研究者詳細 - 杉本　幸雄

論文 - 杉本　幸雄

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Evaluation methods using tear volume in a conjunctivitis mice model. 国際誌

Haruki Kai, Noriaki Haraoka, Yukio Sugimoto

Journal of pharmacological and toxicological methods 128 107520 - 107520 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Allergic conjunctival disease is an immune-mediated inflammatory disease of the conjunctiva. To develop clinically useful drugs, it is necessary to develop quantitative evaluation methods that reflect the clinical symptoms in experimental animal models. Allergic conjunctivitis model mice were systemically sensitised with ovalbumin (OVA) administered intraperitoneally and locally sensitised with OVA eye drops between day 14-28. Next, conjunctivitis induced by ocular administration of OVA solution to sensitised mice was evaluated based on tear volume. Additionally, we evaluated increase in tear volume induced by direct ocular instillation of histamine, compound 48/80, and carrageenan. An increase in antigen-induced tear volume was observed in the mice model. Additionally, direct instillation of histamine, compound 48/80, and carrageenan increased tear volume. Furthermore, levocabastine inhibited the increase in tear volume in antigen-induced allergic conjunctivitis and histamine- and compound 48/80-induced conjunctivitis models. In contrast, betamethasone suppressed carrageenan-induced tear volume but not histamine- or compound 48/80-induced tear volume. Histamine may be involved in increased tear volume in allergic conjunctivitis. Betamethasone is not directly involved in the action of histamine and is thought to suppress increase in tear volume. Evaluation of tear volume in a conjunctivitis mice model is highly quantitative; therefore, it is possible to evaluate drug efficacy. This is considered a useful index compared with conventional methods.

DOI： 10.1016/j.vascn.2024.107520

A mouse model of food allergy permitting skin and nasal symptoms 査読

Takafumi Morinaga, Takuya Yamamoto, Yukio Sugimoto

Advances in Medical Sciences 68 ( 2 ) 372 - 378 2023年9月

A mouse model of allergic conjunctivitis permitting tear eosinophil quantification. 国際誌

Atsushi Ogura, Yukio Sugimoto

Journal of pharmacological and toxicological methods 118 107225 - 107225 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Allergic conjunctivitis is an immune-mediated inflammatory disease of the conjunctiva that is induced by antigens. Allergic conjunctivitis can cause various symptoms such as ocular itching, hyperemia and edema. Developing experimental animal models that show clinical symptoms and methods for quantitative and objective evaluation is important for understanding allergic conjunctivitis. Therefore, this study aimed to develop an ovalbumin (OVA)-induced mouse model of allergic conjunctivitis and a useful method for evaluating symptoms of allergic conjunctivitis. METHODS: ICR mice were sensitized by an intraperitoneal injection of OVA in PBS containing alum on days 0 and 5. Subsequently, local sensitization was then performed once daily from days 14 to 28, by instilling OVA in PBS into the both eyes. Drug treatment was administered once daily from days 14 to 28. Mice were randomly assigned topical treatment groups: Group 1, 0.1% betamethasone; Group 2, 0.025% levocabastine; Group 3 PBS (control). RESULTS: Mice showed marked eye scratching behavior, hyperemia, edema, infiltration of eosinophils into tears and increased antigen-specific immunoglobulin E antibody levels in tears and the serum. These symptoms were inhibited by instillation of levocabastine and betamethasone, which are used clinically for the treatment of allergic conjunctivitis. DISCUSSION: This method may be useful for evaluation of the symptoms of allergic conjunctivitis in experimental and clinical settings. In particular, the developed method, which measures the number of eosinophils in tears collected with phenol red threads, may enable the quantitative, objective, and noninvasive evaluation of the severity of allergic conjunctivitis.

