Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism
Vivi M. Heine, David H. Rowitch
Vivi M. Heine, David H. Rowitch
Published January 26, 2009
Citation Information: J Clin Invest. 2009;119(2):267-277. https://doi.org/10.1172/JCI36376.
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Research Article

Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism

Abstract

Glucocorticoids (GCs) are administered to human fetuses at risk of premature delivery and to infants with life-threatening respiratory and cardiac conditions. However, there are ongoing concerns about adverse effects of GC treatment on the developing human brain, although the precise molecular mechanisms underlying GC-induced brain injury are unclear. Here, we identified what we believe to be novel cross-antagonistic interactions of Sonic hedgehog (Shh) and GC signaling in proliferating mouse cerebellar granule neuron precursors (CGNPs). Chronic GC treatment (from P0 through P7) in mouse pups inhibited Shh-induced proliferation and upregulation of expression of N-myc, Gli1, and D-type cyclin protein in CGNPs. Conversely, acute GC treatment (on P7 only) caused transient apoptosis. Shh signaling antagonized these effects of GCs, in part by induction of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2). Importantly, 11βHSD2 antagonized the effects of the GCs corticosterone, hydrocortisone, and prednisolone, but not the synthetic GC dexamethasone. Our findings indicate that Shh signaling is protective in the setting of GC-induced mouse neonatal brain injury. Furthermore, they led us to propose that 11βHSD2-sensitive GCs (e.g., hydrocortisone) should be used in preference to dexamethasone in neonatal human infants because of the potential for reduced neurotoxicity.

Authors

Vivi M. Heine, David H. Rowitch

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Figure 1

Timing of chronic and acute treatment protocols.

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Timing of chronic and acute treatment protocols. Chronic GC administrati...
Chronic GC administration from P0 to P7 is shown in black; acute GC treatment at P7 is shown in blue; administration of thymidine analogs CldU and IdU is shown in purple. Dex was given 2 h after CldU. Pups were analyzed to determine weight gain at P7 and P21 (see Table 1).