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 GCinduced 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.

Identification of select glucocorticoids as Smoothened agonists: Potential utility for regenerative medicine

“…6). No such growth-enabling responses were observed in GCPs treated with cortisone, dexamethasone, prednisolone, or corticosterone, observations consistent with recent reports (25)(26)(27) (Fig. 6).…”

“…Interestingly, the glucocorticoid receptor (GR) agonist dexamethasone had a tendency to inhibit the activity of 2% Shh (Fig. 5B), as previously described (25). To verify further the opposite effects that the Smo agonists have on proliferation compared to dexamethasone, we treated GCP cells with Shh (2% and 20%) and various concentrations of halcinonide or dexamethasone in the absence or presence of 2% Shh.…”

“…It has been reported that Hedgehog signaling promotes GCP proliferation through up-regulation of cyclin D2 and inhibition of proteasomal degradation of caspase-3, whereas dexamethasone and several other GR agonists have the opposite effect by inhibiting GCP proliferation and not inhibiting GCP apoptosis (25). Although all the fluorinated glucocorticoid smoothened agonists from our study possess the ability, like dexamethasone, to activate GR as assessed by a GR-GFP nuclear translocation assay (Fig.…”

“…Other glucocorticoids, including dexamethasone, prednisone, cortisone, and corticosterone, are used to treat premature infants and have been observed to cause neuronal apoptosis and to inhibit neuronal precursors of the cerebellar granule neuronal lineage in a mouse model (25,26). On the basis that Shh exposure cannot overcome the effects of dexamethasone but can antagonize the effects of hydrocortisone, Heine and Rowitch (25) recommend that hydrocortisone be used as a replacement for dexamethasone in infants because of the reduced potential for neurotoxicity. We have demonstrated in vitro that fluticasone and the other fluorinated steroids can be used to expand neuronal precursor cell populations and potentiate the ability of 2% Shh stimulation.…”

Dexamethasone but not the equivalent doses of hydrocortisone induces neurotoxicity in neonatal rat brain

“…11βHSD2 is involved in the local metabolic inactivation of endogenous GCs like HC into inert 11-keto derivatives but has no effects on synthetic GCs like Dex. Thus, 11βHSD2 antagonized the antiproliferative and apoptotic effects of 11βHSD2-sensitive HC but not Dex on proliferating mouse cerebellar granule neuron precursors (19).…”