The neuropeptide cocaine- and amphetamine-regulated transcript (CARTp) plays a role in various physiological processes. CARTp is highly expressed in rat hippocampus and can promote the survival and differentiation of neurons in primary hippocampal cell cultures. However, little is known about the neurotrophic mechanism of CARTp on the hippocampal neuron. We show that CARTp fragment 55-102 promoted the survival of cultured hippocampal neurons by increasing the number of surviving neurons and their viability. The tyrosine kinase B (TrkB) antibody, known to inhibit the activity of brain-derived neurotrophic factor (BDNF), blocked the survival-promoting effect of CARTp on hippocampal neurons. Further study by reverse-transcription PCR showed that BDNF mRNA expression significantly increased after CARTp treatment. The prepro BDNF and mature BDNF protein also increased in level as seen on Western blot analysis. Thus, the neurotrophic effects of CARTp on cultured hippocampal neurons are mediated through the upregulation of BDNF mRNA expression and protein synthesis. The results of the present study suggest the therapeutic efficacy of CARTp in neurodegenerative disorders. (c) 2006 Elsevier Inc. All rights reserved.