UMR 788 INSERM-University Paris-Sud 11 Steroids, neuroprotection and neuroregeneration, Bâtiment Grégory Pincus, 80 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cedex, France.
Eur J Neurosci. 2009 Dec;30(11):2100-11. doi: 10.1111/j.1460-9568.2009.07013.x. Epub 2009 Nov 20.
It is well known that progesterone is synthesised and metabolised within the nervous system, and that one of its metabolites, allopregnanolone, potentiates the activity of GABA receptor anionic channels and modulates GABAergic neurotransmission. Progesterone is now under clinical trial for its neuroprotective properties, but its possible effects on neurotransmission have not yet been fully explored. The present study investigated acute effects of progesterone on the other major type of synaptic inhibition, glycinergic neurotransmission. Spontaneous glycinergic miniature currents were recorded in hypoglossal motoneurons, using the whole-cell patch-clamp technique in rat brainstem slices. A 20-min superfusion with progesterone (1 mum) triggered an increase in the frequency of glycinergic miniatures, whereas no effect of progesterone was observed after block with finasteride (5 mum) of 5alpha -reductase, the first enzymatic step leading from progesterone to allopregnanolone. The effect of progesterone could be mimicked by superfusion with allopregnanolone (0.3 mum), whereas no effect was induced by epiallopregnanolone. Thus, progesterone can increase the synaptic miniature release of glycine and this effect appears to be indirect, resulting from its metabolism into 5alpha-reduced derivatives, in particular into allopregnanolone. A low concentration of an exogenous GABA(A) agonist can also increase the frequency of inhibitory miniature currents in hypoglossal motoneurons. Thus, the effects of progesterone and allopregnanolone on glycine release can be at least partly explained by the potentiation of the activity of depolarizing presynaptic GABA receptor channels. The increase in the tonic synaptic release of a major inhibitory neurotransmitter should reduce the excitability of the neurons and contribute to their protection against excitotoxicity.
众所周知，孕激素在神经系统内合成和代谢，其代谢产物之一——别孕烯醇酮能增强 GABA 受体阴离子通道的活性，调节 GABA 能神经传递。目前孕激素正处于神经保护特性的临床试验阶段，但它对神经传递的可能影响尚未得到充分研究。本研究探讨了孕激素对另一种主要突触抑制——甘氨酸能神经传递的急性作用。在大鼠脑干切片中使用全细胞膜片钳技术记录舌下运动神经元的自发性甘氨酸型微小电流。用孕激素（1µM）持续灌流 20 分钟会触发甘氨酸型微小电流频率增加，而用 finasteride（5µM）阻断 5α-还原酶（孕激素转化为别孕烯醇酮的第一步酶）后则没有孕激素的作用。用别孕烯醇酮（0.3µM）灌流可模拟孕激素的作用，而用表孕烯醇酮则无作用。因此，孕激素可以增加甘氨酸的突触微小释放，这种作用似乎是间接的，是由其代谢为 5α-还原衍生物，特别是别孕烯醇酮引起的。外源性 GABA(A)激动剂的低浓度也可以增加舌下运动神经元抑制性微小电流的频率。因此，孕激素和别孕烯醇酮对甘氨酸释放的作用至少部分可以通过增强去极化突触前 GABA 受体通道的活性来解释。主要抑制性神经递质的紧张性突触释放增加，应降低神经元的兴奋性，并有助于保护神经元免受兴奋性毒性。
