Research ArticlePreterm Birth

A Small-Molecule Smoothened Agonist Prevents Glucocorticoid-Induced Neonatal Cerebellar Injury

Science Translational Medicine  19 Oct 2011:
Vol. 3, Issue 105, pp. 105ra104
DOI: 10.1126/scitranslmed.3002731

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Tilting the Risk-Benefit Ratio for Preterm Infants

Preterm babies often develop chronic lung disease, which can be treated by postnatal administration of glucocorticoids (GCs). However, GC treatment can induce permanent neurological deficits and inhibit the growth of the cerebellum, a brain center critical for coordination of movement and higher-order neurological functions. To address this problem, Heine et al. have built on previous work showing that the Smoothened–Sonic hedgehog signaling pathway drives cerebellar cell proliferation during development and that it is this pathway that is disrupted by GCs. It was known that putting this pathway into genetic overdrive can prevent GC-induced injury, and the authors therefore devised a small-molecule mimic of this effect: SAG, an agonist of Smoothened. They showed that SAG crossed the blood-brain barrier to activate Sonic hedgehog targets in the mouse cerebellum and that it prevented the growth-inhibitory effects of GCs. They also showed that this treatment did not induce the cerebellar tumor medulloblastoma or other cancers, a reasonable fear because the Smo pathway is critical for proliferation of some tumors. Most importantly, SAG did not antagonize beneficial effects of GCs for the lung. These findings suggest that adjuvant therapy with SAG is safe and might be an effective way to prevent neurotoxic side effects of GCs when they are given to preterm infants for life-threatening conditions. Further toxicity studies will need to determine the optimal dose schedule and safety parameters before clinical trials in humans, but SAG may tilt the risk-benefit ratio of neonatal GC treatment toward more benefit for preterm infants.


  • * These authors contributed equally to this work.

  • Present address: Center for Children with White Matter Disorders, Center for Neurogenomics and Cognitive Research, Department of Pediatrics, VU University Medical Center, 1081 HV Amsterdam, Netherlands.