Curcuminoids, a major turmeric component, have a sleep-enhancing effect by targeting the histamine H1 receptor.

Turmeric (Curcuma longa) had been considered as a universal panacea in functional foods and traditional medicines. In recent, the sedative-hypnotic effect of turmeric extract (TE) was reported. However, sleep-promoting compounds in TE have been not yet demonstrated. Curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) are the major constituents of turmeric being responsible for its various biological activities. Therefore, they can be first assumed to be sedative-hypnotic compounds of TE. In the present study, we aimed to investigate the effects and underlying mechanisms of curcuminoids and each constituent on the sleep-wake cycle of mice. Molecular docking studies, histamine H1 receptor (H1R) binding assays, and H1R knockout animal studies were used to investigate the molecular mechanisms underlying the sleep-promoting effects. Curcuminoids and their constituents reduced sleep latency and increased sleep duration in the pentobarbital-induced sleep test in mice. In addition, curcuminoids significantly increased the duration of NREMS and reduced sleep latency without altering the REMS and delta activity. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin were predicted to interact with H1R in the molecular model. In the binding affinity assay, we found that curcuminoids, as well as their constituents, significantly bind to H1R with the Ki value of 1.49 µg mL-1. Furthermore, sleep latency was reduced and NREMS frequency was increased following curcuminoid administration in wild-type mice but not in H1R knockout mice. Therefore, we conclude that curcuminoids reduce sleep latency and enhance the quantity of NREMS by acting as modulators of H1R, indicating their usefulness in treating insomnia.

Patho-Pharmacological Research of Anti-allergic Natural Products Targeting Antihistamine-Sensitive and -Insensitive Allergic Mechanisms.

Histamine H1 receptor (H1R) has a special up-regulation mechanism by the stimulation of H1R, mediated by protein kinase C-delta (PKCδ) signaling and H1R gene expression, resulting increase in H1R signaling. Increase in H1R mRNA in nasal mucosa was induced after the provocation of nasal hypersensitivity model rats and suppressed by the pre-treatment of antihistamines. Improvement of nasal symptoms and suppression of H1R mRNA expression in nasal mucosa were also observed by the pre-treatment of antihistamines in pollinosis patients. Elucidation of a correlation between symptoms and H1R mRNA level suggests that H1R gene is an allergic disease (AD)-susceptibility gene, targeted by antihistamines. Similar to antihistamines, pre-treatment of Kujin extract, an anti-allergic Kampo medicine improved nasal symptoms and suppressed H1R mRNA expression in nasal hypersensitivity model rats. (-)-Maackiain targeting heat shock protein 90 (Hsp90) was isolated as an inhibitor of PKCδ signaling-mediated H1R gene expression from Kujin extract. In addition to H1R-mediated activation of H1R gene expression as the first mechanism, nuclear factor of activated T-cells (NFAT)-mediated IL-9 gene expression is suggested to participate to allergic symptoms as the second mechanism insensitive to antihistamines. Pyrogallol and proanthocyanidin suppressing IL-9 gene expression were discovered from Awa-tea and lotus root knots, respectively. Combination therapy using medicines suppressing both H1R gene expression and IL-9 gene expression is promising for outstanding alleviation of AD. Multifactorial diseases involving H1R gene expression may be treated by the combination therapy with antihistamine and complementary drugs, and diseases involving PKCδ signaling may be treated by drugs targeting Hsp90.

A Novel Potent Sleep-Promoting Effect of Turmeric: Turmeric Increases Non-Rapid Eye Movement Sleep in Mice Via Histamine H1Receptor Blockade.

