Metabolic characteristics and antidepressant mechanism of cerebroprotein hydrolysate oral liquid via regulating tyrosine hydroxylase and neurotransmitter balance

Depression is a major global public health challenge, with current treatments often limited by suboptimal efficacy and adverse effects. This study investigated the antidepressant potential of cerebroprotein hydrolysate oral liquid (CHOL), a neuroprotective peptide-based solution derived from porcine brain through enzymatic hydrolysis. In model mice subjected to chronic social defeat stress (CSDS) and chronic restraint stress (CRS), CHOL was found to significantly attenuate depressive-like behaviors. Furthermore, CHOL also effectively reduced corticosterone-induced cell damage in PC12 cells. Metabolomic analysis revealed that depression modeling led to significant disturbances in neurotransmitter-related metabolites, especially norepinephrine, whereas CHOL could restore these metabolites in key brain regions and serum. Mechanism exploration revealed that the elevation of norepinephrine by CHOL was achieved through upregulation of Tyrosine Hydroxylase expression. Pharmacokinetic studies demonstrated that the 8 peptides in CHOL could rapidly distribute to the brain, with serine proteases, cysteine proteases, and metalloproteases identified as the key Enzymes mediating CHOL metabolism. These findings underscored CHOL's preventive and therapeutic potential and provided mechanistic insights for its development as a novel antidepressant strategy. SIGNIFICANCE STATEMENT: This study integrated multiple depression models to confirm the significant antidepressant effects of cerebroprotein hydrolysate oral liquid. For the first time, we elucidated its underlying mechanism by regulating Tyrosine Hydroxylase expression and promoting norepinephrine synthesis. Furthermore, 8 brain-penetrant peptides were identified, and a targeted protease-inhibition strategy was developed to enhance in vivo exposure, thereby providing novel mechanistic insights and potential translational applications in depression therapeutics.

Cerebroprotein hydrolysate oral liquid; Cerebroprotein hydrolysate oral liquid metabolism; Depression; Norepinephrine; Peptide identification; Tyrosine hydroxylase.