Corticosterone Induces Rapid Spinogenesis via Synaptic Glucocorticoid Receptors and Kinase Networks in Hippocampus

BACKGROUND: Modulation of dendritic spines under acute stress is attracting much attention. Exposure to acute stress induces corticosterone (CORT) secretion from the adrenal cortex, resulting in rapid increase of CORT levels in plasma and the hippocampus. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrated the mechanisms of rapid effect (∼1 h) of CORT on the density and morphology of spines by imaging neurons in adult male rat hippocampal slices. The application of CORT at 100-1000 nM induced a rapid increase in the density of spines of CA1 pyramidal neurons. The density of small-head spines (0.2-0.4 µm) was increased even at low CORT levels (100-200 nM). The density of middle-head spines (0.4-0.5 µm) was increased at high CORT levels between 400-1000 nM. The density of large-head spines (0.5-1.0 µm) was increased only at 1000 nM CORT. Co-administration of RU486, an antagonist of glucocorticoid receptor (GR), abolished the effect of CORT. Blocking a single kinase, such as MAPK, PKA, PKC or PI3K, suppressed CORT-induced enhancement of spinogenesis. Blocking NMDA receptors suppressed the CORT effect. CONCLUSIONS/SIGNIFICANCE: These results imply that stress levels of CORT (100-1000 nM) drive the spinogenesis via synaptic GR and multiple kinase pathways

Endogenous Synthesis of Corticosteroids in the Hippocampus

BACKGROUND: Brain synthesis of steroids including sex-steroids is attracting much attention. The endogenous synthesis of corticosteroids in the hippocampus, however, has been doubted because of the inability to detect deoxycorticosterone (DOC) synthase, cytochrome P450(c21). METHODOLOGY/PRINCIPAL FINDINGS: The expression of P450(c21) was demonstrated using mRNA analysis and immmunogold electron microscopic analysis in the adult male rat hippocampus. DOC production from progesterone (PROG) was demonstrated by metabolism analysis of (3)H-steroids. All the enzymes required for corticosteroid synthesis including P450(c21), P450(2D4), P450(11β1) and 3β-hydroxysteroid dehydrogenase (3β-HSD) were localized in the hippocampal principal neurons as shown via in situ hybridization and immunoelectron microscopic analysis. Accurate corticosteroid concentrations in rat hippocampus were determined by liquid chromatography-tandem mass spectrometry. In adrenalectomized rats, net hippocampus-synthesized corticosterone (CORT) and DOC were determined to 6.9 and 5.8 nM, respectively. Enhanced spinogenesis was observed in the hippocampus following application of low nanomolar (10 nM) doses of CORT for 1 h. CONCLUSIONS/SIGNIFICANCE: These results imply the complete pathway of corticosteroid synthesis of 'pregnenolone →PROG→DOC→CORT' in the hippocampal neurons. Both P450(c21) and P450(2D4) can catalyze conversion of PROG to DOC. The low nanomolar level of CORT synthesized in hippocampal neurons may play a role in modulation of synaptic plasticity, in contrast to the stress effects by micromolar CORT from adrenal glands

Study protocol for a multi-center, randomized controlled trial to develop Japanese denture adhesive guidelines for patients with complete dentures : the Denture Adhesive Guideline trial : study protocol for a randomized controlled trial

Background: Denture adhesives, characterized as medical products in 1935 by the American Dental Association, have been considered useful adjuncts for improving denture retention and stability. However, many dentists in Japan are hesitant to acknowledge denture adhesives in daily practice because of the stereotype that dentures should be inherently stable, without the aid of adhesives. The aim of this study is to verify the efficacy of denture adhesives to establish guidelines for Japanese users. The null hypothesis is that the application of denture adhesives, including the cream and powder types, or a control (isotonic sodium chloride solution) would not produce different outcomes nor would they differentially improve the set outcomes between baseline and day 4 post-application. Methods: This ten-center, randomized controlled trial with parallel groups is ongoing. Three hundred edentulous patients with complete dentures will be allocated to three groups (cream-type adhesive, powder-type adhesive, and control groups). The participants will wear their dentures with the denture adhesive for 4 days, including during eight meals (three breakfasts, two lunches, and three dinners). The baseline measurements and final measurements for the denture adhesives will be performed on the first day and after breakfast on the fourth day. The primary outcome is a general satisfaction rating for the denture. The secondary outcomes are denture satisfaction ratings for various denture functions, occlusal bite force, resistance to dislodgement, masticatory performance, perceived chewing ability, and oral health-related quality of life. Between-subjects comparisons among the three groups and within-subjects comparisons of the pre- and post-intervention measurements will be performed. Furthermore, a multiple regression analysis will be performed. The main analyses will be based on the intention-to-treat principle. A sample size of 100 subjects per group, including an assumed dropout rate of 10 %, will be required to achieve 80 % power with a 5 % alpha level. Discussion: This randomized clinical trial will provide information about denture adhesives to complete denture wearers, prosthodontic educators, and dentists in Japan. We believe this new evidence on denture adhesive use from Japan will aid dentists in their daily practice even in other countries

Aging-induced changes in sex-steroidogenic enzymes and sex-steroid receptors in the cortex, hypothalamus and cerebellum.

We investigated age-induced changes in mRNA expression profiles of sex-steroidogenic enzymes and sex-steroid receptors in 3-, 12-, and 24-month-old male rat brain subregions [cerebral cortex (CC), hypothalamus (Hy) and cerebellum (CL)]. In many cases, the expression levels of mRNA decreased with age for androgen synthesis enzyme systems, including Cyp17a1, Hsd17b and Srd5a in the CC and CL, but not in the Hy. Estradiol synthase Cyp19a1 did not show age-induced decline in the Hy, and nearly no expression of Cyp19a1 was observed in the CC and CL over 3-24 m. Androgen receptor Ar increased in the Hy but decreased in the CC with age. Estrogen receptor Esr1 increased in the CC and Hy, and did not change in the CL with age. Esr2 did not change in the CC and Hy, but decreased in the CL with age. As a comparison, age-induced changes of brain-derived neurotrophic factor mRNA were also investigated