Division of Neonatology, Department of Pediatrics, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA.
Sci Transl Med. 2011 Oct 19;3(105):105ra104. doi: 10.1126/scitranslmed.3002731.
Glucocorticoids are used for treating preterm neonatal infants suffering from life-threatening lung, airway, and cardiovascular conditions. However, several studies have raised concerns about detrimental effects of postnatal glucocorticoid administration on the developing brain leading to cognitive impairment, cerebral palsy, and hypoplasia of the cerebellum, a brain region critical for coordination of movement and higher-order neurological functions. Previously, we showed that glucocorticoids inhibit Sonic hedgehog-Smoothened (Shh-Smo) signaling, the major mitogenic pathway for cerebellar granule neuron precursors. Conversely, activation of Shh-Smo in transgenic mice protects against glucocorticoid-induced neurotoxic effects through induction of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) pathway. Here, we show that systemic administration of a small-molecule agonist of the Shh-Smo pathway (SAG) prevented the neurotoxic effects of glucocorticoids. SAG did not interfere with the beneficial effects of glucocorticoids on lung maturation, and despite the known associations of the Shh pathway with neoplasia, we found that transient (1-week-long) SAG treatment of neonatal animals was well tolerated and did not promote tumor formation. These findings suggest that a small-molecule agonist of Smo has potential as a neuroprotective agent in neonates at risk for glucocorticoid-induced neonatal cerebellar injury.
糖皮质激素用于治疗患有危及生命的肺部、气道和心血管疾病的早产儿。然而，几项研究对产后糖皮质激素给药对发育中的大脑产生的有害影响表示担忧，导致认知障碍、脑瘫和小脑发育不良，小脑是协调运动和更高阶神经功能的关键区域。此前，我们表明糖皮质激素抑制 Sonic hedgehog-Smoothened（Shh-Smo）信号通路，这是小脑颗粒神经元前体细胞的主要有丝分裂途径。相反，转基因小鼠中 Shh-Smo 的激活通过诱导 11β-羟类固醇脱氢酶 2（11β-HSD2）途径来保护免受糖皮质激素诱导的神经毒性作用。在这里，我们表明 Shh-Smo 通路的小分子激动剂（SAG）的全身给药可防止糖皮质激素的神经毒性作用。SAG 不干扰糖皮质激素对肺成熟的有益作用，尽管 Shh 通路与肿瘤形成有关，但我们发现新生动物的短暂（1 周）SAG 治疗耐受性良好，并且不会促进肿瘤形成。这些发现表明，Smo 的小分子激动剂有可能成为有发生糖皮质激素诱导的新生儿小脑损伤风险的新生儿的神经保护剂。
