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A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury

Vivi M Heine1, Amelie Griveau, Cheryl Chapin

  • 1Division of Neonatology, Department of Pediatrics, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA.

Science Translational Medicine
|October 21, 2011
PubMed

Insights

Glucocorticoids can harm the developing brain in preterm infants. A new study shows activating the Sonic hedgehog-Smoothened (Shh-Smo) pathway may protect against this neurotoxicity, offering potential neuroprotection.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Pharmacology

Background:

  • Glucocorticoids treat preterm infant conditions but risk neurodevelopmental issues like cerebral palsy.
  • Concerns exist regarding glucocorticoid-induced cerebellar hypoplasia and cognitive impairment.
  • Sonic hedgehog-Smoothened (Shh-Smo) signaling is crucial for cerebellar granule neuron precursor development.

Purpose of the Study:

  • To investigate if activating the Shh-Smo pathway can prevent glucocorticoid-induced neurotoxicity in the developing cerebellum.
  • To assess the safety and efficacy of a Shh-Smo pathway agonist (SAG) in neonatal mice.

Main Methods:

  • Systemic administration of a small-molecule agonist of the Shh-Smo pathway (SAG) in neonatal mice.
  • Evaluation of neurotoxic effects of glucocorticoids.
  • Assessment of Shh-Smo pathway activation and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) pathway induction.
  • Monitoring for tumor formation after transient SAG treatment.

Main Results:

  • Systemic SAG administration prevented glucocorticoid-induced neurotoxic effects on the cerebellum.
  • SAG treatment did not interfere with the beneficial effects of glucocorticoids on lung maturation.
  • Transient SAG treatment was well tolerated and did not promote tumor formation in neonatal animals.

Conclusions:

  • A small-molecule agonist of the Shh-Smo pathway (SAG) shows potential as a neuroprotective agent.
  • This approach may mitigate glucocorticoid-induced neonatal cerebellar injury in at-risk infants.
  • Targeting the Shh-Smo pathway offers a promising strategy for neonatal neuroprotection.

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