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 6

CGNPs in Math1cre,SmoM2 transgenic mice are protected against antiproliferative effects of GCs in an 11βHSD2-dependent manner in vitro and in vivo.

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CGNPs in Math1cre,SmoM2 transgenic mice are protected against antiprolif...
(A) Immunocytochemistry for pH3 and Zic1 in vehicle- and Dex-treated Math1cre,SmoM2 P7 mice. (B) Mean ± SD number of pH3+ cells per section in the whole EGL of Math1cre,SmoM2 mice. Animals were protected against Pred and Cort treatment, but only partly so against Dex. (C) To determine whether inhibition of 11βHSD2 by CBX could induce a decrease in CGNP proliferation by 11βHSD2-sensitive Pred in vitro, Math1cre,SmoM2 cultures were exposed to 80 μM Dex or Pred in the presence or absence of CBX. The number of pH3+ cells significantly decreased when CBX was added to 80 μM Pred. (D) Similar to A, with Math1cre,SmoM2 P7 mice treated with CBX alone or in combination with Pred. (E) Treatment of Pred in combination with CBX resulted in significantly decreased numbers of pH3+ cells. (F) Area measurements showed that the mean surface area of the EGL also significantly decreased in pups treated with Dex and with Pred plus CBX. Scale bars: 100 μm. For each group, n is shown within the corresponding bar. Asterisks denote significant differences versus respective vehicle groups (brackets denote comparisons other than with vehicle); exact P values are shown in Results.