DOI： 10.1016/j.vascn.2022.107225

Involvement of glucocorticoid receptor activation on anti-inflammatory effect induced by peroxisome proliferator-activated receptor γ agonist in mice. 国際誌

Atsuki Yamamoto, Hiroki Kakuta, Yukio Sugimoto

International immunopharmacology 22 ( 1 ) 204 - 8 2014年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Glucocorticoids are effective anti-inflammatory agents widely used for the treatment of acute and chronic inflammatory diseases. Recent in vitro studies have proposed that glucocorticoid receptor (GR) activation is involved in peroxisome proliferator-activated receptor γ (PPARγ) agonist-induced effects. In this study, to examine the involvement of the GR in PPARγ agonist- and retinoid X receptor (RXR) agonist-mediated anti-inflammatory effects in vivo, we tested the anti-inflammatory effects of dexamethasone (a GR agonist) with pioglitazone (a PPARγ agonist) or 6-[N-ethyl-N-(3-isopropoxy-4-isopropylphenyl)-amino] nicotinic acid (NEt-3IP; an RXR agonist) by using an experimental model of carrageenan-induced inflammation. We also evaluated the effects of a GR antagonist on PPARγ agonist- or RXR agonist-induced anti-inflammatory effects. Results showed that the GR antagonist RU486 reduced the anti-inflammatory effects of GR or PPARγ agonists but not those of the RXR agonist. In addition, combinations of GR and PPARγ agonists or GR and RXR agonists had no effect on carrageenan-induced paw edema. Moreover, the PPARγ antagonist GW9662 and RXR antagonist 6-[N-4-(trifluoromethyl)-benzenesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-amino] nicotinic acid (NS-4TF) had no effect on the anti-inflammatory effect of the GR agonist dexamethasone. Therefore, it is suggested that GR activation in vivo does not play a direct role in PPARγ/RXR heterodimer signaling. In contrast, pioglitazone showed a partial anti-inflammatory effect via GR activation. These data provide evidence for the pro-inflammatory activity of pioglitazone.

DOI： 10.1016/j.intimp.2014.06.028

Genomic and non-genomic effects of glucocorticoids on allergic rhinitis model in mice. 国際誌

Eriko Kusaka, Mayu Sugiyama, Norie Senoo, Atsuki Yamamoto, Yukio Sugimoto

International immunopharmacology 16 ( 2 ) 279 - 87 2013年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Glucocorticoids (GCs) are well known for their anti-inflammatory effects, which are elicited through a transcriptional mechanism via a cytosolic glucocorticoid receptor (cGR)-mediated genomic effect. However, recent in vitro studies report that GCs can act as a membrane glucocorticoid receptor (mGR). This study aimed to examine whether mometasone furoate (MF) influences the nasal symptoms induced by histamine, substance P, ATP. Furthermore, the influences of various compounds on MF action were studied in vivo. The mice were intranasally administered with nasal symptom-inciting agents, and the occurrences of sneezing and nasal rubbing were counted. MF repressed the nasal symptoms caused when it was administered 10, 30 and 60min before the induction of nasal symptoms. The repressive effect observed 10min after the administration of MF was inhibited by RU486, a GR antagonist, but not by actinomycin D, a transcriptional inhibitor. In contrast, the repressive effect observed 60min after the administration of MF was inhibited by RU486 and actinomycin D. Therefore, the effects observed 10 and 60min after the MF administration were classified as non-genomic and genomic effects, respectively. The non-genomic effect suppressed the nasal symptoms induced by m-3M3FBS, a phospholipase C (PLC) activator, and was inhibited by U-73122, a PLC inhibitor. The genomic effect was inhibited by N-(p-amylcinnamoyl) anthranilic acid, a phospholipase A2 (PLA2) inhibitor. These results indicate that MF has a non-genomic effect through repression of the activation of PLC via the mGR, and MF has also a genomic effect that was influenced by the inhibition of PLA2 through transcriptional regulation via cGR.

DOI： 10.1016/j.intimp.2013.03.030

In vivo anti-inflammatory and antioxidant properties of ellagitannin metabolite urolithin A. 国際誌

Hidekazu Ishimoto, Mari Shibata, Yuki Myojin, Hideyuki Ito, Yukio Sugimoto, Akihiro Tai, Tsutomu Hatano

Bioorganic & medicinal chemistry letters 21 ( 19 ) 5901 - 4 2011年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Urolithin A is a major metabolite produced by rats and humans after consumption of pomegranate juice or pure ellagitannin geraniin. In this study, we investigated the anti-inflammatory effect of urolithin A on carrageenan-induced paw edema in mice. The volume of paw edema was reduced at 1h after oral administration of urolithin A. In addition, plasma in treated mice exhibited significant oxygen radical antioxidant capacity (ORAC) scores with high plasma levels of the unconjugated form at 1h after oral administration of urolithin A. These results indicate strong associations among plasma urolithin A levels, the plasma ORAC scores, and anti-inflammatory effects and may help explain a mechanism by which ellagitannins confer protection against inflammatory diseases.

