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Sonic Hedgehog Agonist Protects Against Complex Neonatal Cerebellar Injury
Vien Nguyen1,2, Khalida Sabeur1, Emin Maltepe3
1Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regenerative Medicine, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA, 94143, USA.
Insights
Neonatal hypoxia and glucocorticoids cause cerebellar hypoplasia. A Hedgehog pathway agonist (SAG) protected against this injury, suggesting a potential therapeutic strategy for premature infants.
Area of Science:
- Neuroscience
- Developmental Biology
- Neonatal Medicine
Background:
- The cerebellum grows rapidly in the third trimester, making premature infants vulnerable to cerebellar hypoplasia.
- Chronic lung disease and postnatal glucocorticoids are linked to preterm cerebellar hypoplasia.
Purpose of the Study:
- To model the effects of chronic hypoxemia and glucocorticoid administration on cerebellar development in neonatal mice.
- To investigate cell type-specific roles of the hypoxia-inducible factor (HIF) pathway in neonatal cerebellar injury.
Main Methods:
- Neonatal mice were exposed to chronic hypoxia and administered prednisolone.
- Conditional knockout of von Hippel Lindau (VHL) was used to hyperactivate HIF1α in specific cerebellar cell types.
- A Smoothened-Hedgehog agonist (SAG) was administered to assess neuroprotection.
Main Results:
- Chronic neonatal hypoxia caused permanent cerebellar hypoplasia, exacerbated by prednisolone, leading to volume loss and Purkinje cell death.
- SAG administration preserved cerebellar volume and protected Purkinje cells, even as a single dose.
- HIF activation alone did not cause deficits, but in the presence of prednisolone, it led to hypoplasia in granule neuron precursors and cell death in Purkinje cells.
Conclusions:
- Hypoxia-inducible factor (HIF) primes cerebellar cells for glucocorticoid-induced injury via distinct pathways.
- Dual exposure to hypoxia and postnatal glucocorticoids causes complex cerebellar injury.
- Smoothened-Hedgehog agonist (SAG) demonstrates neuroprotective effects in neonatal cerebellar injury models.
Abstract:
The cerebellum undergoes rapid growth during the third trimester and is vulnerable to injury and deficient growth in infants born prematurely. Factors associated with preterm cerebellar hypoplasia include chronic lung disease and postnatal glucocorticoid administration. We modeled chronic hypoxemia and glucocorticoid administration in neonatal mice to study whole cerebellar and cell type-specific effects of dual exposure. Chronic neonatal hypoxia resulted in permanent cerebellar hypoplasia. This was compounded by administration of prednisolone as shown by greater volume loss and Purkinje cell death. In the setting of hypoxia and prednisolone, administration of a small molecule Smoothened-Hedgehog agonist (SAG) preserved cerebellar volume and protected against Purkinje cell death. Such protective effects were observed even when SAG was given as a one-time dose after dual insult. To model complex injury and determine cell type-specific roles for the hypoxia inducible factor (HIF) pathway, we performed conditional knockout of von Hippel Lindau (VHL) to hyperactivate HIF1α in cerebellar granule neuron precursors (CGNP) or Purkinje cells. Surprisingly, HIF activation in either cell type resulted in no cerebellar deficit. However, in mice administered prednisolone, HIF overactivation in CGNPs resulted in significant cerebellar hypoplasia, whereas HIF overactivation in Purkinje cells caused cell death. Together, these findings indicate that HIF primes both cell types for injury via glucocorticoids, and that hypoxia/HIF + postnatal glucocorticoid administration act on distinct cellular pathways to cause cerebellar injury. They further suggest that SAG is neuroprotective in the setting of complex neonatal cerebellar injury.
