Conventional clinical treatments for allergy management remain suboptimal; new, orally available medications that improve a wide range of allergic signs have been desired. We previously demonstrated that JTE-852, a novel spleen tyrosine kinase inhibitor, potently and simultaneously suppresses secretion of granule contents, arachidonate metabolites, and cytokines from mast cells stimulated by immunoglobulin E-crosslinking. In the present study, we investigated the effects of JTE-852 in four rat models (sneezing, rhinorrhea, airway constriction, and airway inflammation) as representatives of allergy models. Rats were sensitized and challenged with antigen. Allergic reactions developed after challenge were detected. JTE-852 and current anti-allergic drugs (ketotifen, pranlukast, and prednisolone) were administered orally before challenge. JTE-852 showed significant blocking effects on antigen-induced allergic reactions in all models, indicating that JTE-852 in oral dosage form would improve a wide range of allergic signs. The current anti-allergic drugs, on the other hand, failed to display significant suppression in several models. Because JTE-852 suppresses the secretion of all three groups of allergic mediators from mast cells, it would be capable of targeting signs that current drugs cannot sufficiently relieve. We anticipate JTE-852 to be a promising new anti-allergic drug that is potentially more effective than conventional drugs.

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease, and some patients develop hepatic cirrhosis/carcinoma. Animal models play key roles in the development of new therapies for NASH. In this study, the pharmacological effects of metformin and pioglitazone were investigated in female Spontaneously Diabetic Torii (SDT) fatty rats to verify the utility of this model. The anti-diabetic drugs were administered to SDT fatty rats fed a cholesterol-enriched diet from 4 to 25 weeks, and changes in food intake, body weight, and blood chemistry parameters were evaluated every 4 weeks. The hepatic lipid content, mRNA expression in relation to lipid synthesis, inflammation, and fibrosis, and histopathological analyses were performed at 25 weeks. Pioglitazone improved hyperglycemia, hyperlipidemia, and abnormalities in hepatic parameters. The insulin levels were lower than those in the control rats before 16 weeks. Plasma glucose levels in the metformin-treated rats were lower than those in the control rats, and plasma alanine aminotransferase levels temporarily decreased. The lipid content and some mRNA expression in relation to fibrosis in the liver decreased with pioglitazone treatment, and the mRNA expression of microsomal triglyceride transfer protein increased. Hepatic fibrosis observed in the SDT fatty rats improved with pioglitazone treatment; however, the effect with metformin treatment was partial. These results in both drugs are in line with results in the human study, suggesting that the SDT fatty rat is useful for developing new anti-NASH drugs that show potential to regulate glucose/lipid metabolism.

In recent years, a relationship between diabetes and neurodegenerative diseases, such as Parkinson's disease, Alzheimer disease or depression, has been proposed. In this study, pathophysiological changes in the brain, especially in the hippocampus, of male SDT fatty rats with obesity and hyperglycemia were investigated. Brains of SD rats and SDT fatty rats were collected at 32 and 58 weeks of age, and parietal cortical thickness and number of pyramidal cells in the hippocampal cornu ammonis 1 and 3 (CA1 and CA3) regions were measured. At 58 weeks of age, the parietal cortical thickness and number of pyramidal cells in the hippocampal CA1 and CA3 regions were lower in SDT fatty rats than in age-matched SD rats. Measurements of mRNA in rat brains at 58 weeks of age showed that the expression of genes related to inflammatory responses (S100a9, TNFα, NF-κB) was elevated in SDT fatty rats. From the aforementioned results, changes suggestive of brain atrophy and impairment in cognitive function were observed in male SDT fatty rat brains.

Ferric citrate is an oral iron-based phosphate binder, being known to affect iron status and improve iron deficiency anemia (IDA) in chronic kidney disease (CKD) patients. We examined whether oral administration of ferric citrate could change iron status and improve anemia without affecting phosphorus metabolism in iron deficiency anemia rats. In Normal rat study, normal rats were fed a diet containing 0.3 or 3% ferric citrate for 11 days for setting the dose and administration period of ferric citrate. The effects of ferric citrate on iron status- and phosphorus metabolism-related parameters were evaluated using blood and urine samples. Next, an iron deficiency anemia was induced by feeding iron-depleted diet in rats. After 7 days of starting the iron-depleted diet, 0.3% ferric citrate was administered for 7 days by dietary admixture. Iron status- and phosphorus metabolism-related parameters were evaluated with blood and urine samples. In Normal rat study, 3% ferric citrate treatment increased serum iron level and transferrin saturation (TSAT), and decreased serum phosphorus level, intact fibroblast growth factor 23 (iFGF23) level, and urinary phosphorus excretion, but 0.3% ferric citrate treatment showed no effects. On the other hand, in Iron deficiency anemia rat study, 0.3% ferric citrate treatment increased iron status-related parameters and improved anemia, but did not show any apparent changes in phosphorus metabolism-related parameters. In conclusion, ferric citrate could have hematopoietic effects without affecting phosphorus metabolism, and could be a potential option for the treatment of IDA in patients without CKD.

Diabetes mellitus (DM) and obesity are associated with neurodegenerative diseases such as Alzheimer's disease and psychiatric disorders such as major depression. In this study, we investigated pathophysiological changes in the brains of female Spontaneously Diabetic Torii (SDT) fatty rats with diabetes and obesity. Brains of Sprague-Dawley (SD), SDT and SDT fatty rats were collected at 58 weeks of age. The parietal cortical thickness was measured and the number of pyramidal cells in the hippocampal cornu ammonis 1 and 3 (CA1 and CA3) and the number of granule cells in the dentate gyrus (DG) regions were counted. The area of glial fibrillary acidic protein (GFAP) positivity in CA1, CA3 and DG regions were measured. The parietal cortical thickness and the number of cells in CA3 and DG regions of SDT and SDT fatty rats did not show obvious changes. On the other hand, in the CA1 region, the number of cells in SDT rats and SDT fatty rats was significantly lower than that in SD rats, and that in SDT fatty rats was significantly lower than that in SDT rats. The GFAP-positive area in SDT fatty rats was significantly reduced compared to that in SD rats only in the DG region. Preliminarily result showed that the expression of S100a9, an inflammation-related gene, was increased in the brains of SDT fatty rats. These results suggest that female SDT fatty rat may exhibit central nervous system diseases due to obesity and DM.