Gulino Alberto, De Smaele Enrico, Ferretti Elisabetta
Department of Experimental Medicine, Sapienza University, Rome, Italy.
J Clin Invest. 2009 Feb;119(2):243-6. doi: 10.1172/jci38387.
Glucocorticoids (GCs) play a critical role in neural development; however, their prenatal or neonatal therapeutic use can have detrimental effects on the developing brain. In this issue of the JCI, Heine and Rowitch report that the molecular mechanisms underlying these detrimental effects involve the sonic hedgehog (Shh) signaling pathway, a crucial regulator of brain development and neural stem/progenitor cells (see the related study beginning on page 267). They show that GCs suppress Shh-induced proliferation of cerebellar progenitor cells in postnatal mice and that, conversely, Shh signaling is protective against GC-induced neonatal cerebellar injury by inducing the enzyme 11betaHSD2, which inactivates the GCs corticosterone and prednisolone, but not dexamethasone. The data provide a rationale for the therapeutic use of 11betaHSD2-sensitive GCs, but not dexamethasone, or for the exploitation of the neuroprotective effect of Shh agonists to prevent GC-induced pre- or neonatal brain injury.
糖皮质激素（GCs）在神经发育中起关键作用；然而，它们在产前或新生儿期的治疗应用可能会对发育中的大脑产生有害影响。在本期《临床研究杂志》中，海涅和罗维奇报告称，这些有害影响背后的分子机制涉及音猬因子（Shh）信号通路，这是大脑发育和神经干/祖细胞的关键调节因子（见第267页开始的相关研究）。他们表明，糖皮质激素会抑制出生后小鼠小脑祖细胞中Shh诱导的增殖，相反，Shh信号通过诱导11βHSD2酶对糖皮质激素诱导的新生儿小脑损伤具有保护作用，该酶可使糖皮质激素皮质酮和泼尼松龙失活，但对地塞米松无效。这些数据为使用对11βHSD2敏感的糖皮质激素（而非地塞米松）进行治疗，或利用Shh激动剂的神经保护作用预防糖皮质激素诱导的产前或新生儿脑损伤提供了理论依据。
