Key factors driving eating behavior are hunger and satiety, which are controlled by a complex interplay of central neurotransmitter systems and peripheral stimuli. The lipid-derived messenger oleoylethanolamide (OEA) is released by enterocytes in response to fat intake and indirectly signals satiety to hypothalamic nuclei. Brain histamine is released during the appetitive phase to provide a high level of arousal in anticipation of feeding, and mediates satiety. However, despite the possible functional overlap of satiety signals, it is not known whether histamine participates in OEA-induced hypophagia. Using different experimental settings and diets, we report that the anorexiant effect of OEA is significantly attenuated in mice deficient in the histamine-synthesizing enzyme histidine decarboxylase (HDC-KO) or acutely depleted of histamine via interocerebroventricular infusion of the HDC blocker α-fluoromethylhistidine (α-FMH). α-FMH abolished OEA-induced early occurrence of satiety onset while increasing histamine release in the CNS with an H 3 receptor antagonist-increased hypophagia. OEA augmented histamine release in the cortex of fasted mice within a time window compatible to its anorexic effects. OEA also increased c-Fos expression in the oxytocin neurons of the paraventricular nuclei of WT but not HDC-KO mice. The density of c-Fos immunoreactive neurons in other brain regions that receive histaminergic innervation and participate in the expression of feeding behavior was comparable in OEA-treated WT and HDC-KO mice. Our results demonstrate that OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect and that the oxytocin neuron-rich nuclei are the likely hypothalamic area where brain histamine influences the central effects of OEA.histamine receptors | behavioral satiety sequence | BSS | paraventricular hypothalamic nuclei | PVN E ating behavior is regulated by central neurotransmitter systems and peripheral stimuli that interact to change the behavioral state and concur to alter homeostatic aspects of appetite and energy expenditure. The fatty acid amide oleoylethanolamide (OEA) is released by the small intestine in a stimulus-dependent manner and suppresses food intake by activating peroxisome proliferator-activated receptor-α (PPAR-α) (1). Systemic administration of OEA induces c-Fos mRNA expression through the vagus nerve to the nucleus of the solitary tract (NST), supraoptic nuclei (SON), and paraventricular hypothalamic nuclei (PVN) and increases the expression of oxytocin (2, 3), which is involved in the central coordination of homeostatic signals and feeding behavior (4). However, it is not known whether OEA recruits other neurotransmitter systems in the brain to reduce food intake. Histaminergic neurons are clustered in the hypothalamic tuberomammillary nuclei (TMN). They send projections organized in functionally distinct circuits impinging on different brain regions (5), and their firing frequency changes according to the behavioral state (6). Brain histamin...

Abstract. It has been shown that probiotic bacteria are effective for the treatment of allergic diseases. As histamine plays a central role in allergic diseases, it is possible that probiotic bacteria affect the allergy-related histamine signaling. Here, we investigated the effect of Lac-B, a mixture of freeze-dried Bifidobacterium infantis and Bifidobacterium longum, on the allergyrelated histamine signaling. In the nasal allergy model rats made by sensitization and provocation with toluene 2,4-diisocyanate (TDI) for 3 weeks, TDI provocation caused acute allergy-like behaviors along with significant up-regulation of histamine H 1 receptor (H1R) and histidine decarboxylase (HDC) mRNA expression, increased HDC activity, histamine content, and [ 3 H]mepyramine binding activity in nasal mucosa. Prolonged treatment with Lac-B (40 mg / rat, p.o.) significantly suppressed both the allergy-like behaviors and all of the above mentioned factors involved in histamine signaling. Our findings indicate that oral administration of Lac-B showed significant anti-allergic effect through suppression of both H1R and HDC gene expression followed by decrease in H1R, HDC protein level, and histamine content. Suppression of histamine signaling may be a novel target of probiotics in preventing allergic diseases.

