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Thyroid hormones (THs) have been suggested to play an important role in both physiological and pathological events in the central nervous system. Hypothyroidism, which is characterized by low levels of serum THs, has been associated with aggravation of ischemic neuronal injuries in stroke patients. We hypothesized that administration of T 3 , the main active form of THs, may attenuate the ischemic neuronal injuries. In mice, global cerebral ischemia (GCI), which is induced by transient occlusion of the bilateral common carotid artery, causes neuronal injuries by inducing neuronal death and activating inflammatory responses after reperfusion in the hippocampus. In this study, we examined the effect of T 3 administration on DNA fragmentation induced by neuronal death and the activation of inflammatory cells such as astrocytes and microglia in the hippocampus following GCI. The content of nucleosomes generated by DNA fragmentation in the hippocampus was increased by GCI and further increased by T 3 administration. The protein expression levels of glial fibrillary acidic protein (GFAP), an astrocytic marker, and Ionized calcium binding adaptor protein 1 (Iba1), a microglial marker, in the hippocampus were also increased by GCI and further increased by T 3 administration. The levels of T 3 in both the serum and hippocampus were elevated by T 3 administration. Our results indicate that T 3 administration aggravates GCI-reperfusion injury in mice. There may be an increased risk of aggravation of ischemic stroke by the excessive elevation of T 3 levels during the drug treatment of hypothyroidism.

Thirty minutes incubation at room temperature elevates the uric acid (UA) level of mouse blood in a test tube, and has previously been reported as "false in vitro elevation of the uric acid level." However the UA level of human blood does not elevate using the same incubation. We clarified the mechanism of the false in vitro UA elevation using mice with highly active hypoxanthine phosphoribosyl transferase (Hprt) of B6-ChrXC(MSM), a consomic mouse strain with the chromosome portion of Mus musculus morocinus in the Hprt gene site, or mice with a targeted deletion of the urate oxidase gene (Uox) (Uox-knockout (KO)). The plasma levels of UA, hypoxanthine, and xanthine, determined by HPLC, were compared with those of C57BL/6J laboratory mice used as controls. The uric acid level of Uox-KO mice was approximately 10 times higher than that of control, did not elevated after incubation in the test tube. With allopurinol, the hypoxanthine levels of B6-ChrXC(MSM) and Uox-KO were significantly lower than that of controls. Without allopurinol, the UA and xanthine levels of B6-ChrXC(MSM) were significantly lower than those of C57BL/6J controls. Even with allopurinol, the UA and xanthine levels were still significantly lower than that of controls. In conclusion, "false in vitro elevation of uric acid level" seems to be caused by low levels of erythrocyte HPRT activity and the low plasma uric acid level of laboratory mice.

Preventing the onset of microalbuminuria in diabetic nephropathy is a problem that needs urgent rectification. The use of a mouse model for diabetes is vital in this regard. For example, db/db mice exhibit defects in the leptin receptor Ob-Rb sub-type, while the ob/ob strain exhibits defects in the leptin ligand. These mouse strains demonstrate type 2 diabetes, either with or without microalbuminuria, respectively. The purpose of the present study was to use DNA microarray technology to screen for the gene responsible for the onset of diabetic microalbuminuria. Using Affymetrix Mouse Gene ST 1.0 arrays, microarray analysis was performed using total RNA from the kidneys of ob control, ob/ob, db/m, and db/db mice. Microarray and quantitative reverse transcription-polymerase chain reaction (RT-PCR) indicated that transcription of the macrophage migration inhibitory factor (MIF) gene was significantly enhanced in the kidneys of db/db mice. Western blotting showed that levels of MIF protein was enhanced in the kidneys of both diabetic db/db and ob/ob mice. On the other hand, elevation of urinary MIF excretion detected by enzyme-linked immunosorbent assay (ELISA) was only in db/db mice and preceded the onset of microalbuminuria. Immunofluorescence studies revealed that MIF was expressed in mouse kidney glomeruli. While MIF expression was enhanced in the diabetic kidneys of both mouse strains, the elevated secretion from db/db mouse kidneys may be responsible for initiating the onset of microalbuminuria in diabetic nephropathy.

The effects of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), were studied in normophagic and food-restriction-induced hyperphagic middle-aged Wistar rats. Normophagic intact Wistar rats were given fluvoxamine (100 mg/kg/d, per os (p.o.)) or vehicle for 10 d. Hyperphagic middle-aged Wistar rats were subjected to 10 d of food restriction; they were allowed to refeed for 10 d, with ad libitum food access and administered fluvoxamine (100 mg/kg/d, p.o.) or vehicle during the 10-d refeeding period. Fluvoxamine administration to normophagic middle-aged Wistar rats affected neither their weight nor food intake. However, administration to food-restricted rats showed inhibitory effects of weight gain and food intake during 10 d of refeeding. Fluvoxamine-treated rats showed significantly lower neuropeptide Y (NPY) immunostaining levels in the paraventricular nucleus (PVN) and dorsomedial hypothalamic nucleus (DMH) than untreated controls. Hypophagic and weight-inhibiting effects of fluvoxamine might be mediated via decreased NPY in PVN and DMH. These results suggest that the appetite-controlling effect of fluvoxamine might be responsive to the rats' appetite condition.

Familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease type 2 (MCKD2) are autosomal dominant disorders characterized by juvenile hyperuricemia of the underexcretion type, juvenile gout and chronic renal failure in the adult. FJHN/MCKD2 constitute diseases caused by mutations of the human uromodulin (UMOD) gene that encodes uromodulin, the most abundant glycoprotein in normal human urine. The mutations affect the transport of uromodulin, resulting in the accumulation of uromodulin in the kidneys of FJHN/MCKD2 patients. The purpose of this study was to confirm the accumulation of uromodulin in the kidneys of transgenic mice harboring the mutant human UMOD gene with mouse UMOD gene promoter, and to determine the relationship between its accumulation and the effect on uromodulin transport. The mutant human UMOD mRNA and its protein were expressed in the kidneys of transgenic mice. Moreover, the staining of human uromodulin was colocalized with that of mouse uromodulin. Although the human UMOD mRNA levels increased, the protein levels did not change and the accumulation of human uromodulin was not observed. However, the mouse uromodulin consists of two forms, 103 and 117 kDa, and the 103 kDa protein was gradually increased in the kidneys of transgenic mice. Human and mouse uromodulins in the kidneys of transgenic mice were mainly detected in the Triton X-100 insoluble microsomal fraction. Therefore, the progressive accumulation of uromodulin was observed in the plasma membrane of the kidneys of transgenic mice but the accumulated uromodulin protein was not that encoded by the transgene.