DOI： 10.1016/j.bmcl.2011.07.086

Involvement of the Retinoid X Receptor Ligand in the Anti-Inflammatory Effect Induced by Peroxisome Proliferator-Activated Receptor γ Agonist In Vivo. 国際誌

Atsuki Yamamoto, Hiroki Kakuta, Hiroyuki Miyachi, Yukio Sugimoto

PPAR research 2011 840194 - 840194 2011年

記述言語：英語掲載種別：研究論文（学術雑誌）

Peroxisome proliferator-activated receptor γ (PPARγ) forms a heterodimeric DNA-binding complex with retinoid X receptors (RXRs). It has been reported that the effect of the PPAR agonist is reduced in hepatocyte RXR-deficient mice. Therefore, it is suggested that the endogenous RXR ligand is involved in the PPARγ agonist-induced anti-inflammatory effect. However, the participation of the RXR ligand in the PPARγ-induced anti-inflammatory effect is unknown. Here, we investigated the influence of RXR antagonist on the anti-inflammatory effect of PPARγ agonist pioglitazone in carrageenan test. In addition, we also examined the influence of PPAR antagonist on the anti-inflammatory effect induced by RXR agonist NEt-3IP. The RXR antagonist suppressed the antiedema effect of PPARγ agonist. In addition, the anti-inflammatory effect of RXR agonist was suppressed by PPARγ antagonist. PPARγ agonist-induced anti-inflammatory effects were reversed by the RXR antagonist. Thus, we showed that the endogenous RXR ligand might contribute to the PPARγ agonist-induced anti-inflammatory effect.

DOI： 10.1155/2011/840194

Prophylactic effects of the histamine H1 receptor antagonist epinastine and the dual thromboxane A2 receptor and chemoattractant receptor-homologous molecule expressed on Th2 cells antagonist ramatroban on allergic rhinitis model in mice.

Yuh Suzuki, Toshio Inoue, Atsuki Yamamoto, Yukio Sugimoto

Biological & pharmaceutical bulletin 34 ( 4 ) 507 - 10 2011年

記述言語：英語掲載種別：研究論文（学術雑誌）

The prophylactic use of anti-allergic drugs has been proposed to be effective in the treatment of seasonal allergic rhinitis in humans. However, there is little information regarding the prophylactic effect of thromboxane A(2) (TXA(2)) receptor antagonist on allergic rhinitis. Recent studies revealed that a TXA(2) receptor antagonist ramatroban could block the prostaglandin D(2) (PGD(2)) receptor and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). In the present study, we investigated the prophylactic effects of the histamine H(1) receptor antagonist epinastine and the TXA(2) receptor antagonist ramatroban and seratrodast on mouse models of allergic rhinitis. Female BALB/c mice were sensitized by an intraperitoneal injection of ovalbumin and alum on days 0, 5, 14 and 21. Seven days later, mice were sensitized by intranasal application of ovalbumin thrice a week. Drugs were administered once a day from day 22. The severity of allergic rhinitis was assessed by determining the extent of 2 nasal allergic symptoms (sneezing and nasal rubbing). Histamine sensitivity and eosinophil infiltration into the nasal mucosa were also determined. Epinastine and ramatroban significantly reduced nasal symptoms and the number of eosinophils in the nasal mucosa. Seratrodast showed no effect on nasal symptoms and eosinophil infiltration into the nasal mucosa. In addition, histamine sensitivity was reduced by epinastine and ramatroban. These results indicate that epinastine and ramatroban induce the prophylactic effect on allergic rhinitis.

