Histamine In Rats Research Articles

Effects of catgut embedding and PGLA embedding at "Zusanli" (ST 36) on skin mast cells, substance P and histamine in healthy rats

To observe the effects of catgut embedding and polyglycolic acid/poly-lactic acid (PGLA) embedding at "Zusanli" (ST 36) on the activation of local skin mast cells (MC), and expression of substance P (SP) and histamine (HA), and to explore the mechanism of the temporal stimulation effect of acupoint catgut embedding and provide a foundation for further research on the initiation mechanism of acupoint catgut embedding. One hundred and sixty male SPF-grade SD rats were randomly divided into a blank group (10 rats), a sham-embedding group (50 rats), a catgut group (50 rats), and a PGLA group (50 rats). Each intervention group was further randomly divided into five subgroups according to the time points after intervention: 8 hours, 3 days, 7 days, 14 days, and 21 days, with 10 rats in each subgroup. One-time sham-embedding, catgut embedding and PGLA embedding was given at left "Zusanli" (ST 36) in each intervention group, respectively. The skin and subcutaneous connective tissue of the left "Zusanli" (ST 36) were collected at the corresponding time points after intervention, except for the blank group (only one day before intervention). Toluidine blue staining was used to detect MC count and degranulation, and immunohistochemical staining was used to detect the expression of SP and HA positive cells. There was no significant difference in MC count between the subgroups of each intervention group and the blank group (P>0.05). There was no significant difference in MC count between the subgroups of the catgut group and the PGLA group (P>0.05). The MC count in the 8-hour subgroup of PGLA group was higher than that in the 8-hour subgroup of catgut group (P<0.05), while the MC count in the 21-day subgroup of PGLA group was lower than that in the 21-day subgroup of catgut group (P<0.05). Compared with the blank group, the degranulation rates of MC were increased in the 8-hour and 3-day subgroups of sham-embedding group, 8-hour, 3-day, and 7-day subgroups of catgut group, and 8-hour, 3-day, 7-day, and 14-day subgroups of PGLA group (P<0.01, P<0.05, P<0.001). There was no significant difference in the degranulation rate of MC between the subgroups of the catgut group and the PGLA group (P>0.05), and no significant difference in the degranulation rate of MC between the two embedding groups at the same time point (P>0.05). Compared with the blank group, the expression of SP positive cells was increased in the 8-hour subgroup of sham-embedding group, 8-hour, 3-day, 7-day, and 14-day subgroups of catgut group, and 3-day, 7-day, and 14-day subgroups of PGLA group (P<0.001, P<0.05). The expression of SP positive cells in the 7-day subgroup of catgut group was higher than that in the 8-hour subgroup of catgut group (P<0.05), while the expression of SP positive cells in the 14-day subgroup of catgut group was lower than that in the 7-day subgroup of catgut group (P<0.001). The expression of SP positive cells in the 7-day subgroup of PGLA group was higher than that in the 3-day subgroup of PGLA group (P<0.05), while the expression of SP positive cells in the 14-day subgroup of PGLA group was lower than that in the 7-day subgroup of PGLA group (P<0.01). There was no significant difference in the expression of SP positive cells between the subgroups of the two embedding groups at the same time point (P>0.05). Compared with the blank group, the expression of HA positive cells was increased in the 8-hour, 3-day subgroups of sham-embedding group, 8-hour, 3-day, 7-day, and 14-day subgroups of catgut group, and 8-hour, 3-day, 7-day, 14-day, and 21-day subgroups of PGLA group (P<0.001, P<0.01, P<0.05). The expression of HA positive cells in the 14-day subgroup of catgut group was lower than that in the 7-day subgroup of catgut group (P<0.05), while the expression of HA positive cells in the 3-day subgroup of PGLA group was higher than that in the 8-hour subgroup of PGLA group (P<0.05), and the expression of HA positive cells in the 14-day subgroup of PGLA group was lower than that in the 7-day subgroup of PGLA group (P<0.05). The expression of HA positive cells in the 3-day subgroup of PGLA group was higher than that in the 3-day subgroup of catgut group (P<0.05). Catgut and PGLA embedding at "Zusanli" (ST 36) in healthy rats could induce changes in local skin MC, SP, and HA, which may be one of the mechanisms of the temporal stimulation effect after acupoint embedding. There are certain differences between different suture materials. A moderate inflammatory response in the acupoint area, mediated by MC and involving SP and HA, may be one of the initiating factors for the effect of acupoint catgut embedding.

