Impaired monoamine neural system in the mPFC of SHRSP/Ezo as an animal model of attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood-onset psychiatric disorder. We investigated the effects of systemic administration of monoamine reuptake inhibitors on long-term potentiation (LTP) formation and monoamine release in the medial prefrontal cortex (mPFC) of the stroke-prone spontaneously hypertensive rat (SHRSP)/Ezo, an animal model of ADHD, and its genetic control, Wistar Kyoto (WKY)/Ezo, to elucidate the functional changes in the mPFC monoamine neural system. Methylphenidate (dopamine (DA) and noradrenaline (NA) reuptake inhibitor) and desipramine (NA reuptake inhibitor) improved LTP formation defects in the mPFC of SHRSP/Ezo, suggesting that NA or both DA and NA are required for improvement of impaired LTP. Methylphenidate increased mPFC DA in both WKY/Ezo and SHRSP/Ezo, but the increase was greater in the former. GBR-12909 (DA reuptake inhibitor) increased mPFC DA in WKY/Ezo but had no effect in SHRSP/Ezo. This may be because DA transporter in SHRSP/Ezo is functionally impaired and contributes less to DA reuptake, so its inhibition did not increase DA level. Meanwhile, basal DA levels in the mPFC of SHRSP/Ezo were paradoxically decreased. These results suggest that functional changes in the DA and NA neural system in the frontal lobe are involved in the pathology of ADHD.

Pressure stress delays cyclooxygenase-2 expression induced by interleukin-1ß in cultured human pulmonary artery smooth muscle cells.

Introduction: Pulmonary artery smooth muscle cells (PASMCs) play an important role in the sequence of events leading to the formation of pulmonary hypertension (PH). However, little is known about the direct effects of high pressure on the function and intercellular signaling pathways of PASMCs. The aim of this study was to evaluate the effect of pressure stress that simulates PH on interleukin (IL)-1ß- or angiotensin II-induced cyclooxygenase-2 (COX-2) expression in cultured human PASMCs. Methods: Either 20 or 60 mmHg atmospheric pressure was applied to PASMCs by a pressure-loading apparatus. Protein expression and phosphorylation were analyzed by western blotting. mRNA expression was analyzed by quantitative real-time reverse transcription-polymerase chain reaction. Results: IL-1ß-induced COX-2 protein expression peaked at 6 h in non-pressurized cells, whereas COX-2 expression was delayed, peaking at 12 h, in 20 and 60 mmHg pressurized cells. Both pressures also delayed the time to peak COX-2 mRNA expression induced by IL-1ß. In addition, pressure stress delayed the time to peak mitogen-activated protein kinase (MAPK) phosphorylation induced by IL-1ß. In contrast, angiotensin II-induced transient COX-2 mRNA expression and MAPK phosphorylation were not affected by pressure stress. Conclusion: These results suggest that pressure stress delays IL-1ß-induced COX-2 expression via the delayed activation of MAPKs in PASMCs, and the effects of pressure stress differ according to the bioactive substance being stimulated. Our results demonstrate that the application of pressure stress to PASMCs directly alters cell function, which may provide a basic insight into our understanding of the pathogenesis of PH.

[Consideration of the Characteristics of Oral Iron Preparations from the Viewpoint of the Mechanism of Nausea and Vomiting].

The nausea and vomiting that occur as a result of oral iron administration for the treatment of iron-deficiency anemia (IDA) can cause significant physical and emotional stress in patients. Because iron is absorbed from the intestine as ferrous iron, the most widely used treatment for IDA is oral ferrous agents. However, ferrous forms are more toxic than ferric forms because ferrous forms readily generate free radicals. A randomized, double-blind, active-controlled, multicenter non-inferiority study conducted in Japan showed that ferric citrate hydrate (FC) was just as effective as sodium ferrous citrate (SF) in the treatment of IDA, with a lower incidence of adverse reactions such as nausea and vomiting compared with SF. Animal studies have shown that chemotherapy-induced nausea and vomiting (CINV) involves the release of 5-hydroxytryptamine from enterochromaffin cells by free radicals, and that some chemotherapeutic agents cause hyperplasia of these cells. Enterochromaffin cells also contain substance P, which is known to be also closely related to CINV. We found that administration of SF to rats causes hyperplasia of enterochromaffin cells in the small intestine, whereas FC has no effect on enterochromaffin cells. Oral iron agents may induce nausea and vomiting via the effect of ferrous iron on reactive oxygen species production in the intestine and subsequent enterochromaffin cell hyperplasia. Further research to elucidate the detailed mechanism of enterochromaffin cell hyperplasia induced by ferrous iron preparations is needed to develop a treatment for iron deficiency anemia that causes less gastrointestinal damage.