SCOPE: Turmeric has a broad spectrum of biological properties; however, the sleep-promoting effects of turmeric have not yet been reported. Thus, this study aims to investigate the effect of turmeric on sleep and the molecular mechanism underlying this effect. METHODS AND RESULTS: Pentobarbital-induce sleep test and sleep-wake profile assessment using recorded electroencephalography are used to evaluate the hypnotic effects of the turmeric extract (TE) compared to diazepam on sleep in mice. Additionally, the molecular mechanism of TE's sleep effect is investigated using ex vivo electrophysiological recordings from brain slices in histamine H1 receptor (H1 R) knockout mice. Oral administration of TE and diazepam significantly reduce sleep latency and increase non-rapid eye movement sleep (NREMS) duration without delta activity in mice. Like doxepin, TE inhibits the H1 R agonist (2-pyridylethylamine dihydrochloride)-induced increase in action potentials in the hypothalamic neurons. In animal tests using neurotransmitter agonists or antagonists, TE effect mimick H1 R antagonistic effect of doxepin. Additionally, both reduce sleep latency and increase NREMS in wild-type mice, although these effects are not observed in H1 R knockout mice. CONCLUSION: TE has a sleep-promoting effect owing to reduction in sleep latency and enhancement of NREMS via H1 R blockade; therefore, it could be useful in insomnia.

Ameliorative Effect of Hesperidin Against Motion Sickness by Modulating Histamine and Histamine H1 Receptor Expression.

Motion sickness (MS) is the visceral discomfort caused due to contradicting visual and vestibular inputs to the brain leading to nausea and vomiting. Sensory conflict theory which proves histamine elevations as the primary reason for MS provides a path for an effective pharmaco-therapy. We aimed to evaluate the anti-MS effect of hesperidin (HSP) by modulating histamine and histamine receptor H1 (HRH1) expression. The inhibitory effect of HSP on histamine release was studied in KU812 cells treated with 10 µM calcium ionophore. The in vivo anti-MS effect of HSP was evaluated in Balb/c mice. Thirty six mice were divided into six groups namely, normal control (NC, no rotation), hesperidin at 80 mg/kg body weight control (HSP80, no rotation), motion sickness (MS, rotation induced), dimenhydrinate (Standard drug) at 20 mg/kg body weight + rotation (STD + MS), hesperidin at 40 mg/kg body weight + rotation (HSP40 + MS) and hesperidin at 80 mg/kg body weight + rotation (HSP80 + MS). Hypothalamus and brainstem samples were analysed for histamine levels and HRH1 expression by RT-PCR, Western blot and immunohistochemistry analysis. Calcium ionophore treated KU812 cells significantly increased histamine release when compared to control cells. Pre-treatment with HSP inhibited histamine, HRH1 mRNA and protein expression. Histamine, HRH1 mRNA and protein expression in hypothalamus and brainstem samples of MS group increased significantly when compared to the NC group. Pre-treatment with HSP significantly reduced histamine, HRH1 mRNA and protein expression. Thus, indicating that HSP has a potent anti- MS effect by decreasing the elevated levels of histamine, HRH1 mRNA and protein expression in hypothalamus and brainstem regions.

Ethanol Induces Sedation and Hypnosis via Inhibiting Histamine Release in Mice.

Ethanol is one of the most highly abused psychoactive compounds worldwide and induces sedation and hypnosis. The histaminergic system is involved in the regulation of sleep/wake function and is a crucial player in promoting wakefulness. To explore the role and mechanism of the histaminergic system in ethanol-induced sedation and hypnosis, we recorded locomotor activity (LMA) and electroencephalography (EEG)/electromyography (EMG) in mice using an infrared ray passive sensor recording system and an EEG/EMG recording system, respectively, after administration of ethanol. In vivo microdialysis coupled with high performance liquid chromatography and fluorometry technology were used to detect histamine release in the mouse frontal cortex (FrCx). The results revealed that ethanol significantly suppressed LMA of histamine receptor 1 (H1R)-knockout (KO) and wild-type (WT) mice in the range of 1.5-2.5 g/kg, but suppression was remarkably stronger in WT mice than in H1R-KO mice. At 2.0 and 2.5 g/kg, ethanol remarkably increased non-rapid eye movement sleep and decreased wakefulness, respectively. Neurochemistry experimental data indicated that ethanol inhibited histamine release in the FrCx in a dose-dependent manner. These findings suggest that ethanol induces sedation and hypnosis via inhibiting histamine release in mice.