Pharmacological Screening Model and Its Treatment of Peptic Ulcer Disease

Peptic ulcer is a ceaseless sickness influencing up to 10% of the total population. Peptic ulcer created by the unevenness of gastric juice pH and mucosal protections. Two fundamental components delivered Peptic ulcer. Frist is central point it included bacterial disease, for example, Helicobacter Pylori (H. Pylori) and medicine non-steroidal anti-inflammatory medication and synthetic E.g., HCL, Ethanol. Second is minor factor it included pressure, smoking, fiery food and nourishment lopsidedness. Ordinary treatment of Peptic ulcer, for example, proton siphon inhibitor (PPI) and Histamine-2 (H2) Receptor Antagonist. Also, other Hand therapeutic plant and their concoction compound are valuable in the counteraction and treatment of peptic ulcer infection. Various creature models are utilizing to influenced ulcer to identifying the antiulcer activity of many new existed drugs such as Pylorus ligated (shay) rats, Stress ulcers, Restraint ulcer in rats, Water immersion-induced restraint ulcers, Cold and restraint ulcers, Gastric mucosal damage induced by NSAID in rats, Induced solitary chronic gastric ulcer, Acetic acid induced kissing gastric ulcers in rats Histamine induced gastric ulcer in guinea pig, Duodenal anti-ulcer activity, Gastric cytoprotective action.

Evaluation of Anti-Inflammatory Potential of Turmimax® an in vivo and in vitro Study

The main objective of this study was to investigate the in vivo and in vitro anti-inflammatory effects of the Turmimax® bio-enhanced turmeric formulation. By comparing the relative fluorescence intensities of the interleukins IL-8 (Interleukin-8) and IL-12 (Interleukin-12) cytokines in stimulated murine Raw 264.7 macrophages, Turmimax® was evaluated for its anti-inflammatory in vitro efficacy. Turmimax® was administered orally in two doses, 100 and 200 mg/kg, to assess its in vivo anti-inflammatory potential in ear edema induced by croton oil in mice and paw edema induced by histamine in albino rats. Diclofenac sodium 10 mg/kg p.o. is the standard drug. The results demonstrated that Turmimax® significantly and dose-dependently decreased the production of the inflammatory mediator’s interleukin-8 and IL-12. According to the current investigation results, Turmimax® has shown strong anti-inflammatory effects.

005 Samelisant (SUVN-G3031), a histamine H3 receptor inverse agonist in animal models of sleep disorders

Abstract Introduction Narcolepsy is a chronic sleep disorder characterized by overwhelming daytime drowsiness, sudden attacks of sleep and sometimes accompanied by cataplexy. Although the orexin deficiency is considered to be the primary cause of this disorder, lot of attention has been diverted on targeting histaminergic neurotransmission by blockade of histamine H3 receptor (H3R). Samelisant (SUVN-G3031) is one of the potent and selective H3R inverse agonist currently being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). In the current research work, Samelisant was evaluated for neurotransmitter changes in rats and sleep EEG in orexin knockout mice, a reliable proof-of-concept study for treatment of excessive daytime sleepiness and cataplexy in narcolepsy. Methods Binding affinity of Samelisant towards human and rat histamine H3R was evaluated in in-vitro radioligand binding assay and functionality in GTP□S assay. Effect of Samelisant was studied in (R)-α-methyl histamine induced dipsogenia. In rat brain microdialysis, Samelisant was evaluated for its effects on modulation of neurotransmitters like histamine, dopamine and norepinephrine. Male orexin knockout mice were implanted with telemetric device for simultaneous monitoring of electroencephalography (EEG) and electromyography. Effects of Samelisant (3 and 10 mg/kg, p.o.) were evaluated during active period of animals. Results Samelisant is an inverse agonist at histamine H3 receptors with hKi of 8.7 nM and showed minimal binding against over 70 target sites. Samelisant produced significant increase in histamine, dopamine and norepinephrine levels in cortex. Samelisant produced no change in the striatal and accumbal dopamine levels in rats, suggesting no propensity to induce abuse liability. Samelisant blocked R-α-methyl histamine induced water intake and produced dose dependent increase in tele-methylhistamine levels in various brain regions and in cerebrospinal fluid of male Wistar rats. Samelisant produced significant increase in wakefulness with concomitant decrease in non-rapid eye movement sleep in orexin knockout mice. Samelisant also significantly decreased number of cataplectic episodes in orexin knockout mice. Conclusion Samelisant is an inverse agonist at histamine H3 receptor and results from the preclinical studies presented here provide a strong evidence for the potential utility of Samelisant in the treatment of narcolepsy with and without cataplexy. Support (if any):

