Do-Rego J L, Mensah-Nyagan A G, Beaujean D, Leprince J, Tonon M C, Luu-The V, Pelletier G, Vaudry H
European Institute for Peptide Research, Laboratory of Cellular and Molecular Neuroendocrinology, INSERM, UA CNRS, University of Rouen, Mont-Saint-Aignan, France.
J Neurochem. 2001 Jan;76(1):128-38. doi: 10.1046/j.1471-4159.2001.00053.x.
Neurosteroids may play a major role in the regulation of various neurophysiological and behavioural processes. However, while the biochemical pathways involved in the synthesis of neuroactive steroids in the central nervous system are now elucidated, the mechanisms controlling the activity of neurosteroid-producing cells remain almost completely unknown. In the present study, we have investigated the effect of the octadecaneuropeptide (ODN), an endogenous ligand of benzodiazepine receptors, in the control of steroid biosynthesis in the frog hypothalamus. Glial cells containing ODN-like immunoreactivity were found to send their thick processes in the close vicinity of neurones expressing the steroidogenic enzyme 3 beta-hydroxysteroid dehydrogenase. Exposure of frog hypothalamic explants to graded concentrations of ODN (10(-10)-10(-5) M) produced a dose-dependent increase in the conversion of tritiated pregnenolone into various radioactive steroids, including 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone and dihydrotestosterone. The ODN-induced stimulation of neurosteroid biosynthesis was mimicked by the central-type benzodiazepine receptor (CBR) inverse agonists methyl beta-carboline-3-carboxylate (beta-CCM) and methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). The stimulatory effects of ODN, beta-CCM and DMCM on steroid formation was markedly reduced by the CBR antagonist flumazenil. The ODN-evoked stimulation of neurosteroid production was also significantly attenuated by GABA. Collectively, these data indicate that the endozepine ODN, released by glial cell processes in the vicinity of 3 beta-hydroxysteroid dehydrogenase-containing neurones, stimulates the biosynthesis of neurosteroids through activation of central-type benzodiazepines receptors.
神经甾体可能在各种神经生理和行为过程的调节中发挥主要作用。然而，尽管中枢神经系统中参与神经活性甾体合成的生化途径现已阐明，但控制神经甾体产生细胞活性的机制几乎仍然完全未知。在本研究中，我们研究了苯二氮䓬受体的内源性配体十八烷神经肽（ODN）对青蛙下丘脑甾体生物合成的控制作用。发现含有ODN样免疫反应性的胶质细胞将其粗大突起伸向表达甾体生成酶3β-羟基甾体脱氢酶的神经元附近。将青蛙下丘脑外植体暴露于不同浓度的ODN（10^(-10)-10^(-5) M）下，会使氚化孕烯醇酮转化为各种放射性甾体，包括17-羟孕烯醇酮、孕酮、17-羟孕酮、脱氢表雄酮和双氢睾酮的转化率呈剂量依赖性增加。中枢型苯二氮䓬受体（CBR）反向激动剂β-咔啉-3-羧酸甲酯（β-CCM）和6,7-二甲氧基-4-乙基-β-咔啉-3-羧酸甲酯（DMCM）模拟了ODN诱导的神经甾体生物合成刺激作用。CBR拮抗剂氟马西尼显著降低了ODN、β-CCM和DMCM对甾体形成的刺激作用。GABA也显著减弱了ODN引起的神经甾体产生刺激作用。总体而言，这些数据表明，由含3β-羟基甾体脱氢酶的神经元附近的胶质细胞突起释放的内源性安定肽ODN，通过激活中枢型苯二氮䓬受体来刺激神经甾体的生物合成。
