Prothymosin alpha (ProTα) has been identified as an anti-necrotic factor from the conditioned medium of primary cultured of rat cortical neurons under the serum-free starving condition. ProTα is released in a non-vesicular manner from neurons or astrocytes by the help of cargo protein S100A13. Thus released ProTα is found to have robustness roles in the brain under the condition of neuronal necrosis or apoptosis. ProTα inhibits necrosis by plasma membrane-translocation of glucose transporters endocytosed by ischemia/starving stress, through an activation of unidentified G protein-coupled receptor and protein kinase Cβ. In the cerebral or retinal ischemia model, systemic injection of ProTα protects brain or retina from ischemic damages by converting necrosis to apoptosis, which is in turn blocked by neurotrophic factors. In the retinal ischemia model, ProTα prevents the damages by another mechanism through toll-like receptor 4 (TLR4) and downstream TRIF signaling. The direct interaction between ProTα and TLR4/MD2 is also evidenced by the study of molecular dynamics and protein-protein interaction. All these findings indicate that ProTα could be called a cytoprotective member of damage-associated molecular patterns (DAMPs) or alarmins. ProTα and its modified peptide fragment, NEVDQE (P6Q) show the vasculoprotective actions by itself in a model of cerebral ischemia as well as neuroprotective actions. The concomitant administration of these peptides abolishes the cerebral hemorrhage induced tissue plasminogen activator (tPA), which is treated late after cerebral ischemia models. Thus, ProTα and P6Q seem to have promising therapeutic potencies to directly protect neurons and inhibit the hemorrhage by late treatment with tPA against stroke.