Involvement of peripheral mu opioid receptors in scratching behavior in mice. 国際誌

Atsuki Yamamoto, Yukio Sugimoto

European journal of pharmacology 649 ( 1-3 ) 336 - 41 2010年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pruritus is a common adverse effect of opioid treatment. However, the mechanism by which pruritus is induced by opioid administration is unclear. In this study, we examined the effects of the intradermal injection of loperamide, a peripherally restricted opioid receptor agonist, on the itch sensation. When injected intradermally into the rostral part of the back in mice, loperamide elicited scratching behavior. We also examined the effects of the selective mu opioid receptor agonist [d-Ala², N-Me-Phe⁴, Gly⁵-ol]-enkephalin acetate (DAMGO), the selective delta opioid receptor agonist [d-Pen(2,5)]-enkephalin (DPDPE), and the selective kappa opioid receptor agonist U-50488H on scratching behavior in mice in order to determine which subtype is involved in opioid-induced pruritus. Following intradermal injection into the rostral part of the back in mice, DAMGO elicited scratching behavior, while DPDPE and U-50488H did not. This suggests that peripheral mu opioid activation elicits the itch sensation. Next, we focused on the treatment of opioid-induced itch sensation without central adverse effects. Naloxone methiodide is a peripherally restricted opioid receptor antagonist. In the present study, naloxone methiodide significantly suppressed scratching behavior induced by loperamide and DAMGO. These findings suggest that mu opioid receptors play a primary role in peripheral pruritus and that naloxone methiodide may represent a possible remedy for opioid-induced itching.

DOI： 10.1016/j.ejphar.2010.07.039

Effect of 5-aminosalicylate on allergic rhinitis model in mice. 国際誌

Shoji Kuyama, Atsuki Yamamoto, Mayu Sugiyama, Hiroki Kakuta, Yukio Sugimoto

International immunopharmacology 10 ( 6 ) 713 - 6 2010年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Previous studies have shown that peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in allergic rhinitis. It has been reported that 5-aminosalicylate (5-ASA) has an affinity for PPARgamma, but the effects of 5-ASA on the nasal symptoms of allergic rhinitis are unclear. This study aimed to clarify the effects of 5-ASA on nasal symptoms in an allergic rhinitis model in mice. Female BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA) and aluminium hydroxide hydrate gel (alum) on days 0, 5, 14 and 21. Seven days later, mice were sensitized by the intranasal application of OVA thrice a week. 5-ASA was also administered orally after instillation of the antigen from day 28. The severity of allergic rhinitis was assessed by determining the extent of 2 nasal allergic symptoms-sneezing and nasal rubbing. In addition, serum OVA-specific immunoglobulin E (IgE) antibody, interleukin (IL)-4, and IL-10 levels in nasal lavage fluid and histamine sensitivity were determined. Repeated oral administration of 5-ASA attenuated the progression of nasal symptoms in sensitized mice in a dose-dependent manner. Additionally, 5-ASA prevented an increase in histamine sensitivity. Finally, 5-ASA inhibited both OVA-specific IgE antibody and IL-4 production; however, it had no effect on IL-10 levels. These results indicate that 5-ASA has a prophylactic effect on allergic rhinitis.

DOI： 10.1016/j.intimp.2010.03.007

Characterization of scratching behavior induced by intradermal administration of morphine and fentanyl in mice. 国際誌

Atsuki Yamamoto, Shoji Kuyama, Chiaki Kamei, Yukio Sugimoto

European journal of pharmacology 627 ( 1-3 ) 162 - 6 2010年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Itching is known as a commonly side effect of opioid administration. However, the relationship of opioid receptors to itching is unclear. In this study, we examined the effect of intradermal injection of morphine and fentanyl on the itching sensation. When injected intradermally into the rostral back of mice, morphine and fentanyl elicited scratching behavior. In addition, an opioid receptor antagonist, naloxone, and a peripherally restricted opioid receptor antagonist, naloxone methiodide, significantly suppressed morphine- and fentanyl-induced scratching behavior. Moreover, the morphine-induced scratching behavior was suppressed by histamine H(1) receptor antagonists, such as diphenhydramine, chlorpheniramine, epinastine and cetirizine. On the other hand, fentanyl-induced scratching behavior was not suppressed by histamine H(1) receptor antagonists. Additionally, scratching behavior induced by morphine and fentanyl were not suppressed by glucocorticoids (predonisolone and dexamethasone). In conclusion, opioid-induced itching may involve in peripheral opioid receptors. Moreover, histamine and arachidonic acid metabolites played no main role in opioid-induced scratching behavior.

