stimulator and continued until a generalized convulsion was obtained. In the maximal electroshock (MES) seizure test, electroconvulsion was induced by stimulating animals through ear-clip electrodes, and the durations of tonic and clonic seizures were measured. Thioperamide, clobenpropit, iodophenpropit, VUF5514, VUF5515 and VUF4929 caused a dose-dependent inhibition of both seizure stage and afterdischarge (AD) duration of amygdaloid kindled seizures. The duration of tonic seizure induced by MES was also inhibited by H3 antagonists, but the duration of clonic seizures were unchanged. Among the H3 antagonists tested, clobenpropit and iodophenpropit were somewhat more potent than the other drugs on amygdaloid kindled seizures and MES seizures, respectively. These results indicate that some H3 antagonists may be useful as antiepileptic drugs, especially for secondary generalized seizures and/or tonic-clonic seizures in humans.

Topics: Amygdala; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Electroshock; Epilepsy, Tonic-Clonic; Histamine Agonists; Histamine Antagonists; Imidazoles; Injections, Intraventricular; Isothiuronium; Kindling, Neurologic; Lateral Ventricles; Male; Methylhistamines; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Seizures; Thiourea

Experimental anxiety in mice was evaluated using a light/dark test at 60 min after injection of various histaminergics. Thioperamide, a histamine H(3) receptor inhibitor (5-20 mg/kg, intraperitoneal [IP]), Compound 48/80, a mast cell degranulator (0.1-10 microg/2 microl, intracerebroventricularly [ICV]), mepyramine, a histamine H(1) receptor antagonist (0.1-10 microg/2 microl, ICV) or cimetidine, a histamine H(2) receptor antagonist (0.1-10 microg/2 microl, ICV) alone did not affect the locomotive activity, the time spent in the light zone, and number of shuttle crossings in the light/dark test. However, the time spent in the light zone and the number of shuttle crossings significantly decreased only when cimetidine (0.1-10 microg/2 microl, ICV) was co-treated with either thioperamide (10 mg/10 ml/kg, IP) or Compound 48/80 (1.0 microg/2 microl, ICV). The decrease in these behavioral parameters suggests induced experimental anxiety in mice. The experimental anxiety was antagonized by mepyramine (10 microg/2 microl, ICV). These results suggest that not only neuronal histamine release induced by thioperamide but also non-neuronal (mast cells) histamine release induced by Compound 48/80 play an important role in inducing experimental anxiety via post-synaptic H(1) and H(2) receptors. In addition, it is likely that the anxiety may be mediated by the stimulation of H(1) receptors, while H(2) receptors may inhibit the anxiety produced by the activation of H(1) receptors.

Topics: Animals; Anxiety; Cimetidine; Disease Models, Animal; Histamine Antagonists; Histamine Release; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; p-Methoxy-N-methylphenethylamine; Piperidines; Pyrilamine

Whether or not peptide YY (PYY)-induced hyperphagia is modified by the histaminergic system in the brain is not yet known.. We investigated the effect on feeding of intracerebroventricular (ICV) administration of a specific histamine H3 receptor antagonist prior to ICV administration of PYY in rats.. PYY (1, 3, and 10 micrograms/10 microL) strongly induced feeding behavior in a dose-dependent manner in sated rats. The 4-hour food intake induced by 3 micrograms/10 microL of PYY was equal to that induced by a 16-hour fast. The ICV administration of thioperamide (40.8, 122.4, and 408.5 micrograms/10 microL) did not suppress the 4-hour food intake induced by 16-hour fasting; however, thioperamide produced dose-dependent and strong inhibition of hyperphagia induced by a 3-microgram dose of PYY.. These results suggest that the effect of PYY on appetite is different than that induced by fasting and may involve a histaminergic mechanism.

Topics: Analysis of Variance; Animals; Appetite Regulation; Bulimia; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Eating; Fasting; Histamine Antagonists; Hyperphagia; Injections, Intraventricular; Male; Peptide YY; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Satiation; Time Factors

Histamine H3 receptor ligands have been proposed to be of potential therapeutic interest for the treatment of different central nervous system disorders; however, the psychopharmacological properties of these drugs have not been studied extensively. In this work, we investigated the possible involvement of histamine H3 receptor function in experimental models of anxiety (elevated plus-maze) and depression (forced swimming test). Male Sprague-Dawley rats were treated i.p. with the histamine H3 receptor agonist R-alpha-methylhistamine (10 mg/kg) or the histamine H3 receptor antagonist thioperamide (0.2, 2 and 10 mg/kg) and 30 min afterwards the time spent in the open arms of an elevated plus-maze was registered for 5 min. The immobility time of male OF1 mice in the forced swimming test was recorded for 6 min, 1 h after the i.p. administration of R-alpha-methylhistamine (10 and 20 mg/kg), thioperamide (0.2, 2, 10 and 20 mg/kg) or another histamine H3 receptor antagonist, clobenpropit (5 mg/kg). The locomotor activity of mice was checked in parallel by means of an activity meter. Both saline controls and active drug controls were used in all the paradigms. Neither thioperamide nor R-alpha-methylhistamine significantly changed animal behaviour in the elevated plus-maze. R-alpha-methylhistamine and the higher dose of thioperamide assayed (20 mg/kg) were also inactive in the forced swimming test. By contrast, thioperamide (0.2-10 mg/kg) dose-dependently decreased immobility, the effect being significant at 10 mg/kg (33% reduction of immobility); clobenpropit produced an effect qualitatively similar (24% reduction of immobility). None of these histamine H3 receptor antagonists affected locomotor activity. These preliminary results suggest that the histamine H3 receptor blockade could be devoid of anxiolytic potential but have antidepressant effects. Besides, the stimulation of these receptors does not seem to be followed by changes in the behavioural parameters studied.

