Effect of the glucocorticoid receptor antagonist Org 34850 on basal and stress-induced corticosterone secretion
Effect of the glucocorticoid receptor antagonist Org 34850 on basal and stress-induced corticosterone secretion
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DOI：
10.1111/j.1365-2826.2007.01605.x
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发表时间：
2007-11-01
影响因子：
3.2
通讯作者：
Lightman, S. L.
中科院分区：
文献类型：
--
作者：
Spiga, F.;Harrison, L. R.;Lightman, S. L.
下丘脑-垂体-肾上腺（HPA）轴的活动特征是糖皮质激素分泌的超昼夜脉动模式和内源性昼夜节律。糖皮质激素反馈在调节HPA轴活性中起主要作用，并且该机制通过两种不同的受体发生：盐皮质激素（MR）和糖皮质激素受体（GR）。在本研究中，急性和亚慢性治疗与GR拮抗剂GAR 34850对基础和应激诱导的HPA轴活动的影响进行了评估。为了研究在24小时周期内，RP 34850对基础昼夜皮质酮节律的影响，自动血液取样系统每10分钟收集样品。不影响基础或应激诱导的皮质酮分泌，但能够拮抗糖皮质激素激动剂甲基强的松龙对应激诱导的皮质酮分泌的抑制作用。然而，用10 mg/kg，s.c.，一天两次），与用载体（5%马高芬在0.9%盐水中，1 ml/kg，s.c.）处理的大鼠相比，增加皮质酮分泌超过24小时的周期，并导致激素释放的脉动模式的变化，但对促肾上腺皮质激素分泌或应激诱导的皮质酮分泌没有显着影响。亚慢性给药组大鼠海马、下丘脑室旁核或垂体前叶GR mRNA表达无明显变化，海马MR mRNA表达无明显变化。我们的数据表明，需要延长GR的阻断以增加基础HPA轴活性。在ORG 34850中观察到的变化与GR介导的HPA轴负反馈的抑制一致。鉴于有证据表明HPA轴功能障碍参与抑郁症的病理生理学，因此，P34850可能是治疗情绪障碍的潜在药物。
The activity of the hypothalamic-pituitary-adrenal (HPA) axis is characterised both by an ultradian pulsatile pattern of glucocorticoid secretion and an endogenous diurnal rhythm. Glucocorticoid feedback plays a major role in regulating HPA axis activity and this mechanism occurs via two different receptors: mineralocorticoid (MR) and glucocorticoid receptors (GR). In the present study, the effects of both acute and subchronic treatment with the GR antagonist Org 34850 on basal and stress-induced HPA axis activity in male rats were evaluated. To investigate the effect of Org 34850 on basal diurnal corticosterone rhythm over the 24-h cycle, an automated blood sampling system collected samples every 10 min. Acute injection of Org 34850 (10 mg/kg, s.c.) did not affect basal or stress-induced corticosterone secretion, but was able to antagonise the inhibitory effect of the glucocorticoid agonist methylprednisolone on stress-induced corticosterone secretion. However, 5 days of treatment with Org 34850 (10 mg/kg, s.c., two times a day), compared to rats treated with vehicle (5% mulgofen in 0.9% saline, 1 ml/kg, s.c.), increased corticosterone secretion over the 24-h cycle and resulted in changes in the pulsatile pattern of hormone release, but had no significant effect on adrenocorticotrophic hormone secretion or on stress-induced corticosterone secretion. Subchronic treatment with Org 34850 did not alter GR mRNA expression in the hippocampus, paraventricular nucleus of the hypothalamus or anterior-pituitary, or MR mRNA expression in the hippocampus. Our data suggest that a prolonged blockade of GRs is required to increase basal HPA axis activity. The changes observed here with ORG 34850 are consistent with inhibition of GR-mediated negative feedback of the HPA axis. In light of the evidence showing an involvement of dysfunctional HPA axis in the pathophysiology of depression, Org 34850 could be a potential treatment for mood disorders.