High Expression of IL-1RI and EP2 Receptors in the IL-1ß/COX-2 Pathway, and a New Alternative to Non-Steroidal Drugs-Osthole in Inhibition COX-2.

BACKGROUND: Osthole (7-methoxy-8-isopentenylcoumarin) is natural coumarin isolated from the fruit of Cnidium monnieri (L.) Cusson, which is commonly used in medical practice of traditional Chinese medicine (TCM) in various diseases including allergies and asthma disorders. PURPOSE: Osthole was tested for the anti-histamine, anti-allergic, and inhibitory effects of COX-2 (cyclooxygenase-2) in children with diagnosed allergies. Additionally, we hypothesize that stated alterations in children with diagnosed allergies including increased expression of interleukin 1-ß receptor type 1 (IL-1 type I) and E-prostanoid (EP) 2 receptors, as well as raised expression, production, and activity of COX-2 and IL-1ß in incubated medium are approximately connected. Furthermore, we establish the mechanisms included in the changed regulation of the COX-2 pathway and determine whether osthole may be COX-2 inhibitor in peripheral blood mononuclear cells (PBMCs). METHOD: PBMCs were obtained from peripheral blood of healthy children (control, n = 28) and patients with diagnosed allergies (allergy, n = 30). Expression of the autocrine loop components regulating PGE2 production and signaling namely IL-1 type I receptor (IL-1RI), cyclooksygenaze-2 (COX-2), E-prostanoid (EP) 2, and also histamine receptor-1 (HRH-1) was assessed at baseline and after stimulation with histamine, osthole, and a mixture of histamine/osthole 1:2 (v/v). This comprised the expression of histamine receptor 1 (HRH-1), IL-1RI, COX-2, EP2 receptor, and the secretion of IL-1ß and COX-2 in cultured media and sera. RESULTS: Compared with control group, basal mRNA expression levels of HRH-1, IL-1RI, COX-2, and EP2 were higher in the allergy group. Histamine-induced EP2 and COX-2 expression mRNA levels were also increased. CONCLUSIONS: Osthole successively inhibits PGE2 and COX-2 mRNA expression. Furthermore, osthole reduces the secretion of COX-2 protein in signaling cellular mechanisms. Changed EP2 expression in children with allergies provides higher IL-1RI induction, increasing IL-1ß capacity to increase COX-2 expression. This effects in higher PGE2 production, which in turn increases its capability to induce IL-1RI.

Effects of irradiation with narrowband-ultraviolet B on up-regulation of histamine H1 receptor mRNA and induction of apoptosis in HeLa cells and nasal mucosa of rats.

Narrowband-ultraviolet B (NB-UVB) phototherapy is used for the treatment of atopic dermatitis. Previously, we reported that irradiation with 200 mJ/cm2 of 310 nm NB-UVB suppressed phorbol-12-myristate-13-acetate (PMA)-induced up-regulation of histamine H1 receptor (H1R) gene expression without induction of apoptosis in HeLa cells. However, the effect of NB-UVB irradiation on nasal symptoms is still unclear. Here, we show that low dose irradiation with 310 nm NB-UVB alleviates nasal symptoms in toluene 2,4-diisocyanate (TDI)-sensitized allergy model rats. Irradiation with 310 nm NB-UVB suppressed PMA-induced H1R mRNA up-regulation in HeLa cells dose-dependently at doses of 75-200 mJ/cm2 and reversibly at a dose of 150 mJ/cm2 without induction of apoptosis. While, at doses of more than 200 mJ/cm2, irradiation with 310 nm NB-UVB induced apoptosis. Western blot analysis showed that the suppressive effect of NB-UVB irradiation on H1R gene expression was through the inhibition of ERK phosphorylation. In TDI-sensitized rat, intranasal irradiation with 310 nm NB-UVB at an estimated dose of 100 mJ/cm2 once a day for three days suppressed TDI-induced sneezes and up-regulation of H1R mRNA in nasal mucosa without induction of apoptosis. These findings suggest that repeated intranasal irradiation with low dose of NB-UVB could be clinically used as phototherapy of AR.

