Homoplantaginin\nAntagonizes <i>N</i>‑Methyl‑d‑aspartate\nReceptor and Extracellular Signal-Regulated\nKinase Signaling in Aβ Oligomers-Induced Neuropathology/Toxicity

Extracts from plants/herbals are great resources of drugs\nand nutrients.\nBaicalein, a component present in Scutellaria baicalensis, was previously found to alleviate the abnormal depolarization brought\nabout by Aβ oligomers. We extended this promising outcome by\nscreening baicalein derivatives, and a natural compound named homoplantaginin\nwas pinpointed. In this study, we aimed to investigate the effects\nof homoplantaginin on animal behavior and explore its neuronal functioning/mechanism.\nIn behavior tests, impairments of novel object recognition and of\nspatial learning/memory were reversed by homoplantaginin in a J20\nAlzheimer’s disease (AD) mouse model. Utilizing primary glutamatergic\nneurons, homoplantaginin was found to prevent the Aβ oligomer-induced\nincrease in ERK phosphorylation. Furthermore, homoplantaginin inhibits\nboth AMPA-insult and NMDA-insult depolarization; this was assessed\nusing DiBAC4(3), a membrane potential sensitive dye. Finally, homoplantaginin\nblocks both Aβ oligomer-induced and NMDA-induced calcium influx,\nwhich was assessed by intracellular calcium measurement using Fura2/AM.\nInterestingly, homoplantaginin immediately blunts the steady state\ncalcium influx caused by NMDA. Taken together, homoplantaginin is\ncapable of inhibiting Aβ oligomer-induced pathophysiology, in\nparticular at the receptor level. This pure compound has great potential\nto be developed as a clinical therapeutic drug.