Low-dose nafamostat mesilate ameliorates tissue injury and inhibits 5-hydroxytryptamine synthesis in the rat intestine after methotrexate administration.

We aimed to clarify the effect of nafamostat mesilate (nafamostat) on intestinal mucositis as well as the potentiation of intestinal 5-hydroxytryptamine (5-HT) dynamics induced by methotrexate, an anti-cancer drug, in rats. Rats received intraperitoneal methotrexate at 12.5 mg/kg/day for 4 days. In addition, 1, 3, or 10 mg/kg/day of nafamostat was given subcutaneously for 4 days. Ninety-six hours after the first administration of methotrexate, jejunal tissues were collected for analysis. The results showed that 1 mg/kg, but not 3 or 10 mg/kg, of nafamostat significantly ameliorated the methotrexate-induced body weight loss. Moreover, 1 mg/kg of nafamostat significantly improved methotrexate-induced mucositis, including villus atrophy. Nafamostat (1 mg/kg) significantly inhibited the methotrexate-induced mRNA expression of pro-inflammatory cytokines and cyclooxygenase-2, as well as methotrexate-induced 5-HT content and tryptophan hydroxylase (TPH) activity. In addition, it tended to inhibit the number of anti-TPH antibody-positive cells and significantly inhibited the number of anti-substance P antibody-positive cells. These findings suggest that low-dose nafamostat ameliorates tissue injury and 5-HT and substance P synthesis in methotrexate-induced mucositis. Nafamostat may be a novel therapeutic strategy for the prevention and treatment of mucositis as well as 5-HT- and/or substance P-related adverse effects in cancer chemotherapy.

Ferric Citrate Hydrate Has Little Impact on Hyperplasia of Enterochromaffin Cells in the Rat Small Intestine Compared to Sodium Ferrous Citrate.

INTRODUCTION: The most detrimental factor preventing the use of oral iron in the treatment of iron deficiency anemia is gastrointestinal side effects accompanied by nausea and vomiting. Anorexia is a known secondary effect of nausea and vomiting. The important gastrointestinal signaling molecule 5-hydroxytryptamine (5-HT) is critically involved in not only physiological function but also nausea and vomiting. The present study was designed to compare the effects of the administration of sodium ferrous citrate (SF) and ferric citrate hydrate (FC) to rats on anorexia and hyperplasia of enterochromaffin cells, which mainly synthesize and store 5-HT. METHODS: Rats received either SF (3 or 30 mg/kg/day) or FC (30 mg/kg/day) orally for 4 days. Food and water intakes were measured every 24 h during the study. At 96 h after the first administration of the oral iron preparation, the duodenal and jejunal tissues were collected for analysis. Enterochromaffin cells were detected by immunohistochemical analysis. RESULTS: Administration of 3 mg/kg SF had no effect on anorexia but led to increased hyperplasia of enterochromaffin cells in the duodenum (p < 0.1). Administration of 30 mg/kg SF significantly decreased food and water intakes and significantly increased hyperplasia of enterochromaffin cells in the duodenum and jejunum. Alternatively, administration of 30 mg/kg FC had no significant effect on food and water intakes or hyperplasia of enterochromaffin cells. CONCLUSION: The lower impact on the hyperplasia of enterochromaffin cells of FC compared to SF may contribute to the maintenance of rats' physical condition.

D-serine metabolism in the medial prefrontal cortex, but not the hippocampus, is involved in AD/HD-like behaviors in SHRSP/Ezo.

