Ameliorating reduced brain-derived neurotrophic factor (BDNF) expression or maintaining high BDNF levels in the brain has been suggested to improve brain function in neurological diseases and prevent aging-related brain dysfunction. In this study, we found that a food-derived product, AminothioneineÂź (AT), which is prepared from the extract of golden oyster mushrooms (
Pleurotus cornucopiae
var.
citrinopileatus
), increased
Bdnf
mRNA expression levels in primary rat cortical neuron cultures. Ergothioneine (ET) comprises more than 1% in AT and is an active constituent of AT, and ET has been reported to increase neurotrophin-4/5, but not BDNF, expression levels in neural stem cells. ET also did not affect
Bdnf
mRNA expression in cultured cortical neurons, suggesting that AT contains other active constituents that induce
Bdnf
mRNA expression in neurons. AT-induced
Bdnf
mRNA expression was completely blocked by
d
-(â)-2-Amino-5-phosphonopentanoic acid but partially blocked by nicardipine, U0126, and FK506. This result suggested that
N
-methyl-
d
-aspartate receptor-derived Ca
2+
signals, including those mediated by extracellular signal-regulated kinase/mitogen-activated protein kinase and calcineurin, are the main contributors to
Bdnf
mRNA induction. In addition, AT increased cAMP-response element-binding protein (CREB) phosphorylation and the nuclear localization of CREB-regulated transcriptional coactivator 1 in neurons. Thus, AT can increase
Bdnf
mRNA expression via Ca
2+
signal-induced CREB-dependent transcription in neurons. Because AT is a food-derived product, increasing and/or maintaining BDNF levels in the brain by daily intake of the product could be possible, which may be beneficial for neurological and aging-related disorders.