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Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide and produced by alternative splicing of the transcript of the calcitonin/CGRP gene. Originally identified as a strong vasodilatory and hypotensive peptide, CGRP is now known to be a pleiotropic molecule distributed in various organs, including the brain.In this study, we used CGRP knockout mice (CGRP−/−) to examine the actions of endogenous CGRP during cerebral ischemia. To induce acute and chronic cerebral ischemia, mice were subjected to middle cerebral artery occlusion (MCAO) and bilateral common carotid artery stenosis (BCAS).In the cerebral cortex of wild-type mice, CGRP expression was upregulated after acute infarction. In CGRP−/− subjected to MCAO or BCAS, recovery of cerebral blood flow was slower and exhibited more extensive neuronal cell death. Expression of the inflammatory cytokines was higher in CGRP−/− than wild type in the acute phase of ischemia. Pathological analysis during the chronic phase revealed more extensive neuronal cell loss and demyelination and higher levels of oxidative stress in CGRP−/− than wild-type. CGRP−/− also showed less compensatory capillary growth. In an eight-arm radial maze test, CGRP−/− exhibited poorer reference memory than wild-type. On the other hand, CGRP administration promoted cerebral blood flow recovery after cerebral ischemia. We also found that CGRP directly inhibited the cell death of primary cortical neurons.These results indicate endogenous CGRP is protective against ischemia-induced neuronal cell injury. CGRP could, thus, be a novel candidate for use in the treatment of both cerebral ischemia and progression of cognitive decline.