Attention-deficit/hyperactivity disorder (AD/HD) is a mild neurodevelopmental disorder with inattention, hyperactivity, and impulsivity as its core symptoms. We previously revealed that an AD/HD animal model, juvenile stroke-prone spontaneously hypertensive rats (SHRSP/Ezo) exhibited functional abnormalities in N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex. D-serine is an endogenous co-ligand that acts on the glycine-binding site of NMDA receptors, which is essential for the physiological activation of NMDA receptors. We herein performed neurochemical and pharmacological behavioral experiments to elucidate dysfunctions in D-serine metabolism (namely, biosynthesis and catabolism) associated to AD/HD. The serine enantiomers ratio (D-serine/D-serine + L-serine, DL ratio) in the medial prefrontal cortex (mPFC) and hippocampus (HIP) was lower in SHRSP/Ezo than in its genetic control. The level of D-amino acid oxidase (DAAO, D-serine degrading enzyme) was higher in the mPFC, and the level of serine racemase (SR, D-serine biosynthetic enzyme), was lower in the HIP in SHRSP/Ezo. Thus, changes in these enzymes may contribute to the lower DL ratio of SHRSP/Ezo. Moreover, a microinjection of a DAAO inhibitor into the mPFC in SHRSP/Ezo increased DL ratio and attenuated AD/HD-like behaviors, such as inattention and hyperactivity, in the Y-maze test. Injection into the HIP also increased the DL ratio, but had no effect on behaviors. These results suggest that AD/HD-like behaviors in SHRSP/Ezo are associated with an abnormal D-serine metabolism underlying NMDA receptor dysfunction in the mPFC. These results will contribute to elucidating the pathogenesis of AD/HD and the development of new treatment strategies for AD/HD.

Methotrexate mediates the integrity of intestinal stem cells partly through nitric oxide-dependent Wnt/ß-catenin signaling in methotrexate-induced rat ileal mucositis.

This study aimed to elucidate the role of nitric oxide (NO) in intestinal stem cells in methotrexate-induced ileal mucositis in rats. Methotrexate induced the mRNA expressions of the Wnt/ß-catenin target genes Wnt3a, Sox9, and Lgr5 and the Wnt-antagonist gene sFRP-1 and the protein expressions of Lgr5 and sFRP-1. Methotrexate also induced Lgr5+ cells and lysozyme+ cells. A non-selective NO inhibitor inhibited the methotrexate induction of Wnt/ß-catenin target genes and Lgr5+ cells but enhanced that of sFRP-1 expression. Thus, methotrexate mediates the integrity of intestinal stem cells partly through NO-dependent Wnt/ß-catenin signaling and may enhance tolerability to methotrexate-induced injury.

Noradrenaline increases intracellular Ca2+ concentration in epithelial cells via α2-adrenoceptors in isolated mouse ileal crypts.

The stimulation of α2-adrenoceptors caused a transient increase of intracellular calcium concentration ([Ca2+]i) monitored by ratiometry using Fura-2 in epithelial cells including enterochromaffin cells in isolated mouse ileal crypts, while stimulation of α1-and ß-adrenoceptors had no effect. The effect of noradrenaline was suppressed by α2-adrenoceptor antagonists, but not by α1-and ß-adrenoceptor antagonists, and partially suppressed by Ni2+ and nicardipine, but not by ω-conotoxin and ω-agatoxin. These results suggest that noradrenaline causes an increase of [Ca2+]i by the influx of extracellular Ca2+ through certain Ca2+ channels via α2-adrenoceptors in epithelial cells of mouse ileal crypts.

Administration of cyclophosphamide to rats induces pica and potentiates 5-hydroxytryptamine synthesis in the intestine without causing severe intestinal injury.

The effects of cyclophosphamide on 5-hydroxytryptamine (5-HT) synthesis in the intestinal tissue of rats were investigated. Rats received 120 mg/kg cyclophosphamide intraperitoneally as a single administration, and kaolin and food intake was measured by an automatic monitoring apparatus. Ileal tissues were collected at either 24 or 72 h after administration. Cyclophosphamide caused a significant increase in kaolin intake at the acute and the delayed phases and was associated with a decrease in food intake, and body weight. Cyclophosphamide had no significant effect on intestinal mucosal morphology, or inducible nitric oxide synthase and cyclooxygenase-2 expression in the intestine. Cyclophosphamide significantly increased tryptophan hydroxylase 1 (TPH1) mRNA expression, number of anti-TPH antibody-positive cells, and 5-HT content in the intestine. Cyclophosphamide also significantly increased the expression of Tac1 mRNA, encoding preprotachykinin-1, which is a preprotein of substance P, and the number of anti-substance P antibody-positive cells in the intestine. Cyclophosphamide significantly increased Lgr5, Bmi1, and Atoh1 mRNA levels, which are markers for the proliferation and differentiation of stem cells. This study demonstrated that cyclophosphamide induced pica in rats, and potentiated 5-HT synthesis associated with hyperplasia of substance P-containing enterochromaffin cells without causing severe intestinal injury.

Abnormal Pressure Stress Reduces Interleukin-1ß-Induced Cyclooxygenase-2 Expression in Cultured Rat Vascular Smooth Muscle Cells.

