Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism
Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism
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DOI：
10.1172/jci36376
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发表时间：
2009-02-01
影响因子：
15.9
通讯作者：
Rowitch, David H.
中科院分区：
文献类型：
--
作者：
Heine, Vivi M.;Rowitch, David H.
糖皮质激素（GC）用于有早产风险的胎儿和患有危及生命的呼吸和心脏疾病的婴儿。然而，尽管GC诱导的脑损伤的确切分子机制尚不清楚，但GC治疗对发育中的人脑的不良影响仍存在持续的担忧。在这里，我们确定了我们认为是新的交叉拮抗相互作用的Sonic刺猬（Shh）和GC信号在增殖小鼠小脑颗粒神经元前体（CGNP）。慢性GC治疗（从PO到P7）在小鼠幼崽抑制Shh诱导的增殖和上调表达的N-myc，Glil，和D型细胞周期蛋白在CGNP。相反，急性GC处理（仅在P7上）引起瞬时细胞凋亡。Shh信号传导部分通过诱导11 β-羟类固醇脱氢酶2型（11 β HSD 2）来拮抗GC的这些作用。重要的是，11 β HSD 2拮抗GC皮质酮、氢化可的松和泼尼松龙的作用，但不拮抗合成GC地塞米松的作用。我们的研究结果表明，Shh信号在GC诱导的小鼠新生儿脑损伤中具有保护作用。此外，他们使我们提出，11 β HSD 2敏感的GC（例如，氢化可的松）应优先于地塞米松用于新生人类婴儿，因为其具有降低神经毒性的潜力。
Glucocorticoids (GCs) are administered to human fetuses at risk of premature delivery and to infants with life-threatening respiratory and cardiac conditions. However, there are ongoing concerns about adverse effects of GC treatment on the developing human brain, although the precise molecular mechanisms underlying GC-induced brain injury are unclear. Here, we identified what we believe to be novel cross-antagonistic interactions of Sonic hedgehog (Shh) and GC signaling in proliferating mouse cerebellar granule neuron precursors (CGNPs). Chronic GC treatment (from PO through P7) in mouse pups inhibited Shh-induced proliferation and upregulation of expression of N-myc, Glil, and D-type cyclin protein in CGNPs. Conversely, acute GC treatment (on P7 only) caused transient apoptosis. Shh signaling antagonized these effects of GCs, in part by induction of 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2). Importantly, 11 beta HSD2 antagonized the effects of the GCs corticosterone, hydrocortisone, and prednisolone, but not the synthetic GC dexamethasone. Our findings indicate that Shh signaling is protective in the setting of GC-induced mouse neonatal brain injury. Furthermore, they led us to propose that 11 beta HSD2-sensitive GCs (e.g., hydrocortisone) should be used in preference to dexamethasone in neonatal human infants because of the potential for reduced neurotoxicity.