Cocaine-and amphetamine-regulated transcript (CART) is a neuroendocrinal peptide.Our previous work has shown that CART promoted the survival of primary cultured hippocampal neurons by upregulating the expression of brain derived neurotrophic factor (BDNF).CART also showed the protective effect on oxygen and glucose deprived (OGD) insulted primary cultured neurons.In this study, we investigated the relationship between upregulating BDNF expression and neuroprotective effect of CART.The results revealed that expression of BDNF and receptor in primary cultured cerebral neuron was upregulated by CART under OGD insults.CART also promoted the phosphorylation and nuclear translocation of cAMP-response element binding protein (CREB).The effect of CART on BDNF could be inhibited by CREB siRNA.Our results indicated that BDNF and receptor mediated the neuroprotective effect of CART.CART promoting BDNF expression was mediated by CREB.