Elevated mechanical stress on blood vessels associated with hypertension has a direct effect on the function of vascular endothelial cells and vascular smooth muscle cells (VSMCs). In the present study, we have identified the effect of pulsatile pressure stress on cyclooxygenase-2 (COX-2) expression induced by interleukin (IL)-1ß in cultured rat VSMCs. VSMCs were isolated from aortic media of Wistar rats and cultured. Pulsatile pressure applied to VSMCs was repeatedly given between either 80 and 160 mmHg, which simulates systolic hypertension, or 80 and 120 mmHg, which simulates normal blood pressure, at a frequency of 4 cycles per min using our original apparatus. Pressure loading that simulates systolic hypertension reduced IL-1ß-induced COX-2 expression. The pressure also inhibited the rapid and transient phosphorylation of extracellular signal-regulated kinase (ERK) induced by IL-1ß. IL-1ß-induced COX-2 expression was significantly inhibited by a specific conventional protein kinase C (PKC) inhibitor. Pressure loading that simulates systolic hypertension also reduced phorbol myristate 13-acetate (PMA) (a PKC activator)-induced COX-2 expression and the rapid and transient phosphorylation of ERK. Pressure loading that simulates normal blood pressure had no effect on IL-1ß- and PMA-induced COX-2 expression. The present study shows that pressure stress between 80 and 160 mmHg, which simulates systolic hypertension reduces IL-1ß-induced COX-2 expression by affecting a mechanism involving PKC and ERK signaling pathways. Downregulation of COX-2 expression in VSMCs by abnormal pressure stress may further worsen local vascular injury associated with hypertension.

Effects of nafamostat mesilate on 5-hydroxytryptamine release from isolated ileal tissues induced by anti-cancer drugs in rats.

Administration of cisplatin and methotrexate significantly increased 5-hydroxytryptamine (5-HT) release from intestinal tissues isolated at 72 h after administration in rats. Daily administration with nafamostat mesilate, a potent serine protease inhibitor, significantly inhibited the release of 5-HT induced by methotrexate, but not by cisplatin, in a dose-dependent manner. When applied to isolated ileal tissues in vitro, nafamostat mesilate also significantly inhibited the release of 5-HT induced by methotrexate, but not by cisplatin, in a concentration-dependent manner. These results suggest that serine proteases are involved in the mechanism of the methotrexate-induced release of 5-HT from the rat small intestine.

Role of Nitric Oxide in the Change of 5-Hydroxytryptamine Synthesis in the Intestine by a Consecutive Administration of Methotrexate to Rats.

This study aimed to investigate whether the consecutive administration of methotrexate affects 5-hydroxytryptamine (5-HT) synthesis in the rat small intestine. Rats received methotrexate at a dose of 12.5 mg/kg intraperitoneally on 4 consecutive days. NG-nitro-L-arginine methyl ester (L-NAME) was given subcutaneously to inhibit nitric oxide (NO) synthase. Methotrexate moderately altered 5-HT synthesis, whereas the combined administration of methotrexate and L-NAME significantly changed 5-HT synthesis in the rat ileal tissue. These results suggest that endogenous NO has an antagonistic role in the induction of 5-HT synthesis in rats following the consecutive administration of methotrexate.

The role of nitric oxide in small intestine differs between a single and a consecutive administration of methotrexate to rats.

The role of nitric oxide (NO) on intestinal mucosal injury induced by single or consecutive administration of methotrexate was investigated in a rodent model. Rats received methotrexate intraperitoneally either as a single administration (50 mg/kg) or as a consecutive administration (12.5 mg/kg/day) for 4 days. NG-nitro-l-arginine methyl ester (L-NAME) was given subcutaneously to inhibit NO synthase (NOS). Ninety-six hours after the first administration of methotrexate, ileal tissues were collected for analysis. Consecutive administration of methotrexate led to decreased body weight and reduced intake of food and water, which were further worsened by L-NAME. Although a slight mucosal injury resulted from single administration of methotrexate, L-NAME had almost no effect. Consecutive administration of methotrexate caused a significant mucosal injury, which was further worsened by L-NAME. Consecutive, but not single, administration of methotrexate induced mRNA expression of inflammatory cytokines in ileal tissue. Consecutive administration of methotrexate significantly induced constitutive NOS expression in ileal tissue. These results suggest that consecutive administration, rather than single administration, of methotrexate aggravates mucosal injury. Potentiation of constitutive NOS expression by consecutive administration might be one of the main reason to antagonize the intestinal mucosal injury as well as lead to a reduction in rat quality of life.