Effect of wild grape on the signaling of histamine H1 receptor gene expression responsible for the pathogenesis of allergic rhinitis.

As expression level of allergic disease-sensitive genes are correlated with allergic symptom severity, suppression of these gene expressions could be good therapeutics. We have demonstrated that PKCδ signaling and NFAT signaling, involve in histamine H1 receptor (H1R) and IL-9 gene expressions, respectively, are responsible for the pathogenesis of allergic rhinitis. We explore anti-allergic compounds that suppress these signaling pathways and found that wild grape (WG) contains such compounds. Here, we investigated the effect of WG hot water extract (WGE) on the signaling pathways for PKCδ-mediated H1R and NFAT-mediated IL-9 gene expressions. WGE suppressed histamine/PMA-induced H1R gene up-regulation in HeLa cells. Toluene-2,4-diisocyanate (TDI)-induced H1R mRNA elevation in TDI-sensitized rats was also suppressed by WGE treatment. Treatment with WGE in combination with Awa-tea, suppresses NFAT signaling-mediated IL-9 gene, markedly alleviated nasal symptoms. Furthermore, WGE suppressed PMA-induced IL-33 gene up-regulation in Swiss 3T3 cells. Data suggest that combination of WGE, suppresses PKCδ signaling with Awa-tea, suppresses NFAT signaling would have distinct clinical and therapeutic advantages as a substitute for anti-allergic drugs. In addition, as the expression level of IL-33 mRNA was correlated with the blood eosinophils number in patients with pollinosis, WG could alleviate eosinophilic inflammation through the suppression of IL-33 gene expression. J. Med. Invest. 65:242-250, August, 2018.

A novel neurological function of rice bran: a standardized rice bran supplement promotes non-rapid eye movement sleep in mice through histamine H1 receptors.

SCOPE: Although rice bran has been shown to be associated with a wide spectrum of health benefits, to date, there are no reports on its effects on sleep. We investigated the effect of rice bran on sleep and the mechanism underlying this effect. METHODS AND RESULTS: Electroencephalography was used to evaluate the effects of standardized rice bran supplement (RBS) and doxepin hydrochloride (DH), a histamine H1 receptor (H1 R) antagonist used as a positive control, on sleep in mice. The mechanism of RBS action was investigated using knockout (KO) mice and ex vivo electrophysiological recordings. Oral administration of RBS and DH significantly decreased sleep latency and increased the amount of non-rapid eye movement sleep (NREMS) in mice. Similar to DH, RBS fully inhibited H1 R agonist-induced increase in action potential frequency in tuberomammillary nucleus neurons. In H1 R KO mice, neither RBS nor DH administration led to the increase in NREMS and decrease in sleep latency observed in WT mice. These results indicate that the sleep-promoting effect of RBS is completely dependent on H1 R antagonism. CONCLUSIONS: RBS decreases sleep latency and promotes NREMS through the inhibition of H1 R, suggesting that it could be a promising therapeutic agent for insomnia.

Function-specific virtual screening for GPCR ligands using a combined scoring method.

The ability of scoring functions to correctly select and rank docking poses of small molecules in protein binding sites is highly target dependent, which presents a challenge for structure-based drug discovery. Here we describe a virtual screening method that combines an energy-based docking scoring function with a molecular interaction fingerprint (IFP) to identify new ligands based on G protein-coupled receptor (GPCR) crystal structures. The consensus scoring method is prospectively evaluated by: 1) the discovery of chemically novel, fragment-like, high affinity histamine H1 receptor (H1R) antagonists/inverse agonists, 2) the selective structure-based identification of ß2-adrenoceptor (ß2R) agonists, and 3) the experimental validation and comparison of the combined and individual scoring approaches. Systematic retrospective virtual screening simulations allowed the definition of scoring cut-offs for the identification of H1R and ß2R ligands and the selection of an optimal ß-adrenoceptor crystal structure for the discrimination between ß2R agonists and antagonists. The consensus approach resulted in the experimental validation of 53% of the ß2R and 73% of the H1R virtual screening hits with up to nanomolar affinities and potencies. The selective identification of ß2R agonists shows the possibilities of structure-based prediction of GPCR ligand function by integrating protein-ligand binding mode information.