A Novel Potent and Selective Histamine H3 Receptor Antagonist Enerisant: In Vitro Profiles, In Vivo Receptor Occupancy, and Wake-Promoting and Procognitive Effects in Rodents.

Histamine H3 receptor antagonists/inverse agonists are known to enhance the activity of histaminergic neurons in the brain, thereby promoting arousal and cognition. Here, we report the in vitro and in vivo pharmacological profiles for a newly synthesized histamine H3 receptor antagonist/inverse agonist: [1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl](morpholin-4-yl)methanone monohydrochloride (enerisant hydrochloride). In vitro assays showed that enerisant was a competitive antagonist/inverse agonist with a high affinity and selectivity for human and rat histamine H3 receptors. Enerisant showed antagonist activity in vivo, as assessed using R-α-methylhistamine (a histamine H3 receptor agonist)-induced dipsogenia, and occupied the histamine H3 receptor in the frontal cortex in a dose-dependent manner. Enerisant also enhanced the extracellular levels of histamine in the posterior hypothalamus and the levels of dopamine and acetylcholine in the medial prefrontal cortex of rats. Enerisant exerted a procognitive effect or reversed scopolamine-induced cognitive impairment in a social recognition test and a novel object recognition test in rats at doses at which less than 50% of the histamine H3 receptor were occupied (0.03-0.3 mg/kg, p.o.). In contrast, higher doses (3-10 mg/kg, p.o.) at which nearly all the histamine H3 receptors were occupied were needed to exert wake-promoting effects in rats. These results indicate that enerisant is a potent and selective histamine H3 receptor antagonist/inverse agonist with the potential to promote arousal and procognition in rats. Moreover, the results also suggest that the histamine H3 receptor occupancy required to exert a pharmacological effect may vary depending on the domain that is being tested. SIGNIFICANCE STATEMENT: Enerisant is a novel histamine H3 receptor antagonist/inverse agonist that exerts wake-promoting and procognitive effects in addition to increasing the release of neurotransmitters related to these pharmacological effects in rodents. Moreover, an in vivo receptor binding study revealed that the in vivo occupancy of the histamine H3 receptor required to exert the pharmacological effects of enerisant varied, and such variations in required occupancy should be taken into account when performing dose selection in clinical studies.

