Tyrosine-containing small peptides from soy protein isolate act as an antidepressant against chronic immobilization stress–induced depressive male mice through glutamine synthetase activation

Abstract

Depressive behaviors are closely associated with dysfunction of the glutamate (Glu)-glutamine (Gln) cycle in the medial prefrontal cortex (mPFC) due to hypoactive glutamine synthetase (GS) following tyrosine nitration. Recently, the antidepressant effects of tyrosyl-Gln and glutamyl-tyrosine were found. Therefore, we tested whether tyrosine-containing small peptides from soy protein (SP) isolate have an antidepressive effect. To this end, SP hydrolysate (SPH) enriched with tyrosine-containing small peptides was prepared and provided to a depression mouse model as a dietary supplement. As a result, we found a dose-dependent antidepressive effect of SPH, which was achieved by GS activation with tyrosine denitration. Moreover, SPH decreased plasma corticosterone and restored the levels of Glu and Gln in the mPFC. These results suggest that SPH can be used as a nutraceutical to ameliorate chronic stress–related illnesses, such as depression and anxiety. © 2025