Hydrolyzed Chicken Meat Extract and Its Bioactive Cyclopeptides Protect Neural Function by Attenuating Inflammation and Apoptosis via PI3K/AKT and AMPK Pathways.

Cognitive decline is inevitable with age, and due to the lack of well-established pharmacotherapies for neurodegenerative disorders, dietary supplements have become important alternatives to ameliorate brain deterioration. Hydrolyzed chicken meat extract (HCE) and its bioactive components were previously found to improve neuroinflammation and cognitive decline by regulating microglia polarization. However, the effects and mechanisms of these bioactives on neurons remain unclear. Here, the most potent bioactive component on neural function in HCE was screened out, and the detailed mechanism was clarified through in vivo and in vitro experiments. We found that HCE, cyclo(Val-Pro), cyclo(Phe-Phe), cyclo(His-Pro), cyclo(Leu-Lys), and arginine exerted stronger anti-inflammatory and antioxidant effects among the 12 bioactives in amyloid β (Aβ)-treated HT-22 cells. Further transcriptome sequencing and polymerase chain reaction (PCR) array analysis showed that these bioactives participated in different signaling pathways, and cyclo(Val-Pro) was identified as the most potent cyclic dipeptide. In addition, the antiapoptotic and neuroprotective effect of cyclo(Val-Pro) was partly regulated by the activation of PI3K/AKT and AMPK pathways, and the inhibition of these pathways abolished the effect of cyclo(Val-Pro). Moreover, cyclo(Val-Pro) enhanced cognitive function and neurogenesis and alleviated neuroinflammation and oxidative stress in middle-aged mice, with an effect similar to HCE. Hippocampal transcriptome analysis further revealed that HCE and cyclo(Val-Pro) significantly enriched the neuroactive ligand-receptor interaction pathway, verified by enhanced neurotransmitter levels and upregulated neurotransmitter receptor-related gene expression. Therefore, the mechanism of cyclo(Val-Pro) on neural function might be associated with PI3K/AKT and AMPK pathway-mediated antiapoptotic effect and neurogenesis and the activation of the neurotransmitter-receptor pathway.