0072 Preclinical Characterization of SUVN-G3031, a Histamine H3 Receptor Inverse Agonist for the Treatment of Narcolepsy

Abstract Introduction Narcolepsy is a chronic sleep disorder characterized by overwhelming daytime drowsiness, sudden attacks of sleep and sometimes accompanied by cataplexy. Although the orexin deficiency is considered to be the primary cause of this disorder, lot of attention has been focused recently on targeting histaminergic neurotransmission by blockade of histamine H3 receptor (H3R). SUVN-G3031 is one of the potent and selective H3R inverse agonist currently being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Methods Binding of SUVN-G3031 in human and rat histamine H3R was evaluated in in vitro radioligand binding assay and functionality was assessed in GTPγS assay. Pharmacokinetic properties were evaluated after oral administration in rat and dog. Neurotransmitters like histamine, dopamine and norepinephrine were estimated in rat cortex using microdialysis. Results SUVN-G3031 is an inverse agonist at histamine H3R with hKi of 8.7 nM and showed minimal binding against over 70 target sites. SUVN-G3031 exhibited desired pharmacokinetic properties in rat and dog with excellent brain penetration in rats. SUVN-G3031 produced significant increase in histamine, dopamine and norepinephrine levels in cortex. SUVN-G3031 produced no change in the striatal and accumbal dopamine levels in rats, suggesting no propensity to induce abuse liability. SUVN-G3031 blocked R-α-methylhistamine induced water intake and produced dose dependent increase in tele-methylhistamine levels in various brain regions and in cerebrospinal fluid of male Wistar rats. Conclusion SUVN-G3031 is an inverse agonist at histamine H3 receptor and results from the preclinical studies presented here provide a strong evidence for the potential utility of SUVN-G3031 in the treatment of narcolepsy with and without cataplexy. Support None

Effects of Bambara Nut (Vigna subterranean) on Basal and Stimulated Gastric Acid Secretion due to Histamine, Pentagastrin and Carbachol in rats

The seed extracts of V. subterranean (Bambara nuts) have many therapeutic applications in folkloric medicine owing to their effective secondary metabolites such as alkaloids, flavonoids, saponins, resins, and glycosides (Andzouana et al., 2014). The infusions and decoctions of the seeds are used to treat venereal diseases, diarrhoea, cataract, beriberi and polymenorrhea (Brink and Belay, 2006; Basu et al., 2007). The raw seeds are chewed to alleviate nausea and vomiting in pregnant women. V. Subterranea seed extracts have been shown to possess some biological properties such as antioxidant and hepatoprotective (Nyau et al., 2015; Iweala and Elekwa, 2001). In spite of multi‐functional properties of V. subterranea, its gastroprotective effect has not been fully explored. This study was carried out to examine the effects of V. Subterranea on basal and stimulated gastric acid secretion (GAS) in the Wistar rats. Each group of rats consisting of 5 rats (180–210g) was treated with aqueous extract of V. Subterranea (150 mg/kg, 250mg/kg and 400mg/kg) orally for 21 days. The animals were handled in accordance with guide for the care and use of laboratory animals (NIH, 2011). At the last day of the treatment, the rats were fasted for 24 hours, anaesthetized with ketamine. GAS (mEq/l) induced by histamine, carbachol and pentagastrin administration were assessed by the continuous perfusion technique using phenolphthalein as indicator. Data obtained were expressed as the Mean ± SEM) and analyzed using one way Analysis of Variance (ANOVA) and Graph Pad prism 5. The differences in mean were considered significant at p≤ 0.05. The aqueous extract of V. Subterranea significantly decreased (p&lt;0.05) GAS induced by the histamine, carbachol and pentagastrin in a dose‐dependent manner over 80 minutes period in all the treated groups, although at varying rates. The gastroprotective action of V. Subterranea may be multifactorial that may include an anti‐secretory action.Support or Funding InformationWe wish to thank Usmanu Danfodiyo University, Sokoto, Nigeria for their support.Effect of Histamine on BambaraFigure 1Effect of Carbachol on BambaraFigure 2Effect of Pentagastrin on BambaraFigure 3

Bulleyaconitine A Inhibits Itch and Itch Sensitization Induced by Histamine and Chloroquine