Effects of antihistamine on up-regulation of histamine H1 receptor mRNA in the nasal mucosa of patients with pollinosis induced by controlled cedar pollen challenge in an environmental exposure unit.

In the present study, we examined the effects of antihistamine on the up-regulation of H1R mRNA in the nasal mucosa of patients with pollinosis induced by controlled exposure to pollen using an environmental exposure unit. Out of 20 patients, we designated 14 responders, whose levels of H1R mRNA in the nasal mucosa were increased after the first pollen exposure and excluded 6 non-responders. Accordingly, the first exposure to pollen without treatment significantly induced both nasal symptoms and the up-regulation of H1R mRNA in the nasal mucosa of the responders. Subsequently, prophylactic administration of antihistamine prior to the second pollen exposure significantly inhibited both of the above effects in the responders. Moreover, the nasal expression of H1R mRNA before the second pollen exposure in the responders pretreated with antihistamine was significantly decreased, as compared with that before the first pollen exposure without treatment. These findings suggest that antihistamines suppressed histamine-induced transcriptional activation of H1R gene in the nasal mucosa, in addition to their blocking effect against histamine on H1R, resulting in a decrease of nasal symptoms. These findings further suggest that by their inverse agonistic activity, antihistamines suppress the basal transcription of nasal H1R in the absence of histamine in responders.

Usefulness of HeLa cells to evaluate inverse agonistic activity of antihistamines.

Antihistamines are thought to antagonize histamine and prevent it from binding to the histamine H1 receptor (H1R). However, recent studies indicate that antihistamines are classified into two groups, i.e., inverse agonists and neutral antagonists on the basis of their ability to down-regulate the constitutive activity of H1R. As H1R is an allergy-sensitive gene whose expression influences the severity of allergic symptoms, inverse agonists should more potently alleviate allergic symptoms than neutral antagonists by inhibiting H1R constitutive activity. Therefore, it is important to assess inverse agonistic activity of antihistamines. Here we report a novel assay method using HeLa cells expressing H1R endogenously for evaluation of inverse agonistic activity of antihistamines. Pretreatment with inverse agonists down-regulated H1R gene expression below to its basal level. On the other hand, basal H1R mRNA expression was unchanged by neutral antagonist pretreatment. Both inverse agonists and neutral antagonists suppressed histamine-induced H1R mRNA elevation. Classification of antihistamines on the basis of their suppressive activity of basal H1R gene expression was consistent with that of inositol phosphate accumulation in H1R-overexpressed cells. Our data suggest that the assay method using HeLa cells is more convenient and useful than the existing methods and may contribute to develop new antihistamines with inverse agonistic activity.

Amylin-leptin coadministration stimulates central histaminergic signaling in rats.

Combined amylin+leptin (AMN+LEP) can reduce diet induced obesity and is very effective in combating LEP resistance. The purpose of this study was to evaluate the effect of AMN+LEP on central histaminergic signaling in lean and obese rats. Male rats were administered LEP (300 µg/kg/d), AMN (100 µg/kg/d), AMN+LEP or vehicle (SAL, 0.9% normal saline), via a subcutaneous mini-osmotic pump or single injection (LEP, 300 µg/kg and AMN, 100 µg/kg) for acute studies. AMN+LEP administration increased expression of histamine H1 receptor (HIR) and histidine decarboxylase (HDC) mRNA in the hypothalamus. Increased levels of H1R were seen in arcuate (Arc) and ventromedial hypothalamus (VMH) as well as the area postrema (APOS) and nucleus of solitary tract (NTS) following AMN+LEP administration. APOS and NTS also showed expression of immediate early gene c-FOS in the hindbrain in AMN+LEP-treated rats. We confirmed previous evidence indicating that AMN+LEP increased STAT-3 protein phosphorylation in Arc and VMH. Finally, by in vivo microdialysis, we observed an increase in methyl HIS levels in the VMH of AMN, LEP and AMN+LEP-treated rats. Taken together, these observations are consistent with an important role that neuronal HIS may play in mediating the potent effects of AMN+LEP on food intake and body weight.

