An increase in extracellular K+ concentration ([K+]c) of the rat hippocampus following fluid-percussion concussive brain injury was demonstrated with microdialysis. The role of neuronal discharge was examined with in situ administration of 0.1 mM tetrodotoxin, a potent depressant of neuronal discharges, and of 0.5 to 20 mM cobalt, a blocker of Ca++ channels. While a small short-lasting [K+]c increase (1.40- to 2.15-fold) was observed after a mild insult, a more pronounced longer-lasting increase (4.28- to 5.90-fold) was induced without overt morphological damage as the severity of injury rose above a certain threshold (unconscious for 200 to 250 seconds). The small short-lasting increase was reduced with prior administration of tetrodotoxin but not with cobalt, indicating that neuronal discharges are the source of this increase. In contrast, the larger longer-lasting increase was resistant to tetrodotoxin and partially dependent on Ca++, suggesting that neurotransmitter release is involved. In order to test the hypothesis that the release of the excitatory amino acid neurotransmitter glutamate mediates this increase in [K+]c, the extracellular concentration of glutamate ([Glu]c) was measured along with [K+]c. The results indicate that a relatively specific increase in [Glu]c (as compared with other amino acids) was induced concomitantly with the increase in [K+]c. Furthermore, the in situ administration of 1 to 25 mM kynurenic acid, an excitatory amino acid antagonist, effectively attenuated the increase in [K+]c. A dose-response curve suggested that a maximum effect of kynurenic acid is obtained at a concentration that substantially blocks all receptor subtypes of excitatory amino acids. These data suggest that concussive brain injury causes a massive K+ flux which is likely to be related to an indiscriminate release of excitatory amino acids occurring immediately after brain injury.

No abstract

No abstract

No abstract

In association with the international validation project to establish a test protocol for the 'Enhanced OECD Test Guideline 407', we performed a preliminary 28-day, repeated-dose toxicity study of flutamide, a non-steroidal androgen antagonist, and assessed the sensitivity of a list of parameters for detecting endocrine-related effects of endocrine-disrupting chemicals (EDCs). Seven-week-old CD(SD)IGS rats were divided into four groups, each consisting of 10 males and 10 females, and administered flutamide once daily by oral gavage at doses of 0 (control), 0.25, 1 and 4 mg/kg body weight/day. Male rats were killed 1 day after the 28th administration. Female rats were killed on the day they entered the diestrus stage in the estrous cycle following the last treatment. Male rats receiving flutamide at dose levels of 1 and 4 mg/kg showed lobular atrophy of the mammary gland and a decrease in epididymal weight. In addition, 4 mg/kg flutamide-treated males exhibited raised serum testosterone and estradiol levels and decreased weight of the accessory sex glands. In females, a slight prolongation of the estrous cycle was also observed in the 4 mg/kg flutamide-treated group. No dose-related changes could be detected by haematology, serum biochemistry and sperm analysis. Thus, among the parameters tested in the present experimental system, the weight of endocrine-linked organs and their histopathological assessment, serum hormone levels, and estrous cycle stage allowed the detection of endocrine-related effects of flutamide.

No abstract

Bezafibrate improved hepatic steatosis and potently prevented inflammation, oxidative stress, HSC activation, and fibrogenesis in the liver. Moreover, this study was the first to demonstrate that bezafibrate directly inhibits hepatic fibrogenic response induced by TGF-beta1 in vitro. Hence bezafibrate may be a new therapeutic strategy against NASH and hepatic fibrosis.

To clarify the mechanism of tumorigenesis by kojic acid (KA), dose and time dependence of iodine uptake in the thyroid gland and serum thyroid stimulating hormone (TSH) and thyroid hormone levels were investigated in F344 rats fed a diet containing 2% KA. After 4 weeks, thyroid hyperplasia was apparent in males, associated with a decrease in (125)I uptake into the thyroid gland to only 3% of that in controls. The serum triiodothyronine (T(3)) and thyroxine (T(4)) levels dropped to 0.36 ng/ml, 1.7 micrograms/dl from the initial values of 0.61 ng/ml, 4.0 micrograms/dl and TSH increased seven times to 15 ng/ml. In females, the effects on thyroid weight and (125)I uptake were less prominent, although the changes in serum T(3), T(4) and TSH levels were similar to those in males. Time-dependent changes in serum T(3), T(4) and TSH levels correlated with the inhibition of iodine uptake in the thyroid. Inhibition of organic iodine formation was only observed after 3 weeks treatment. On return to the control diet, normal serum T(3), T(4) and TSH levels became evident within 48 h in both sexes. These data suggest that KA interrupts thyroid function, primarily by inhibiting iodine intake, consequently causing a decrease in serum T(3) and T(4). Increased TSH from the pituitary gland in turn stimulates thyroid hyperplasia, which is reversible on withdrawal of KA.