DOI： 10.1016/j.ejphar.2009.10.066

Effect of the oral absorption of benzenesulfonanilide-type cyclooxygenase-1 inhibitors on analgesic action and gastric ulcer formation. 国際誌

Xiaoxia Zheng, Hiroyuki Oda, Shun Harada, Yukio Sugimoto, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

Journal of pharmaceutical sciences 97 ( 12 ) 5446 - 52 2008年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

A benzensulfonanilide-type cyclooxygenase-1 (COX-1)-selective inhibitor, ZXX2-77: 4-amino-4'-chloro-N-methylbenzenesulfonanilide (4a), has been reported as a novel analgesic that does not cause gastric damage. This compound has a weak analgesic effect but has potent in vitro COX-1 inhibitory activity. Since the reason for the weak analgesic effect in vivo was thought to be the low rate of oral absorption, the blood concentration of ZXX2-77 (4a) was measured in rats. It was found that the C(max) value (1.2 microM) of ZXX2-77 (4a) at a dose of 30 mg/kg did not reach the COX-1 IC(50) value (3.2 microM). On the other hand, ZXX2-79 (4b) (SO(2)NH derivative of ZXX2-77 (4a); 4-amino-4'-chlorobenzenesulfonanilide), which shows less potent COX inhibitory activities (COX-1 IC(50) = 12 microM, COX-2 IC(50) = 150 microM) than those of ZXX2-77 (4a) in vitro, was found to be more absorbable (C(max) = 16 microM at a dose of 30 mg/kg in rats) than ZXX2-77 (4a). Furthermore, ZXX2-79 (4b) not only showed a potent analgesic effect in a formalin test but also caused little gastric damage. These findings indicate that demethylated sulfonamide compounds are more easily absorbed than are N-methylated sulfonamide compounds and suggest that COX-1-selective inhibitors will be useful as analgesics that do not cause gastric damage.

DOI： 10.1002/jps.21388

Participation of histamine H3 receptors in experimental allergic rhinitis of mice.

Emiko Yokota, Shoji Kuyama, Yukio Sugimoto, Masami Ogawa, Chiaki Kamei

Journal of pharmacological sciences 108 ( 2 ) 206 - 11 2008年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

The present study was performed to study the participation of histamine H(3) receptors in nasal symptoms using Sch 50971, a potent and selective agonist of the H(3) receptor. Repeated topical application of antigen caused an increase in sneezing and nasal rubbing in sensitized mice. Oral administration of Sch 50971 and imetit, specific H(3)-receptor agonists, resulted in an inhibition of nasal symptoms induced by an antigen similar to an H(1)-receptor antagonist, cetirizine. Furthermore, simultaneous use of H(3)-receptor agonists, Sch 50971 or imetit, and an H(1)-receptor antagonist, cetirizine, caused a significant inhibitory effect on nasal symptoms at doses that showed no effect when used separately. The number of eosinophils in the nasal mucosa of mice sensitized with antigen was significantly decreased by cetirizine; however, Sch 50971 and imetit had no effect on eosinophil infiltration. These results clearly indicate that H(3) receptors are involved in the etiology of nasal allergy, and the stimulation of H(3) receptors may be useful as a novel therapeutic approach in nasal allergy.

Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor. 国際誌

Hiroki Kakuta, Xiaoxia Zheng, Hiroyuki Oda, Shun Harada, Yukio Sugimoto, Kenji Sasaki, Akihiro Tai

Journal of medicinal chemistry 51 ( 8 ) 2400 - 11 2008年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although cyclooxygenase-1 (COX-1) inhibition is thought to be a major mechanism of gastric damage by nonsteroidal anti-inflammatory drugs (NSAIDs), some COX-1-selective inhibitors exhibit strong analgesic effects without causing gastric damage. However, it is not clear whether their analgesic effects are attributable to COX-1-inhibitory activity or other bioactivities. Here, we report that N-(5-amino-2-pyridinyl)-4-(trifluoromethyl)benzamide ( 18f, TFAP), which has a structure clearly different from those of currently available COX-1-selective inhibitors, is a potent COX-1-selective inhibitor (COX-1 IC 50 = 0.80 +/- 0.05 microM, COX-2 IC 50 = 210 +/- 10 microM). This compound causes little gastric damage in rats even at an oral dose of 300 mg/kg, though it has an analgesic effect at as low a dose as 10 mg/kg. Our results show that COX-1-selective inhibitors can be analgesic agents without causing gastric damage.

