A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury.
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.
Division of Neonatology, Department of Pediatrics, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA.
Vivi M
VM
Heine
Amelie
A
Griveau
Cheryl
C
Chapin
Philip L
PL
Ballard
James K
JK
Chen
David H
DH
Rowitch
D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced / Q000188:drug therapy*; D002478:Cells, Cultured; D002531:Cerebellum / Q000293:injuries*; D003514:Cyclohexylamines / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000009:adverse effects*; D053823:Hedgehog Proteins / Q000819:agonists*; D051379:Mice; D008810:Mice, Inbred C57BL; D011239:Prednisolone / Q000009:adverse effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000072086:Smoothened Receptor; D013876:Thiophenes / Q000627:therapeutic use*
D003514:Cyclohexylamines; D005938:Glucocorticoids; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C468918:SAG compound; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D013876:Thiophenes; D011239:Prednisolone