Potentiation of Glucagon-Like Peptide-2 Dynamics by Methotrexate Administration in Rat Small Intestine.

The aim of this study was to clarify the relationship between chemotherapy-induced mucositis and endogenous glucagon-like peptide-2 (GLP-2) dynamics in the small intestine following treatment with either methotrexate or 5-fluorouracil. Rats were injected intraperitoneally with a single dose of either 50 mg/kg methotrexate or 100 mg/kg 5-fluorouracil. At 24 and 72 h after drug administration, ileal tissues and plasma were used to investigate GLP-2 dynamics. Administration of methotrexate caused moderate but not significant intestinal injury within 72 h, while administration of 5-fluorouracil caused severe injury in a time-dependent manner. Methotrexate significantly increased proglucagon mRNA expression and the number of anti-GLP-2 antibody-positive cells in the ileal tissue at 24 h after administration. Methotrexate also significantly induced GLP-2 receptor, insulin-like growth factor-1 (IGF-1), and transforming growth factor-ß2 (TGF-ß2) mRNA expression in ileal tissue. In contrast, 5-fluorouracil significantly inhibited proglucagon, GLP-2 receptor, IGF-1, and TGF-ß2 mRNA expression as well as the number of anti-GLP-2 antibody-positive cells. Methotrexate slightly increased dipeptidyl peptidase IV (DPP-4) mRNA expression, whereas 5-fluorouracil significantly increased DPP-4 mRNA expression. These results suggest that potentiation of endogenous GLP-2 dynamics by methotrexate is associated with a mechanism that preserves gastrointestinal mucosal integrity at a moderate level.

Nitric oxide plays a critical role in methotrexate-induced hyperplasia of enterochromaffin cells containing 5-hydroxytryptamine in rat small intestine.

The role of nitric oxide (NO) in the changes in enterochromaffin cells and ileal 5-hydroxytryptamine (5-HT) content induced by a single i.p. administration of methotrexate was investigated in rats. Methotrexate significantly increased inducible NO synthase (iNOS) mRNA and protein expressions in the intestinal tissue at 96 h. Methotrexate also significantly caused hyperplasia of the enterochromaffin cells at 96 h; this was associated with a significant increase in 5-HT content. The methotrexate-induced hyperplasia of enterochromaffin cells and increase in 5-HT content were, however, completely suppressed by daily treatment with dexamethasone, and with NG-nitro-l-arginine methyl ester (l-NAME); this was not observed when meloxicam was administered. Histological examination showed slight but not pronounced mucosal injury, at 96 h after methotrexate administration. The methotrexate-induced decrease in body weight did not fully recover to the control level up to 96 h; however, the methotrexate-induced decrease in food/water intake slightly returned to the control level up to 96 h. l-NAME had no significant effect on methotrexate-induced body weight loss and anorexia. To conclude, the present study suggests that NO derived from methotrexate-induced iNOS plays a critical role in the mechanism of hyperplasia of enterochromaffin cells containing 5-HT in the intestinal tissue of rats.

N-methyl-d-aspartate receptor dysfunction in the prefrontal cortex of stroke-prone spontaneously hypertensive rat/Ezo as a rat model of attention deficit/hyperactivity disorder.

AIM: We previously reported that stroke-prone spontaneously hypertensive rat/Ezo (SHRSP/Ezo) has high validity as an attention deficit/hyperactivity disorder (AD/HD) animal model, based on its behavioral phenotypes, such as inattention, hyperactivity, and impulsivity. Fronto-cortical dysfunction is implicated in the pathogenesis of AD/HD. In this study, we investigated prefrontal cortex (PFC) function in SHRSP/Ezo rats by electrophysiological methods and radioreceptor assay. METHODS: We recorded excitatory postsynaptic potential in layer V pyramidal neurons in the PFC by intracellular recording method to assess synaptic plasticity in the form of long-term potentiation (LTP). We also performed N-methyl-d-aspartate acid (NMDA) receptor binding assay in the PFC and hippocampus using radiolabeled NMDA receptor antagonist [3 H]MK-801. RESULTS: Theta-burst stimulation induced LTP in the PFC of genetic control, WKY/Ezo, whereas failed to induce LTP in that of SHRSP/Ezo. The Kd value of [3 H]MK-801 binding for NMDA receptors in the PFC of SHRSP/Ezo was higher than in the WKY/Ezo. Neither the Bmax nor Kd of [3 H]MK-801 binding in the SHRSP/Ezo hippocampus was significantly different to WKY/Ezo. CONCLUSION: These results suggest that the AD/HD animal model SHRSP/Ezo has NMDA receptor dysfunction in the PFC.

