We presently found that medium-chain fatty acids (MCFAs) with 8-12 carbons and their esters facilitated activation (phosphorylation) of mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK) 1/2 of cultured embryonic cortical/hippocampal neurons. In particular, trans-2-decenoic acid ethyl ester (DAEE) had the most potent activity. Additionally, DAEE activated phosphatidylinositol 3-kinase and cAMP-response element binding protein (CREB), suggesting that DAEE generates similar intracellular signal as neurotrophins. Therefore, details of the signal elicited by DAEE were examined in comparison with those of a neurotrophin, brain-derived neurotrophic factor (BDNF). We found that 1) DAEE phosphorylated MAPK/ERK1/2 via MEK activation without the involvement of tyrosine kinases of neurotrophin Trk receptors; 2) DAEE activated CREB predominantly through MAPK/ERK1/2 activation, not through other pathways such as cAMP/protein kinase A; and 3) DAEE increased the expression of RNAs of BDNF and neurotrophin-3 and the protein content of synapse-specific proteins such as synaptophysin, synapsin-1, and syntaxin. Based on these observations we propose that DAEE and some other derivatives of MCFAs having neurotrophin-like neurotrophic activities may become therapeutic tools for certain neurological or psychiatric disorders.