A novel neuroprotective peptide against cognitive disorder in mice by regulating hippocampal oxidative stress and synaptic plasticity

The peptide Ser-Phe-Gly-Asp-Ile (SFGDI), derived from sea cucumber, has demonstrated neuroprotective effects in cell models; however, the in vivo neuroprotective efficacy of SFGDI remains unexplored. In this study, we utilized a cognitive disorder mouse model induced by scopolamine and observed that daily oral administration of SFGDI at a dosage of 40 mg/kg resulted in improved behavioral performance in the Passive avoidance test, the Channel-type water maze test, and the Novel object recognition test (P < 0.05). Furthermore, our investigation into the underlying neuroprotective mechanisms of SFGDI revealed that it reduced oxidative stress levels through the activation of the Sirt3/SOD/ROS pathway, thereby balancing hippocampal unsaturated lipids (P < 0.05) in the mouse hippocampus. Moreover, SFGDI significantly decreased hippocampal neuroinflammation by modulating the activation of microglia and hypertrophy of astrocytes. Additionally, SFGDI was found to enhance synaptic plasticity in the mouse hippocampus by activating the ChAT/p-CaMKⅡ/BDNF pathway and increasing spine density in neuron cells (P < 0.05), particularly mushroom spines (P < 0.05). These experiments demonstrate that SFGDI exhibits neuroprotective effects by regulating hippocampal oxidative stress through the Sirt3/SOD/ROS pathway and synaptic plasticity via the ChAT/p-CaMKⅡ/BDNF pathway in the mouse hippocampus, thus emerging as a potential neuro-nutraceutical agent for alleviating memory impairment.