Docosahexaenoic acid suppresses angiotensin II-induced A7r5 vascular smooth muscle cell proliferation and migration under pulsatile pressure stress.

Elevated mechanical stress applied to vascular walls is well known to modulate vascular remodeling and plays a part in the pathogenesis of atherosclerosis. On the other hand, docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, has been shown to protect against several types of cardiovascular diseases including atherosclerosis and hypertension. The aim of this study was to clarify the effect of pulsatile pressure stress and DHA on angiotensin II-induced proliferation and migration in A7r5 vascular smooth muscle cells (VSMCs). Pulsatile pressure of between 80 and 160 mmHg was repeatedly applied to VSMCs at a frequency of 4 cycles per min using an apparatus that we developed. Cell proliferation and migration were evaluated using a live cell movie analyzer. Application of pulsatile pressure stress for 24 h significantly increased cell proliferation. Angiotensin II also significantly increased cell proliferation in the presence or absence of pressure stress. DHA significantly inhibited angiotensin II-induced cell proliferation regardless of the pressure load. Angiotensin II significantly induced cell migration regardless of the pulsatile pressure load. Pulsatile pressure stress alone slightly, but not significantly, induced cell migration. DHA inhibited angiotensin II-induced VSMC proliferation and migration under abnormal pressure conditions. Pressure stress tended to induce extracellular signal-regulated kinase (ERK) phosphorylation in the absence of angiotensin II, whereas it significantly induced ERK phosphorylation in the presence of angiotensin II. However, the pressure-induced ERK phosphorylation was not observed in the DHA-treated VSMCs. Our findings may contribute to the understanding of the beneficial effect of DHA on various cardiovascular disorders.

Cisplatin increases the number of enterochromaffin cells containing substance P in rat intestine.

We previously reported that cisplatin potentiated ileal 5-hydroxytryptamine (5-HT) metabolism and caused pathological changes with an inflammatory response in the delayed phase (72 h) after administration to rats. In the present study, we further investigated the time-dependent effect of cisplatin on ileal 5-HT metabolism and the effects of combining cisplatin and anti-inflammatory drugs on ileal tryptophan hydroxylase expression and pica (the consumption of non-nutritive materials such as kaolin). Cyclooxygenase-2 (COX-2) expression was significantly increased at 24 h after cisplatin (5 mg/kg, intraperitoneal) administration. Cisplatin significantly increased ileal 5-HT content at 48 h after administration and the number of L-tryptophan hydroxylase-expressing cells (i.e., enterochromaffin cells) in the ileal mucosa within 24 h after administration. It also caused a significant increase in the number of substance P-expressing cells. Immunohistochemical double staining revealed that most of the enterochromaffin cells contained substance P. Neither daily treatment with dexamethasone (1 mg/kg, subcutaneous) nor meloxicam (3 mg/kg, subcutaneous), a selective COX-2 inhibitor, affected the cisplatin-induced increase in the number of enterochromaffin cells. Meloxicam had no effect on cisplatin-induced pica, although dexamethasone almost completely inhibited it. This study demonstrated that cisplatin administration induced COX-2 expression and increased the number of enterochromaffin cells in the acute phase (i.e., within 24 h). However, COX-2 expression in the ileum seems to have little direct effect on the mechanism of the induction of enterochromaffin cells and pica.

Tranilast inhibits interleukin-33 production by macrophages.

Tranilast is an anti-allergy medication that inhibits the release of chemical mediators such as histamine. However, the mechanisms underlying its anti-allergy effects are not fully understood. Interleukin (IL)-33, a novel member of the IL-1 cytokine family, promotes T helper type 2 immune responses and plays a pathogenic role in allergic disorders. In the present study, we examined the effects of tranilast on IL-33 production by RAW264.7 macrophages. Lipopolysaccharide (LPS) increased both IL-33 mRNA expression and IL-33 protein synthesis. Tranilast significantly inhibited LPS-induced IL-33 protein production by RAW264.7 macrophages in a dose-dependent manner; these same effects were observed on IL-33 mRNA levels in RAW264.7 macrophages and a primary culture of macrophages. LPS markedly activated Akt in RAW264.7 macrophages, whereas tranilast suppressed LPS-induced Akt activation. The effects of tranilast on Akt activation appeared to be responsible for the decrease in IL-33 production. Our present findings suggest that the inhibition of IL-33 production by tranilast might contribute to the anti-allergy effects of this medication.