Itch (pruritus), specifically chronic itch associated with disease conditions, significantly impairs the patient’s quality of life. At present, the mechanisms underlying this aversive experience are still unclear, and the effective treatment of itch is largely unmet. Here, we report that intragastrical administration of bulleyaconitine A (BLA), which has been used for treating chronic pain for 30 years in China, inhibited itch-like behaviors induced by intradermal injection of histamine and chloroquine in mice and rats, dose-dependently. We found that a single application of the pruritic agents at the skin region innervated by the sural nerve induced long-term potentiation (LTP) of C-fiber field potentials evoked by the stimulation of the same nerve in the spinal dorsal horn of rats. The spinal LTP was remarkably reversed by the spinal application of either BLA or gastrin-releasing peptide receptor (GRPR) antagonist (PD176252). The effect of PD176252 was completely occluded by BLA, while the effect of BLA was only partially occluded by PD176252. Repetitive injection (daily, for four days) of either histamine or chloroquine in the back of the neck enhanced scratching behaviors progressively, and the itch sensitization persisted for at least one week after the discontinuation of the injections. The behavioral change was accompanied with the potentiation of C-fiber synaptic transmission in the dorsal horn. Both the itch sensitization and synaptic potentiation were substantially attenuated by intragastrical BLA. Together, BLA was effective in inhibiting histamine-dependent and histamine-independent itches, and the mechanisms underlying these effects were involved but not limited to the inhibition of gastrin-releasing peptide (GRP)–GRPR signaling in the spinal dorsal horn.

3H]UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H4 Receptors.

Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H4 receptors (H4R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH4Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH4Rs: UR-DEBa148 (N-neopentyl-4-(1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), 43), the most potent [pEC50 (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(R)-4-[3-(dimethylamino)pyrrolidin-1-yl]-N-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), 46, pEC50 (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H4R ligand. After radiolabeling, binding studies with [3H]UR-DEBa176 ([3H]46) at the h/m/rH4Rs revealed comparable Kd values (41/17/22 nM), low nonspecific binding (11-17%, ∼Kd), and fast associations/dissociations (25-30 min) and disclosed [3H]UR-DEBa176 as useful molecular tool to determine h/m/rH4R binding affinities for H4R ligands.

Punishment and reinforcement by opioid receptor agonists in a choice procedure in rats.

Intravenous (i.v.) drug self-administration remains the 'gold standard' for assessing abuse potential of drugs. Failure of a drug to maintain self-administration might indicate merely the absence of positive-reinforcing effects but might also indicate presence of aversive effects. Sensitivity to aversive effects is thought to affect the initiation and maintenance of drug use as well as relapse. Choice procedures are used to study positive-reinforcing effects of drugs and to a much lesser extent to study punishing effects of drugs. Experiment 1 compared the μ-opioid receptor agonist remifentanil (0.001-0.01 mg/kg/infusion), the κ-opioid receptor agonist spiradoline (0.0056-0.056 mg/kg/infusion), and histamine (1.0 mg/kg/infusion) in rats choosing between a food pellet only and an i.v. infusion+a food pellet. To test whether a history with one punishing drug affects the punishing effects of a second drug, experiment 2 compared sensitivity with spiradoline in rats with and without a history of histamine punishment. All rats predominantly chose a pellet alone when histamine+a pellet was the alternative, and they predominantly chose remifentanil+a pellet over a pellet alone. In experiment 2, spiradoline was punishing in rats with a history of histamine punishment but not drug-naive rats. This food choice procedure is sensitive to reinforcing and punishing effects of different drugs in the same subjects, suggesting that the procedure is well-suited for studying drug mixtures (e.g. μ and κ agonists) and the impact of different physiological conditions (e.g. pain) on reinforcement and punishment.

Effect of aqueous extract of Tamarindus indica Linn. (Leguminosae) pulp on basal and stimulated gastric acid secretion due to histamine, pentagastrin and carbachol in rats

Local folklore claims that Tamarindus indica Linn. (Leguminosae) has a gastric beneficial role in humans ( Pankaj et al., 2011). This study was carried out to examine the effects of tamarind on basal and stimulated gastric acid secretion (GAS) in the Wistar rats. Four groups of rats consisting of 6 rats (180 – 210 g) each were treated with aqueous extract of tamarind pulp (1.5 mg/kg, 2.5 mg/kg and 4 mg/kg) orally for 21 days. The ethical guidelines in accordance with NIH Guide for care and use of laboratory animals were followed in the handling of the animals during the studies. At the last day of the treatment, the rats were fasted for 24 hours, anaesthetized with ketamine and cannulated through the femoral vein. GAS (mEq/l−1) induced by histamine, pentagastrin and carbachol administration were assessed by using modified continuous perfusion technique method of Ghosh and Schild (1958) and its acidity determined by titration method. Data were expressed as mean ± SEM. Student's t‐test and one way ANOVA were used to analyze and determine levels of significance at p=0.05.The aqueous extract of tamarind significantly decreased (p&lt;0.05) GAS induced by the histamine, pentagastrin and carbachol at small and medium doses, but not at higher doses over the 80 minute's period in all the treated groups. The gastroprotective action of tamarind may be multifactorial that may include anti‐secretory action.Support or Funding InformationThe financial support of Usmanu Danfodiyo University, Sokoto Nigeria is acknowledgedThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Design, synthesis, and in vitro and in vivo characterization of 1-{4-[4-(substituted)piperazin-1-yl]butyl}guanidines and their piperidine analogues as histamine H3 receptor antagonists.

