2012年12月9日 訊 /生物谷BIOON/ --近日,，來(lái)自倫敦大學(xué)國(guó)王學(xué)院精神病學(xué)研究所的研究人員鑒別出了一種引發(fā)抑郁癥的新型分子路徑，這就為潛在的靶向藥物開(kāi)發(fā)帶來(lái)了幫助,，相關(guān)研究刊登于國(guó)際雜志Neuropsychopharmacology上,，該項(xiàng)研究首次揭示了Hedgehog通路是如何在抑郁癥發(fā)病過(guò)程中調(diào)節(jié)應(yīng)激激素，從而減少大腦細(xì)胞數(shù)量的,。
在英國(guó),，5個(gè)人中會(huì)有一個(gè)人受到抑郁癥的影響，抑郁癥可以引發(fā)患者悲傷和絕望,、嚴(yán)重者甚至自殘或者自殺,。目前治療抑郁癥的療法包括藥物療法或者交流的療法,，通常醫(yī)生們會(huì)進(jìn)行藥物療法和交談療法相結(jié)合來(lái)進(jìn)行病人的治療。
本文研究中,，研究者Christoph Anacker研究了人類(lèi)的干細(xì)胞,，其是人類(lèi)大腦新細(xì)胞的來(lái)源，研究者進(jìn)行研究,，試圖去發(fā)現(xiàn)應(yīng)激激素對(duì)腦細(xì)胞發(fā)育所帶來(lái)的效應(yīng),。應(yīng)激激素，比如皮質(zhì)醇,，通常在個(gè)體壓力狀態(tài)或者抑郁狀態(tài)下水平會(huì)升高,，研究小組在實(shí)驗(yàn)條件下研究發(fā)現(xiàn)，高濃度的皮質(zhì)醇可以損傷大腦干細(xì)胞的功能,，并且減少大腦新生細(xì)胞的數(shù)量,。他們發(fā)現(xiàn)了大腦中的一種特殊的信號(hào)分子路徑，名為Hedgehog通路,，其主要負(fù)責(zé)上述的整個(gè)過(guò)程,，隨后研究者使用動(dòng)物模型確定了，暴露在壓力條件下確實(shí)可以抑制大腦的Hedgehog途徑,。
研究者使用化合物purmorphamine,，其可以刺激Hedgehog途徑，研究者發(fā)現(xiàn)使用這種化合物就可以逆轉(zhuǎn)應(yīng)激激素對(duì)大腦的損傷效應(yīng),，而且可以恢復(fù)大腦新細(xì)胞的產(chǎn)生,。
應(yīng)激激素通過(guò)抑制Hedgehog信號(hào)途徑，就可以抑制大腦中未成熟干細(xì)胞發(fā)育成為成熟的大腦細(xì)胞,。這項(xiàng)研究為研究者們開(kāi)發(fā)新型的靶向抗抑郁癥藥物提供了幫助和希望,，相關(guān)研究由美國(guó)國(guó)立衛(wèi)生研究院等機(jī)構(gòu)提供資助。（生物谷Bioon.com）
doi:10.1038/npp.2012.253
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Glucocorticoid-Related Molecular Signaling Pathways Regulating Hippocampal Neurogenesis
Christoph Anacker1,2,3, Annamaria Cattaneo4, Alessia Luoni5, Ksenia Musaelyan1, Patricia A Zunszain1,2, Elena Milanesi4, Joanna Rybka6, Alessandra Berry7, Francesca Cirulli7, Sandrine Thuret3, Jack Price3, Marco A Riva5, Massimo Gennarelli4,8 and Carmine M Pariante1,2
Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We therefore investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (-24%) and doublecortin (Dcx)-positive neuroblasts (-21%), and increased differentiation into S100ß-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR agonist, aldosterone. In contrast, high concentrations of cortisol (100μM) decreased proliferation (-17%) and neuronal differentiation into MAP2-positive neurons (-22%) and into Dcx-positive neuroblasts (-27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGFß-SMAD2/3 signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGFß-SMAD2/3 and Hedgehog-signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus.
