Using gain- and loss-of-function approaches, we demonstrated that decreased neuronal OSMR expression results in deteriorated stroke outcomes but that OSMR overexpression in neurons is cerebroprotective. Moreover, administering recombinant human OSM to mice before the onset of I/R showed that human OSM can be protective in rodent models of ischemic stroke.;Finally, using an in vivo model of excitotoxic injury, OsM significantly reduced the NMDA-induced lesion volume when coinjected with NMDA into the mouse striatum.;Indeed, our in vivo experiments demonstrate that OSM treatment increases plasticity of serotonergic fibers after SCI. Together, our data show that OSM is produced at the lesion site, where it protects the CNS from further damage and promotes recovery.