Previously, we have shown that 1-substituted-[4-(7-phenoxyheptylpiperazin-1-yl)butyl]guanidine with electron withdrawing substituents at position 4 in the benzyl moiety exhibits high in vitro affinities toward the guinea pig jejunal histamine H3 receptor with pA 2 ranging from 8.49 to 8.43. Here, we present data on the impact of replacement of the piperazine scaffold by the piperidine ring (compounds 2a and 2b), moving benzyl- and 4-trifluoromethylbenzyl substituents from position 1 to 3 of the guanidine moiety (compounds 2c and 2d), which decreases the guanidine basicity (compound 2e), and the influence of individual synthons (compounds 2f-h), present in the lead compounds 1b and 1c, on the antagonistic activity against the histamine H3 receptor. Additionally, the most active compounds 1a, 1c, and 1d were evaluated for their affinity to the rat histamine H3 receptor and the human histamine H3 and H4 receptors. It was also shown that compounds 1a, 1c and 1d, given parenterally for five days, reduced the food intake of rats and did not influence the brain histamine or noradrenaline concentrations; however, significantly reduced serotonin and dopamine concentrations were found in rats administered with compounds 1a and 1c, respectively.

Metabonomics delineates allergic reactions induced by Shuang-huang-lian injection in rats using ultra performance liquid chromatography-mass spectrometry

Shuang-huang-lian Injection (SHLI) is the first successfully developed drug from traditional Chinese medicine (TCM) powder for injection, since its use for the treatment of acute respiratory tract infection, pneumonia, influenza, etc. At the same time, its allergic reactions have also emerged, which limits clinical applications. However, few scholars pay attention to the mechanism of allergic reactions. In this present study, metabonomics technology was used to explore the changes in endogenous metabolites in urine of the rat model of SHLI induced allergic reaction; we and analyzed the metabolites, metabolic pathway, and the mechanism which were closely related to the allergic reactions. The levels of serum histamine and tryptase were examined and changes in histomorphology were also observed. Based on the UPLC-Q-TOF/MS metabonomics, we carried out the pattern recognition analysis, selected potential biomarkers associated with allergic reactions, and explored the pathological mechanism for SHLI induced allergic reaction, which laid the foundation for the safety research of SHLI. Our results showed that SHLI increased the levels of serum histamine and tryptase in rats with allergic reaction; we determined 15 biomarkers in rat allergic reaction model induced by SHLI and found multiple metabolic pathways involved, such as metabolism of linolenic acid, phenylalanine, amino acid, 2-oxo acid, and purine and other metabolic pathways.

