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

A Sonic hedgehog–Smoothened signaling agonist can protect against brain injury in mice caused by glucocorticoids, which are given to treat chronic lung disease in preterm infants. 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. 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.