We report the identification of a novel rat cDNA encoding a peptide homologous to Humanin, a secreted peptide that specifically protects against neuronal cell death induced by beta-amyloid peptide (Ab) or by mutations causing early-onset familial Alzheimer's disease. The rat gene, which we termed Rattin, encodes a peptide of 38 residues (15 residues longer than Humanin) showing 73% identity in the conserved region to Humanin. The expression profile of the 1.6-kb Rattin transcript is comparable to that displayed by Humanin, with significant expression levels in the central nervous system and in cardiac and skeletal muscle. The full-length Rattin peptide and its 1-25 fragment were equally effective as Humanin in protecting rat- and mouse-cultured cortical neurons against Ab-induced toxicity. However, Rattin was much more effective than Humanin against excitotoxic neuronal death induced by a toxic pulse with NMDA. Rattin and its short fragment were protective against excitotoxic death not only when coapplied with NMDA, but also when added to the cultures after the NMDA pulse. Neither Rattin not Humanin could affect neuronal apoptosis by trophic deprivation induced in cultured cerebellar granule cells depleted of extracellular potassium. This suggests that Rattin is the prototype of a novel class of peptides, phylogenetically related to Humanin, endowed with protective activity not only against Ab but also toward excitotoxic neuronal death. The identification of Rattin may be instrumental for the development of novel pharmacological strategies aimed at enhancing the production of endogenous Humanin-like peptides.