Illicium verum Extract Exhibited Anti-inflammatory Action in Rodents

Background: Illicium verum Hook. f. (Star anise) has been traditionally used for the treatment of abdominal colic, vomiting, pain, nervousness, insomnia and rheumatism. Objective: The present study was conducted to investigate the anti-inflammatory properties of Illicium verum extracts. Methods: Different extracts of I. verum (IV-Ext-1, IV-Ext-3 and IV-Ext-4) were screened for their anti-inflammatory potential using carrageenan-induced paw edema in mice. The mechanism of action was explored using paw edema tests (carrageenan, histamine, serotonin and prostaglandins) in rats and anti-oxidant activity (DPPH assay). Reverse phase HPLC was used for chemical characterization of extracts. Results: The IV-Ext-3 was found to be the most potent anti-inflammatory agent (38% inhibition) using carrageenan-induced paw edema. The anti-inflammatory effect was observed during both the initial (IC50: 260 mg/kg) and late phases (IC50: 200 mg/kg). Similar IC50 of 200 mg/kg was observed in both phases of histamine-induced paw edema. However, the extract failed to cause 50% inhibition in serotonin-induced edema (IC25: 400 mg/kg) and was also ineffective against Prostaglandin- E2 induced edema. Furthermore, the IV-Ext-3 appeared to be an effective antioxidant (IC50: 12 µg/ml). The HPLC chromatogram of IV-Ext-3 showed the presence of anti-inflammatory constituents such as shikimic acid (1.6%) and anethole (0.25%), 3, 4-dihydroxybenzoic acid (0.003%) and p-hydroxy methyl benzoate (0.117%) along with some polar hydroxyl derivatives of benzoic acids. Conclusion: Among all the extracts of I. verum, IV-Ext-3 was found to be the most effective antiinflammatory agent which can be attributed to multiple anti-inflammatory constituents, antihistamine and antioxidant potentials. Keywords: Star anise, anti-histamine, prostaglandins synthesis inhibitor, antioxidant, anti-inflammatory, edema.

Gallic acid improves endothelium-dependent vasodilatory response to histamine in the mesenteric vascular bed of diabetic rats.

Endothelial dysfunction is one of the many complications caused by diabetes mellitus. The aim of the present study was to evaluate the effects of gallic acid (GA) on the mesenteric vascular bed (MVB) response to histamine in diabetic rats. Forty male Wistar rats were randomly assigned to a control group, an untreated alloxan-induced diabetic group and three diabetic groups treated with different doses of GA. Six weeks after induction of diabetes and GA treatment, total antioxidant capacity (TAC), malondialdehyde (MDA) concentrations, and the vasodilatory response to histamine of the MVB (measured as changes in perfusion pressure) were determined. The vasodilatory response to histamine and TAC decreased, whereas MDA increased in the plasma from diabetic rats (P < 0.01). However, in the presence of 3 × 10-5 mol/L N G -nitro-l-arginine methyl ester (a nitric oxide synthase inhibitor) and 1 × 10-5 mol/L indomethacin (an inhibitor of prostaglandin production), the vasodilatory response of the MVB to histamine was reduced in all groups (P < 0.001). Treatment of diabetic rats with 20 and 40 mg/kg per day GA, but not 10 mg/kg per day GA, increased TAC and decreased MDA concentrations (P < 0.01 and P < 0.001 vs untreated diabetic rats, respectively) and significantly improved the vasodilatory response to histamine (P < 0.05 and P < 0.001, respectively). The results show that, in diabetic rats, the endothelium-dependent vasodilatory response of the MVB to histamine is significantly decreased and depends on both nitric oxide- and prostaglandin-producing pathways and may be mediated by oxidative stress. Treatment with the antioxidant GA restored the vasodilatory response of the MVB to histamine.

The Effect of Schinus terebinthifolius Raddi (Anacardiaceae) Bark Extract on Histamine-Induced Paw Edema and Ileum Smooth Muscle Contraction.

Schinus terebinthifolius Raddi (Anacardiaceae), popularly known as red aroeira, is used in traditional medicine to treat inflammatory, gastric, and respiratory disorders. The aim of this study was to evaluate the antihistaminic activity of S. terebinthifolius (St) bark extract by using in vivo and in vitro experimental models. The effects of St were investigated on contractions induced by histamine, carbachol, and potassium chloride in isolated guinea pig ileum. St was also studied in response to hind paw edema induced by histamine in rats. Experiments revealed that although St (250, 500, and 1,000 µg/mL) reduced the histamine-induced contractions by 9.1 ± 1.8, 50.2 ± 2.0, and 68.9 ± 2.0%, respectively, it did not inhibit contractions induced by carbachol or KCl. The association of St (250 and 500 µg/mL) with hydroxyzine, an H1-antihistamine (0.125 and 0.250 µM), increased the inhibitory effect to 67.0 ± 3.2 and 85.1 ± 2.1%, respectively. Moreover, St (100, 200, and 400 mg/kg) decreased paw edema from its peak by 33.9, 48.4, and 54.8%, respectively, whereas hydroxyzine (70 mg/kg) inhibited the peak edema by 56.5%. Altogether, the results suggest that the bark extract of S. terebinthifolius has an antihistaminic effect (H1).

