Dipeptide Asp-Arg enhances BDNF expression via Ca²⁺-dependent mechanisms in neuronal cells and increases hippocampal BDNF levels in mice

Abstract

Bioactive dipeptides have emerged as promising candidates for modulating neuronal function and protecting against cognitive decline. In this study, we investigated the effects of the dipeptide Asp-Arg (DR) on brain-derived neurotrophic factor (BDNF) expression. In differentiated SH-SY5Y cells, DR treatment significantly increased BDNF protein levels, and this increase was suppressed by BAPTA-AM, an intracellular Ca²⁺ chelator, suggesting that DR-induced BDNF upregulation requires intracellular Ca²⁺ signaling. Furthermore, in a scopolamine-induced amnesia mouse model, oral administration of DR markedly increased both hippocampal BDNF mRNA and protein levels. These findings suggest that DR enhances BDNF expression through Ca²⁺-dependent mechanisms in neuronal cells and that oral DR may support neuronal plasticity in vivo, highlighting its potential as a neuroprotective dipeptide for maintaining cognitive function.