The histaminergic system regulates wakefulness and orexin/hypocretin neuron development via histamine receptor H1 in zebrafish.

The histaminergic and hypocretin/orexin (hcrt) neurotransmitter systems play crucial roles in alertness/wakefulness in rodents. We elucidated the role of histamine in wakefulness and the interaction of the histamine and hcrt systems in larval zebrafish. Translation inhibition of histidine decarboxylase (hdc) with morpholino oligonucleotides (MOs) led to a behaviorally measurable decline in light-associated activity, which was partially rescued by hdc mRNA injections and mimicked by histamine receptor H1 (Hrh1) antagonist pyrilamine treatment. Histamine-immunoreactive fibers targeted the dorsal telencephalon, an area that expresses histamine receptors hrh1 and hrh3 and contains predominantly glutamatergic neurons. Tract tracing with DiI revealed that projections from dorsal telencephalon innervate the hcrt and histaminergic neurons. Translation inhibition of hdc decreased the number of hcrt neurons in a Hrh1-dependent manner. The reduction was rescued by overexpression of hdc mRNA. hdc mRNA injection alone led to an up-regulation of hcrt neuron numbers. These results suggest that histamine is essential for the development of a functional and intact hcrt system and that histamine has a bidirectional effect on the development of the hcrt neurons. In summary, our findings provide evidence that these two systems are linked both functionally and developmentally, which may have important implications in sleep disorders and narcolepsy. development via histamine receptor H1 in zebrafish.

Preseasonal prophylactic treatment with antihistamines suppresses nasal symptoms and expression of histamine H1 receptor mRNA in the nasal mucosa of patients with pollinosis.

Administration of antihistamines 2-4 weeks before the pollen season showed a greater inhibitory effect on nasal allergy symptoms in patients with seasonal allergic rhinitis. However, the mechanism of slow-onset effects of preseasonal treatment with antihistamines remains unclear. Here, we investigated the effect of preseasonal prophylactic treatment with antihistamines on nasal symptoms and the expression of histamine H1 receptor (H1R) mRNA of the nasal mucosa in patients with cedar pollen pollinosis. During the peak pollen period, the expression of H1R mRNA in the nasal mucosa and the scores of sneezing and watery rhinorrhea in patients receiving preseasonal prophylactic treatment with antihistamines were significantly suppressed in comparison with those in the patients without treatment. Moreover, there was a significant correlation between the nasal symptoms and the expression of H1R mRNA in both patients with or without preseasonal prophylactic treatment. These findings suggest that preseasonal prophylactic treatment with antihistamines is more effective than on-seasonal administration to patients with pollinosis in reducing nasal symptoms during the peak pollen period by suppressing H1R gene expression in the nasal mucosa.

Sho-seiryu-to suppresses histamine signaling at the transcriptional level in TDI-sensitized nasal allergy model rats.

BACKGROUND: The therapeutic use of Kampo medicine, Sho-seiryu-to (SST) in allergic disorders is well known. As histamine plays a central role in allergic diseases, it is possible that SST affects the allergy-related histamine signaling. In this study, we investigated the effect of SST on allergy-related histamine signaling in the nasal mucosa of toluene 2, 4-diisocyanate (TDI)-sensitized nasal allergy model rats. METHODS: Six-week-old male, Brown Norway rats were sensitized for 2 weeks with 10 microl of 10% TDI, and after a 1 week interval, provocation was initiated with the same amount of TDI. SST (0.6g/rat) was given orally 1 hour before TDI treatment began for a period of 3 weeks. Nasal symptoms were scored for 10 minutes immediately after TDI-provocation. The genes expression in nasal mucosa was determined using real-time quantitative RT-PCR. RESULTS: SST significantly suppressed TDI-induced nasal allergy-like symptoms. TDI provocation showed a significant up-regulation of histamine H(1) receptor (H1R) and histidine decarboxylase (HDC) gene expressions. Prolonged pre-treatment of SST significantly suppressed the mRNA levels of H1R and HDC that was up-regulated by TDI. SST also suppressed TDI-induced interleukin (IL)-4 and IL-5 mRNA elevation. However, SST showed no significant effect for TDI-induced mRNA elevation of IL-13. CONCLUSIONS: These results demonstrate that SST alleviates nasal symptoms by the inhibition of histamine signaling through suppression of TDI-induced H1R and HDC gene up-regulation. SST also suppresses cytokine signaling through suppression of IL-4 and IL-5 gene expression. Suppression of histamine signaling may be a novel mechanism of SST in preventing allergic diseases.