Abstract. Kujin, the dried root of Sophorae flavescensis, has been used in Chinese folklore medicine against allergy. Evaluation of its anti-allergic potential as well as its mechanism of action has rarely been established. We investigated the effect of Kujin on toluene-2,4-diisocyanate (TDI)-induced allergic behavior and related histamine signaling including mRNA levels of histamine H 1 receptor (H1R) and histidine decarboxylase (HDC), H1R and HDC activities, and histamine content in rat nasal mucosa. We also investigated the effect of Kujin on the mRNA levels of helper T cell type 2 (Th2)-cytokine genes closely related to histamine signaling. TDI provocation caused acute allergic symptoms accompanied with up-regulations of H1R and HDC mRNAs and increases in HDC activity, histamine content, and [ 3 H]mepyramine binding activity in the nasal mucosa, all of which were significantly suppressed by pretreatment with Kujin for 3 weeks. Kujin also suppressed the TDI-induced IL-4 and IL-5 mRNA elevations. These data suggest that oral administration of Kujin showed anti-allergic activity through suppression of histamine signaling by the inhibition of TDI-induced H1R and HDC mRNA elevations followed by decrease in H1R, HDC protein level, and histamine content in the nasal mucosa of TDI-sensitized rats. Suppression of Th2-cytokine signaling by Kujin also suggests that it could affect the histamine-cytokine network.

Abstract. Antihistamines are effective for treatment of seasonal nasal allergy. Recently, prophylactic treatment with antihistamines in patients with pollinosis was reported to be more effective when started before the pollen season. The administration with antihistamines from 2 to 6 weeks before onset of the pollen season is recommended for management of allergic rhinitis in Japan. To determine the reason for the effectiveness of prophylactic treatment with antihistamines, the effects of repeated pre-treatment with antihistamines before provocation with toluene 2,4-diisocyanate (TDI) on their nasal allergy-like behavior and up-regulations of histamine H 1 receptors (H1R) and interleukin (IL)-4 mRNAs in their nasal mucosa were examined. Provocation with TDI induced sneezing and up-regulations of H1R and IL-4 mRNAs in the nasal mucosa of TDI-sensitized rats. Repeated pre-treatments with antihistamines including epinastine, olopatadine, or d-chlorpheniramine for 1 to 5 weeks before provocation with TDI suppressed TDI-induced sneezing and the up-regulations of H1R and IL-4 mRNAs in the nasal mucosa more than their administrations once or for 3 days before TDI provocation. Our data indicate that repeated pre-treatment with antihistamines before provocation with TDI is more effective than their single treatment in reducing nasal allergy-like behavior by causing additional suppression of up-regulations of H1R and IL-4 mRNAs in the nasal mucosa.

Allergic rhinitis (AR) is an inflammatory disorder typified by symptoms such as sneezing, congestion, and rhinorrhea. Histamine plays important roles in eliciting AR symptoms. Up-regulation of the histamine H1 receptor (H1R) and histidine decarboxylase (HDC) mRNAs was observed in AR patients. Th2 cytokines are also involved in the pathogenesis of AR. We examined the effect of suplatast tosilate on nasal symptoms, and H1R, HDC, and IL-4 gene expression using toluene-2,4-diisocyanate (TDI)-sensitized rats and HeLa cells expressing endogenous H1R. Provocation with TDI increased nasal symptoms, HDC activity, the histamine content of nasal lavage fluid, and the expression of H1R, HDC, and IL-4 mRNAs in TDI-sensitized rats. Pretreatment with suplatast for 2 wk significantly suppressed TDI-induced nasal symptoms and elevation of H1R, HDC, and IL-4 mRNAs. Suplatast also suppressed HDC activity in the nasal mucosa and the histamine content of the nasal lavage fluid. Bilateral injection of IL-4 into the nasal cavity of normal rats up-regulated H1R mRNA, while intranasal application of histamine up-regulated IL-4 mRNA. Suplatast suppressed IL-4-induced up-regulation of H1R mRNA in HeLa cells. However, it did not inhibit histamine-induced H1R mRNA elevation. These results suggest that suplatast alleviates nasal symptoms by inhibiting histamine signaling in TDI-sensitized rats through the suppression of histamine- and IL-4-induced H1R gene expression by the inhibitions of HDC and IL-4 gene transcriptions, respectively.

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.

The sedative properties of the H(1) antihistamines obtained from VAS analysis were very similar to those of H1R occupancy from positron emission tomography (PET) studies and PIR from meta-analysis. Our results indicate that large-scale surveillance using VAS might be useful to evaluate the profiles of H(1) antihistamines.

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