Smoothened agonist (SAG), a chlorobenzothiophene-containing Hh pathway agonist, was shown to be able to bind directly to Smo and activate Shh-dependent pathway. SAG and similar compounds represent attractive molecules to be developed for treatment of disorders where stimulation of the generation and survival of new neural cells would be beneficial. Thus, it was demonstrated that small-molecule agonist of Smo has potential as a neuroprotective agent in neonates at risk for glucocorticoid-induced neonatal cerebellar injury. Moreover, hedgehog agonist therapy corrects structural and cognitive deficits in a Down syndrome mouse model.