DOI： 10.1021/jm701191z

Analgesic agents without gastric damage: Design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors (vol 15, pg 1014, 2007) 査読

Zheng Xiaoxia, Oda Hiroyuki, Takamatsu Kayo, Sugimoto Yukio, Tai Akihiro, Akaho Eiichi, Ali Hamed Ismail, Oshiki Toshiyuki, Kakuta Hiroki, Sasaki Kenji

BIOORGANIC & MEDICINAL CHEMISTRY 15 ( 9 ) 3299 - 3300 2007年5月

Analgesic agents without gastric damage: design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors. 国際誌

Xiaoxia Zheng, Hiroyuki Oda, Kayo Takamatsu, Yukio Sugimoto, Akihiro Tai, Eiichi Akaho, Hamed Ismail Ali, Toshiyuki Oshiki, Hiroki Kakuta, Kenji Sasaki

Bioorganic & medicinal chemistry 15 ( 2 ) 1014 - 21 2007年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

In order to create novel analgesic agents without gastric disturbance, structurally simple cyclooxygenase-1 (COX-1) inhibitors with a benzenesulfonanilide skeleton were designed and synthesized. As a result, compounds 11f and 15a, which possess a p-amino group on the benzenesulfonyl moiety and p-chloro group on the anilino moiety, showed COX-1-selective inhibition. Moreover compound 11f, which is the most potent compound in this study showed more potent analgesic activity than that of aspirin at 30 mg/kg by po. The anti-inflammatory activity and gastric damage, however, were very weak or not detectably different from aspirin. Since the structure of our COX-1 inhibitors are very simple, they may be useful as lead compounds for superior COX-1 inhibitors as analgesic agents without gastric disturbance.

Histamine H<inf>3</inf> receptors regulate vascular permeability changes in the skin of mast cell-deficient mice

Maria Alejandra Hossen, Yoko Fujii, Yukio Sugimoto, Ryoji Kayasuga, Chiaki Kamei

International Immunopharmacology 3 ( 12 ) 1563 - 1568 2003年11月

掲載種別：研究論文（学術雑誌）

The participation of histamine H3 receptors in the regulation of skin vascular permeability changes in mast cell-deficient mice was studied. Although intradermal injection of histamine H3 antagonists, iodophenpropit and clobenpropit, at a dose of 100 nmol/site caused significant increases in skin vascular permeability in both mast cell-deficient (WBB6F1 W/Wv) and wild-type (WBB6F1 +/+) mice, this response was significantly lower in mast cell-deficient mice than in the wild-type controls. Histamine also caused dose-related increases in skin vascular permeability in both wild-type and mast cell-deficient mice. Significant effects were observed at doses of 10 and 100 nmol/site, and no significant difference in skin vascular permeability was observed between mast cell-deficient and wild-type mice. However, histamine contents of dorsal skin in mast cell-deficient mice were significantly lower than in wild-type mice. In addition, the H1 antagonists diphenhydramine and chlorpheniramine and the NK1 antagonists, L-732,138 and L-733,060, were able to antagonize H3 antagonist-induced skin vascular permeability. These results indicated that blockade of H3 receptors by H3 antagonists induce skin vascular permeability through mast cell-dependent mechanisms. In addition, histamine and, to a lesser extent substance P are involved in the reaction. © 2003 Published by Elsevier B.V.

DOI： 10.1016/S1567-5769(03)00009-2

Histamine H3 receptors regulate vascular permeability changes in the skin of mast cell-deficient mice. 国際誌

Maria Alejandra Hossen, Yoko Fujii, Yukio Sugimoto, Ryoji Kayasuga, Chiaki Kamei

International immunopharmacology 3 ( 12 ) 1563 - 8 2003年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

The participation of histamine H(3) receptors in the regulation of skin vascular permeability changes in mast cell-deficient mice was studied. Although intradermal injection of histamine H(3) antagonists, iodophenpropit and clobenpropit, at a dose of 100 nmol/site caused significant increases in skin vascular permeability in both mast cell-deficient (WBB6F1 W/W(v)) and wild-type (WBB6F1 +/+) mice, this response was significantly lower in mast cell-deficient mice than in the wild-type controls. Histamine also caused dose-related increases in skin vascular permeability in both wild-type and mast cell-deficient mice. Significant effects were observed at doses of 10 and 100 nmol/site, and no significant difference in skin vascular permeability was observed between mast cell-deficient and wild-type mice. However, histamine contents of dorsal skin in mast cell-deficient mice were significantly lower than in wild-type mice. In addition, the H(1) antagonists diphenhydramine and chlorpheniramine and the NK(1) antagonists, L-732,138 and L-733,060, were able to antagonize H(3) antagonist-induced skin vascular permeability. These results indicated that blockade of H(3) receptors by H(3) antagonists induce skin vascular permeability through mast cell-dependent mechanisms. In addition, histamine and, to a lesser extent substance P are involved in the reaction.

