Sonic hedgehog (Shh) signaling is a key pathway within the central nervous system (CNS), during both development and adulthood, and its activation via the 7-transmembrane
protein Smoothened (Smo) may promote neuroprotection and restoration during
neurodegenerative disorders. Shh signaling may also be activated by selected
glucocorticoids such as
clobetasol,
fluocinonide and
fluticasone, which therefore act as Smo agonists and hold potential utility for regenerative medicine. However, despite its potential role in
neurodegenerative diseases, the impact of Smo-modulation induced by these
glucocorticoids on adult neural stem cells (NSCs) and the underlying signaling mechanisms are not yet fully elucidated. The aim of the present study was to evaluate the effects of Smo agonists (i.e.,
purmorphamine) and antagonists (i.e.,
cyclopamine) as well as of
glucocorticoids (i.e.,
clobetasol,
fluocinonide and
fluticasone) on NSCs in terms of proliferation and clonal expansion.
Purmorphamine treatment significantly increased NSC proliferation and clonal expansion via GLI-Kruppel family member 1 (Gli1) nuclear translocation and such effects were prevented by
cyclopamine co-treatment.
Clobetasol treatment exhibited an equivalent pharmacological effect. Moreover, cellular thermal shift assay suggested that
clobetasol induces the canonical Smo-dependent activation of Shh signaling, as confirmed by Gli1 nuclear translocation and also by
cyclopamine co-treatment, which abolished these effects. Finally,
fluocinonide and
fluticasone as well as control
glucocorticoids (i.e.,
prednisone,
corticosterone and
dexamethasone) showed no significant effects on NSCs proliferation and clonal expansion. In conclusion, our data suggest that Shh may represent a druggable target system to drive neuroprotection and promote restorative
therapies.