Butterweck V, Winterhoff H, Herkenham M
Institute of Pharmacology and Toxicology, Domagkstrasse 12, 48149 Munster, Germany.
Mol Psychiatry. 2001 Sep;6(5):547-64. doi: 10.1038/sj.mp.4000937.
Clinical studies demonstrate that the antidepressant efficacy of St John's wort (Hypericum) is comparable to that of tricyclic antidepressants such as imipramine. Onset of efficacy of these drugs occurs after several weeks of treatment. Therefore, we used in situhybridization histochemistry to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) administration of imipramine, Hypericum extract, and hypericin (an active constituent of St John's wort) on the expression of genes that may be involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Imipramine (15 mg kg(-1)), Hypericum (500 mg kg(-1)), and hypericin (0.2 mg kg(-1)) given daily by gavage for 8 weeks but not for 2 weeks significantly decreased levels of corticotropin-releasing hormone (CRH) mRNA by 16-22% in the hypothalamic paraventricular nucleus (PVN) and serotonin 5-HT(1A) receptor mRNA by 11-17% in the hippocampus. Only imipramine decreased tyrosine hydroxylase (TH) mRNA levels in the locus coeruleus (by 23%), and only at 8 weeks. The similar delayed effects of the three compounds on gene transcription suggests a shared action on the centers that control HPA axis activity. A second study was performed to assess the effects of long-term imipramine and Hypericum administration on stress-induced changes in gene transcription in stress-responsive circuits. Repeated immobilization stress (2 h daily for 7 days) increased mRNA levels of CRH in the PVN, proopiomelanocortin (POMC) in the anterior pituitary, glutamic acid decarboxylase (GAD 65/67) in the bed nucleus of the stria terminalis (BST), cyclic AMP response element binding protein (CREB) in the hippocampus, and TH in the locus coeruleus. It decreased mRNA levels of 5-HT(1A) and brain-derived neurotrophic factor (BDNF) in the hippocampus. Long-term pre-treatment with either imipramine or Hypericum reduced to control levels the stress-induced increases in gene transcription of GAD in the BST, CREB in the hippocampus, and POMC in the pituitary. The stress-induced increases in mRNA levels of CRH in the PVN and TH in the locus coeruleus were reduced by imipramine but not by Hypericum. The stress-induced decreases in BDNF and 5-HT(1A)mRNA levels were not prevented by either drug. Taken together, these data show: (1) that Hypericum and hypericin have delayed effects on HPA axis control centers similar to those of imipramine; and (2) that select stress-induced changes in gene transcription in particular brain areas can be prevented by long-term treatment with either the prototypic tricyclic antidepressant imipramine or the herbiceutical St John's wort. However, imipramine appears to be more effective in blocking stress effects on the HPA axis than the plant extract.
临床研究表明，圣约翰草（金丝桃属植物）的抗抑郁功效与三环类抗抑郁药如丙咪嗪相当。这些药物的疗效在治疗数周后才会显现。因此，我们采用原位杂交组织化学技术，在大鼠中研究了短期（2周）和长期（8周）给予丙咪嗪、圣约翰草提取物和金丝桃素（圣约翰草的一种活性成分）对可能参与下丘脑 - 垂体 - 肾上腺（HPA）轴调节的基因表达的影响。通过灌胃每日给予丙咪嗪（15 mg·kg⁻¹）、圣约翰草（500 mg·kg⁻¹）和金丝桃素（0.2 mg·kg⁻¹）8周而非2周后，下丘脑室旁核（PVN）中促肾上腺皮质激素释放激素（CRH）mRNA水平显著降低16 - 22%，海马中5 - 羟色胺5 - HT(1A)受体mRNA水平显著降低11 - 17%。只有丙咪嗪降低了蓝斑中酪氨酸羟化酶（TH）mRNA水平（降低23%），且仅在8周时出现。这三种化合物对基因转录的类似延迟效应表明它们对控制HPA轴活性的中枢具有共同作用。进行了第二项研究以评估长期给予丙咪嗪和圣约翰草对压力诱导的应激反应回路中基因转录变化的影响。重复固定应激（每天2小时，持续7天）增加了PVN中CRH的mRNA水平、垂体前叶中阿黑皮素原（POMC）的mRNA水平、终纹床核（BST）中谷氨酸脱羧酶（GAD 65/67）的mRNA水平、海马中环磷酸腺苷反应元件结合蛋白（CREB）的mRNA水平以及蓝斑中TH的mRNA水平。它降低了海马中5 - HT(1A)和脑源性神经营养因子（BDNF）的mRNA水平。长期用丙咪嗪或圣约翰草预处理可将应激诱导的BST中GAD、海马中CREB和垂体中POMC的基因转录增加恢复到对照水平。丙咪嗪可降低PVN中CRH mRNA水平和蓝斑中TH mRNA水平的应激诱导增加，但圣约翰草无此作用。两种药物均未阻止应激诱导的BDNF和5 - HT(1A)mRNA水平降低。综上所述，这些数据表明：（1）圣约翰草和金丝桃素对HPA轴控制中枢具有与丙咪嗪类似的延迟效应；（2）长期用原型三环类抗抑郁药丙咪嗪或草药圣约翰草治疗可预防特定脑区中某些应激诱导的基因转录变化。然而，丙咪嗪在阻断应激对HPA轴的影响方面似乎比植物提取物更有效。