Effects of hypergravity on histamine H1 receptor mRNA expression in hypothalamus and brainstem of rats: implications for development of motion sickness.

CONCLUSION: The study findings suggest that histamine was released from the axon terminals in the hypothalamus and brainstem and the released histamine activated post-synaptic H1 receptors there, resulting in the development of motion sickness. OBJECTIVES: We first examined which subtype of post-synaptic histaminergic receptor was responsible for the development of motion sickness. We then examined whether H1 receptors were up-regulated in various areas of the rat brain after 2 G hypergravity load, because the stimulation of H1 receptor was reported to up-regulate the level of H1 receptor protein expression through augmentation of H1 receptor mRNA expression. MATERIALS AND METHODS: For this purpose, we used an animal model of motion sickness, using pica (eating non-nutritive substances such as kaolin), as a behavioral index in rats. RESULTS: After 2 G hypergravity load, rats ate a significant amount of kaolin, indicating that they suffered from motion sickness. The hypergravity-induced kaolin intake was suppressed by mepyramine, but not by terfinadine or zolantizine. This finding indicates that cerebral post-synaptic H1 but not H2 or peripheral H1 receptors play an important role in the development of motion sickness. The expression of H1 receptor mRNA was up-regulated in the hypothalamus and brainstem, but not in the cerebral cortex after 2 G hypergravity load in rats.

Hypothalamic neuronal histamine mediates the thyrotropin-releasing hormone-induced suppression of food intake.

We examined the involvement of thyrotropin-releasing hormone (TRH) and TRH type 1 and 2 receptors (TRH-R1 and TRH-R2, respectively) in the regulation of hypothalamic neuronal histamine. Infusion of 100 nmol TRH into the rat third cerebroventricle (3vt) significantly decreased food intake (p < 0.05) compared to controls infused with phosphate- buffered saline. This TRH-induced suppression of food intake was attenuated partially in histamine-depleted rats pre-treated with alpha-fluoromethylhistidine (a specific suicide inhibitor of histidine decarboxylase) and in mice with targeted disruption of histamine H1 receptors. Infusion of TRH into the 3vt increased histamine turnover as assessed by pargyline-induced accumulation of tele-methylhistamine (t-MH, a major metabolite of neuronal histamine in the brain) in the tuberomammillary nucleus (TMN), the paraventricular nucleus, and the ventromedial hypothalamic nucleus in rats. In addition, TRH-induced decrease of food intake and increase of histamine turnover were in a dose-dependent manner. Microinfusion of TRH into the TMN increased t-MH content, histidine decarboxylase (HDC) activity and expression of HDC mRNA in the TMN. Immunohistochemical analysis revealed that TRH-R2, but not TRH-R1, was expressed within the cell bodies of histaminergic neurons in the TMN of rats. These results indicate that hypothalamic neuronal histamine mediates the TRH-induced suppression of feeding behavior.

[Role of therapeutics for allergic diseases in targeting histamine H1 receptor gene expression].

Histamine H(1) receptors are down-regulated as one step in receptor desensitization. Five phosphorylation sites of the H(1) receptor seem to play a key role in receptor down-regulation. In contrast, an increase in the H(1) receptor expression level following its mRNA elevation was found in the nasal mucosa in hypersensitivity model rats. Up-regulation of the H(1) receptor was induced by the direct stimulation of the H(1) receptor. H(1) receptor up-regulation was suppressed by pretreatment with antiallergic agents.