Abstract
BackgroundBrain 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 FindingsThe 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 3H-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/SignificanceThese 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.
Highlights
The hippocampus is a target of corticosterone (CORT) modulatory actions, with high levels of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression [1,2]
Recent evidence shows that the hippocampus expresses steroidogenic enzymes required for corticosteroid synthesis, including cytochromes P450scc, P450(11b1), P450(11b2), and 3b-hydroxysteroid dehydrogenase (3b-HSD) [4,5,6,7,8,9,10]
Cytochrome P450(c21) (DOC synthase), a key enzyme catalyzing the conversion of PROG to DOC, has not been detected in the hippocampus, mRNA expression has been demonstrated in other brain regions including the hypothalamus, cortex, cerebellum and striatum [15,16]
Summary
The hippocampus is a target of corticosterone (CORT) modulatory actions, with high levels of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression [1,2]. Recent evidence shows that the hippocampus expresses steroidogenic enzymes required for corticosteroid synthesis, including cytochromes P450scc, P450(11b1), P450(11b2), and 3b-hydroxysteroid dehydrogenase (3b-HSD) [4,5,6,7,8,9,10]. Some of these enzymes are necessary for sex-steroid synthesis [11,12,13,14]. Cytochrome P450(c21) (DOC synthase), a key enzyme catalyzing the conversion of PROG to DOC, has not been detected in the hippocampus, mRNA expression has been demonstrated in other brain regions including the hypothalamus, cortex, cerebellum and striatum [15,16]. The endogenous synthesis of corticosteroids in the hippocampus, has been doubted because of the inability to detect deoxycorticosterone (DOC) synthase, cytochrome P450(c21)
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