Document Detail

A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury.
MedLine Citation:
PMID:  22013124     Owner:  NLM     Status:  MEDLINE    
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.
Vivi M Heine; Amelie Griveau; Cheryl Chapin; Philip L Ballard; James K Chen; David H Rowitch
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Science translational medicine     Volume:  3     ISSN:  1946-6242     ISO Abbreviation:  Sci Transl Med     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-20     Completed Date:  2012-05-29     Revised Date:  2013-07-02    
Medline Journal Info:
Nlm Unique ID:  101505086     Medline TA:  Sci Transl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  105ra104     Citation Subset:  IM    
Division of Neonatology, Department of Pediatrics, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA.
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MeSH Terms
Brain Injuries / chemically induced,  drug therapy*
Cells, Cultured
Cerebellum / injuries*
Cyclohexylamines / therapeutic use*
Glucocorticoids / adverse effects*
Hedgehog Proteins / agonists*
Mice, Inbred C57BL
Prednisolone / adverse effects
Receptors, G-Protein-Coupled / agonists*
Thiophenes / therapeutic use*
Grant Support
P01 HL024075/HL/NHLBI NIH HHS; R01 CA136574/CA/NCI NIH HHS; R01 CA136574/CA/NCI NIH HHS; R01 HL086323/HL/NHLBI NIH HHS; R01 NS047527/NS/NINDS NIH HHS; R01 NS059893/NS/NINDS NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Cyclohexylamines; 0/Glucocorticoids; 0/Hedgehog Proteins; 0/Receptors, G-Protein-Coupled; 0/SAG compound; 0/Shh protein, mouse; 0/Smo protein, mouse; 0/Thiophenes; 50-24-8/Prednisolone
Comment In:
Sci Transl Med. 2011 Oct 19;3(105):105ps40   [PMID:  22013122 ]

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