| Thyroid hormones (TH) and glucocorticoids (GC) play crucial roles in brain development and maturation. Patients with cretinism, a syndrome caused by lack of sufficient TH during foefetal and neonatal periods, suffer mental retardation, antaxia, spasticity and deafness, indicating severe brain anatomical and functional defects. One key target of thyroid hormones and glucocorticoids is hippocampus, the part of the brain involved in learning, memory and endocrinology. Perinatal insufficiency of TH or GC causes decreased level of nerve growth factor (NGF) in septo-hippocampal pathway (SHP) and hippocampus, resulting in severe developmental disorder of basal forebrain cholinergic system.GC is synthesized and secreted by the adrenal cortex. Its functions in the neural system are mediated by two different glucocorticoid receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). GC binds to MR with higher affinity than GR. This GC -receptor interaction is also controlled at the pre-receptor level by two important factors: corticosteroid binding globulin (CBG) and 11βb-hydroxysteroid dehydrogenases (11β-HSDs). Two types of 11β-HSDs were identified in vertebrates: whereas 11β-HSD2, a NAD-dependent oxidase, functions exclusively to convert biologically active GC into its inert form, attenuating GC's action, 11b-HSD1 was shown to act as a predominant NADP-dependent reductase in tact cells, thus amplifying GC's action. More intriguingly, In hippocampus, 11β-HSD1 and GR were found to co-exist in the same neuron; and 11β-HSD1 can convert biologically inert 11-keto GC metabolites into biologically active GC. GC regeneration by 11β-HSD1 will concentrate GC locally to enable its interaction with the low-affinity GR.In rats, TH secretion from thyroid starts on 17.5-18th gestational day. During the first two postnatal weeks, a critical 'window time' for brain development, TH level continuously increases until it reaches the peak level on the 15th postnatal day. Then it begins to decrease to the adult level. The 11β-HSD1 expression in the fetal brain also gradually increases with gestational age at late gestation and continues to increase in the hippocampus after birth until the 15th postnatal day , which shows a pattern very similar to TH secretion. Furthermore,previous data show injection of thyroxine (T4) to normal newborn rats up-regulates GR expression in the hippocampus. These data suggest that the role of TH in neural development may be partially (if not all) accomplished through regulating GC's activity.Although it was shown that TH could up-regulate the activity of 11β-HSD1 in primary cultured hepatocytes, whether the expression of 11 β -HSD1 was also altered in hippocampus by TH remained unknown.This paper was designed to observe the effect of TH on 11β-HSD1 's activity and expression in the newborn rat's hippocampus.Main results:1 .Hypothyroid model in pregnancy was established by treating the pregnant Sprague-Dawley (SD) rats with propylthiouracil ( PTU, 50mg/d ) in the last week of pregnancy and was confirmed by measuring TH and thyrotropin (TSH) level in the new-bom blood. We found plasma triiodothyronine (T3) and T4 level was decreased 43.3% and 50.4%, while TSH level was increased 30.5% in the new-bom blood. The body weight, organ weights including brain, kedney, lung and heart of the newborn rats bom to the mother treated with PTU decreased 8.2%, 8.1%, 12.8%, 20.2% and 17.3% respectively.2.ln the hippocampus of newborn rats bom to the mother treated with PTU, 11β-HSD1 expression decreased by 41.7%, while NGF expression decreased by 71.9%.3.ln vivo study with primary cultured neonatal rat hippocampal neuron showed that T3 (10-9,10-8,10-7M) and dexamethasone (Dex, 10-7M) up-regulated 11P-HSD1 activity by 29.4%, 45.6%, 60.9% and 39.8%, respectively The effect of T3 appears to be in a dose-dependent manner.4.When exposed 36 hours to T3 (10-9, 10-8, 10-7M) and Dex (10-7M), 11β-HSD1 protein expression increased by 26.0%, 43.2%, 64.9% and 41.1% respective...
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