Inhibitory effects of glucocorticoids on rat eosinophil superoxide generation and chemotaxis

Yukio Sugimoto, Masami Ogawa, Nobuyuki Tai, Chiaki Kamei

International Immunopharmacology 3 ( 6 ) 845 - 852 2003年6月

掲載種別：研究論文（学術雑誌）

Eosinophil infiltration into inflammatory tissues and the subsequent release of inflammatory mediators are the hallmarks of several inflammatory allergic diseases. Although there have been a considerable number of publications on anti-inflammatory effects of glucocorticoids, little is known about whether glucocorticoids affect the activation of eosinophils directly. We studied the effects of three glucocorticoids, mometasone furoate, dexamethasone and beclomethasone dipropionate, on superoxide generation and the chemotaxis of rat eosinophils. Highly purified rat eosinophils were treated for 6 h with mometasone furoate, dexamethasone or beclomethasone dipropionate. Eosinophils were stimulated with phorbol myristate acetate (PMA) for superoxide generation, while for induction of chemotaxis, platelet-activating factor (PAF) or leukotriene B4 (LTB4) was used. None of the glucocorticoids used in the present study caused significant suppressive effects on superoxide generation induced by PMA. On the other hand, both PAF- and LTB4-induced migration of rat eosinophils were inhibited in a concentration-dependent manner by glucocorticoids. Mometasone furoate showed a significant effect at concentrations higher than 10-11 M. Dexamethasone and beclomethasone dipropionate also caused a significant inhibition at concentrations higher than 10-8 and 10-7 M, respectively. These results indicated that the anti-inflammatory effects of glucocorticoids were mediated by direct inhibition of eosinophil migration. Furthermore, mometasone furoate was suggested to be more useful than the other drugs in the treatment of allergic diseases responsible for eosinophil chemotaxis. © 2003 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S1567-5769(03)00055-9

Inhibitory effects of glucocorticoids on rat eosinophil superoxide generation and chemotaxis. 国際誌

Yukio Sugimoto, Masami Ogawa, Nobuyuki Tai, Chiaki Kamei

International immunopharmacology 3 ( 6 ) 845 - 52 2003年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Eosinophil infiltration into inflammatory tissues and the subsequent release of inflammatory mediators are the hallmarks of several inflammatory allergic diseases. Although there have been a considerable number of publications on anti-inflammatory effects of glucocorticoids, little is known about whether glucocorticoids affect the activation of eosinophils directly. We studied the effects of three glucocorticoids, mometasone furoate, dexamethasone and beclomethasone dipropionate, on superoxide generation and the chemotaxis of rat eosinophils. Highly purified rat eosinophils were treated for 6 h with mometasone furoate, dexamethasone or beclomethasone dipropionate. Eosinophils were stimulated with phorbol myristate acetate (PMA) for superoxide generation, while for induction of chemotaxis, platelet-activating factor (PAF) or leukotriene B(4) (LTB(4)) was used. None of the glucocorticoids used in the present study caused significant suppressive effects on superoxide generation induced by PMA. On the other hand, both PAF- and LTB(4)-induced migration of rat eosinophils were inhibited in a concentration-dependent manner by glucocorticoids. Mometasone furoate showed a significant effect at concentrations higher than 10(-11) M. Dexamethasone and beclomethasone dipropionate also caused a significant inhibition at concentrations higher than 10(-8) and 10(-7) M, respectively. These results indicated that the anti-inflammatory effects of glucocorticoids were mediated by direct inhibition of eosinophil migration. Furthermore, mometasone furoate was suggested to be more useful than the other drugs in the treatment of allergic diseases responsible for eosinophil chemotaxis.

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