Periplaneta americana Extract Protects Glutamate-Induced Nerve Cell Damage by Inhibiting N-Methyl-D-Aspartate Receptor Activation

Neurocytotoxicity elicited by <i>N-methyl-D-aspartate</i> receptors (NMDAR) is a substantial contributor to neurodegenerative diseases. Our current study expands on the previous findings in which <i>Periplaneta americana</i> (L.) extract (PAS840) was shown to protect PC12 cells from hydrogen peroxide-induced injury. In this investigation, we performed LC-MS/MS and peptidomics analyses on the constituents of PAS840. Considering Alzheimer's disease (AD) as the primary focus, we utilized network pharmacology and molecular-docking techniques to predict PAS840's influence on AD targets. We established a glutamate (Glu)-induced PC12 cell injury model to conduct a comprehensive examination of PAS840's effects on pivotal cellular parameters, including intracellular Ca²⁺ levels, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, reactive oxygen species (ROS) levels, cell apoptosis rate, mitochondrial membrane potential (MMP) levels, and the expression of key proteins such as NMDAR1, cytochrome c (Cytc), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). The results suggest that PAS840 manifests multi-target actions, robustly attenuating NMDAR activity. It efficaciously suppresses excessive NMDAR1 activation, restricts Ca²⁺ influx, alleviates oxidative stress, and mitigates inflammation, thereby ameliorating neuronal cell damage. Consequently, it establishes a solid scientific foundation for further exploration of PAS840's potential in addressing neurological diseases.