Proglucagon-derived glucagon-like peptide-2 (GLP-2) is liberated in enteroendocrine cells and neurons. GLP-2 regulates energy absorption and epithelial integrity in the gastrointestinal tract whereas GLP-2 action in the central nervous system (CNS) remains poorly defined. We identified proglucagon and GLP-2 Receptor (GLP-2R) mRNA transcripts by RT-PCR in multiple regions of the developing and adult rat CNS. GLP-2R mRNA transcripts were localized by in situ hybridization to the hippocampus, hypothalamus, the nucleus of the solitary tract, the parabrachial nucleus, the supramammillary nucleus, and the substantia nigra. The bioactive form of GLP-2, GLP-2^1-33 was detected by RIA and HPLC analysis in the fetal and adult brain stem and hypothalamus. GLP-2 stimulated increases in cAMP accumulation in postnatal (PN) 8 but not embryonic day 14 dispersed neonatal rat brain stem tissues. The actions of GLP-2 were independent of the GLP-1R antagonist exendin (9-39) and GLP-2 stimulated cAMP accumulation in hippocampal cell cultures from both wild-type and GLP-1R- mice. GLP-2 significantly reduced glutamate-induced excitotoxic injury in hippocampal cells via a protein-kinase A dependent pathway, but had no effect on the rate of cell proliferation. These findings establish the presence of a functional GLP-2:GLP-2R axis in the developing rodent brain and demonstrate that GLP-2 exerts cytoprotective actions in cells derived from the central nervous system.