The effects of crocin and safranal on the yawning induced by intracerebroventricular injection of histamine in rats.

Crocin and safranal, as the major constituents of saffron, have many biological activities. This study investigated the effects of crocin and safranal on yawning response induced by intracerebroventricular (i.c.v.) injection of histamine in rats. In ketamine/xylazine-anesthetized rats, a guide cannula was implanted in the right ventricle of the brain and yawning induced by i.c.v. injection of histamine. Crocin and safranal were intraperitoneally (i.p.) injected alone and before i.c.v. injection of histamine. Histamine at the doses of 10 and 20 µg/rat produced yawning. Mepyramine (a histamine H1 receptor antagonist) 40 µg/rat significantly (p<0.05) prevented histamine (20 µg/rat)-induced yawning. Crocin (30 mg/kg) and safranal (1 mg/kg) significantly (p<0.05) increased histamine (10 µg/rat)-induced yawning. Crocin and safranal also induced yawning when injected before mepyramine plus histamine administration. The results of the present study showed a yawning-inducing effect for central histamine, which was inhibited by mepyramine. Crocin and safranal increased histamine-induced yawning, and also produced yawning when the histamine action is blocked.

ヒスタミンによるラット閉口反射の抑制

ヒスタミンによるラット閉口反射の抑制

Cocaine self-administration punished by intravenous histamine in adolescent and adult rats.

Adolescence is a transitional phase marked by a heightened vulnerability to substances of abuse. It has been hypothesized that both increased sensitivity to reward and decreased sensitivity to aversive events may drive drug-use liability during this phase. To investigate possible age-related differences in sensitivity to the aversive consequences of drug use, adolescent and adult rats were compared on self-administration of cocaine before, during, and after a 10-day period in which an aversive agent, histamine, was added to the cocaine solution. Adult and adolescent female rats were trained to self-administer intravenous cocaine (0.4 mg/kg/infusion) over 10 sessions (2 h/session; 2 sessions/day). Histamine (4 mg/kg/infusion) was then added directly into the cocaine solution for the next 10 sessions. Finally, the cocaine/histamine solution was replaced with a cocaine-only solution, and rats continued to self-administer cocaine (0.4 mg/kg) for 20 sessions. Compared with adolescent rats, adult rats showed a greater decrease in cocaine self-administration when it was punished with intravenous histamine compared with their baseline cocaine self-administration rates. These results suggest that differences in the sensitivity to negative consequences of drug use may partially explain developmental differences in drug use vulnerability.

Assessment of [125I]WYE-230949 as a novel histamine H3 receptor radiopharmaceutical.

Histamine H3 receptor therapeutics have been proposed for several diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease and obesity. We set out to evaluate the novel compound, [125I]WYE-230949, as a potential radionuclide imaging agent for the histamine H3 receptor in brain. [125I]WYE-230949 had a high in vitro affinity for the rat histamine H3 receptor (Kd of 6.9 nM). The regional distribution of [125I]WYE-230949 binding sites in rat brain, demonstrated by in vitro autoradiography, was consistent with the known distribution of the histamine H3 receptor. Rat brain uptake of intravenously injected [125I]WYE-230949 was low (0.11 %ID/g) and the ratio of specific: non-specific binding was less than 1.4, as determined by ex vivo autoradiography. In plasma, metabolism of [125I]WYE-230949 into a less lipophilic species occurred, such that less than 38% of the parent compound remained 30 minutes after injection. Brain uptake and metabolism of [125I]WYE-230949 were increased and specific binding was reduced in anaesthetised compared to conscious rats. [125I]WYE230949 is not a potential radiotracer for imaging rat histamine H3 receptors in vivo due to low brain uptake, in vivo metabolism of the parent compound and low specific binding.