Ergothioneine Stimulates Ca²⁺-Mediated Brain-Derived Neurotrophic Factor Expression in NE-4C Nerve Cells

Ergothioneine (EGT), a naturally occurring histidine derivative, has been reported to modulate neurodegenerative diseases; however, the underlying mechanism remains unclear. This study aimed to investigate the brain-beneficial role of the natural amino acid EGT in NE-4C nerve cells. In the nerve cells, EGT treatment of >10 μM for 48 h significantly increased the expression of brain-derived neurotrophic factor (BDNF), as well as the phosphorylation of cAMP response element-binding protein (CREB), whereas no change was observed in acetylcholine receptor expression. Additionally, EGT induced an increase in intracellular Ca²⁺ levels via stimulation of the inositol 1,4,5-triphosphate receptor (IP₃R) in the endoplasmic reticulum; this increase was abrogated by the inhibition of organic cation transporter 1 (OCTN1). Structure-activity relationship analysis revealed the importance of the trimethylammonium group in EGT for intracellular events. In conclusion, EGT incorporated into cells via the OCTN1 route may act as a nerve transmission stimulator via IP₃R-mediated Ca²⁺-CREB/BDNF activation.