Topics: Analysis of Variance; Animals; Anxiety; Depression; Disease Models, Animal; Histamine Agonists; Histamine Antagonists; Imidazoles; Ligands; Male; Maze Learning; Methylhistamines; Mice; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Swimming; Thiourea

The effects of adenosine and histamine 2 and histamine 3 receptor agonists on the regulation of gastric histamine release were examined in anesthetized mixed-breed dogs. All compounds were infused directly into the gastrosplenic artery to avoid perturbations in systemic hemodynamics, and the gastric histamine release was stimulated with pentagastrin. The histamine concentration in plasma samples was measured utilizing gas chromatography-negative-ion chemical ionization mass spectroscopy. Pentagastrin consistently stimulated gastric histamine release with the peak stimulation occurring at 5 min, while neither 30 nor 100 microM of adenosine altered the effect of pentagastrin on histamine release. In addition, theophylline at 20 microg/ml exhibited no effect on stimulated histamine release. The histamine 2 receptor agonist dimaprit, at 1 and 3 microM, attenuated pentagastrin-stimulated histamine release at the 5-min time period, but the difference was not sustained at later time points (histamine release from 1.4 +/- 0.6 to 92 +/- 18 ng/min at 5 min with pentagastrin alone; from 1.2 +/- 0.5 to 32 +/- 11 ng/min with pentagastrin plus 1 microM dimaprit, and from 2.0 +/- 1.1 to 32 +/- 9 ng/min with pentagastrin plus 3 microM dimaprit), while the H2 receptor antagonist cimetidine exhibited no effect on pentagastrin-stimulated histamine release. The histamine 3 receptor agonist (R)-alpha-methylhistamine attenuated the pentagastrin-stimulated histamine release at the 5- and 10-min time periods only at 1 microM without showing any effect at the higher (3 microM) concentration. Thioperamide, a H3 receptor antagonist, did not modify pentagastrin-stimulated histamine release. These data demonstrate that adenosine has no modulatory role on gastric histamine release, but histamine via H2 and H3 histamine receptors could modulate its own release but only to a modest degree as compared with the potent effect of the paracrine hormone somatostatin.

Topics: Adenosine; Animals; Dimaprit; Disease Models, Animal; Dogs; Female; Gas Chromatography-Mass Spectrometry; Gastric Mucosa; Histamine Agonists; Histamine Antagonists; Histamine Release; Male; Methylhistamines; Multivariate Analysis; Pentagastrin; Piperidines; Receptors, Histamine; Reference Values; Regional Blood Flow; Statistics, Nonparametric; Theophylline

The histamine forming capacity (HFC) of acutely challenged airways from sensitised guinea pigs was investigated. After exposure to nebulised bovine serum albumin (BSA) or normal saline, animals were sacrificed, the pulmonary HFC determined and concurrent in vitro histamine log concentration response curves were constructed for parenchymal strips and tracheal muscle, the latter was field stimulated to record neurogenic responses. Exposure to BSA increased the HFC above controls for 24 hours (p < 0.001) and log concentration response curves for the parenchymal strips were shifted slightly to the left with an increased maximum response. This change appeared 3 hours after exposure and remained elevated at 24 hours. Similar changes did not occur with the trachea. Pre-treatment with thioperamide augmented (p < 0.02) HFC and this increase was inhibited by alpha-methylhistamine (p < 0.05). A possible relationship may exist between increased responsiveness of lower airways to exogenous histamine and a raised endogenous formation, regulated by the H3 receptor.

Topics: Animals; Binding Sites; Bronchial Hyperreactivity; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; Injections, Intraperitoneal; Ligands; Lung; Male; Methylhistamines; Muscle, Smooth; Piperidines; Receptors, Histamine H3; Serum Albumin, Bovine; Trachea

We investigated the effects of thioperamide, a histamine H3-receptor antagonist, in a light/dark test measuring anxiety in mice. Thioperamide (20 mg/kg) slightly affected the locomotion and time spent in a light zone, and shuttle crossing. However, the decreases of these parameters were significant only when the animals were pretreated with zolantidine, a histamine H2-receptor antagonist. Moreover, the decreased parameters induced by the combination of thioperamide and zolantidine were reversed by pretreatment with pyrilamine, a histamine H1-receptor antagonist. These data suggest that thioperamide induces the release of neuronal histamine, which in turn stimulates both H1- and H2-receptors to produce the anxiogenic effect. The stimulation of histamine H1-receptors may mediate the anxiety, while H2-receptors may play a role in masking the anxiogenic effect. Thus, the present study suggests the involvement of endogenous neuronal brain histamine in anxiety. In the biochemical study, a previous report showed that thioperamide accelerated the release of neuronal histamine in the brains of mice [Sakai et al., Life Sciences, 48, 2397-2404(1991)]. This study also demonstrated that thioperamide did not affect the turnover rate of noradrenaline, dopamine, or serotonin in the brains of mice, which indicates that thioperamide is a good pharmacological tool for accelerating the release of neuronal histamine in the brain.

Topics: Animals; Anxiety; Behavior, Animal; Brain; Darkness; Disease Models, Animal; Dopamine; Histamine Antagonists; Light; Male; Mice; Mice, Inbred ICR; Motor Activity; Norepinephrine; Piperidines; Serotonin