Mangiferin Enhances Post-Stroke Neurorestorative Responses through TrkA-Dependent Signaling: A New Function Beyond Antioxidant Activity

Abstract

Mangiferin, a C-glucosyl xanthone from mango fruit, has traditionally been studied as an antioxidant. Whether this natural compound promotes poststroke neural repair remains unknown. Using a genetically engineered high-throughput screen, we identified mangiferin as one of the most potent inducers of nerve growth factor (NGF) expression among the screened natural compounds. Mangiferin enhanced tropomyosin receptor kinase A (TrkA) phosphorylation and downstream extracellular signal-regulated kinase/cAMP response element-binding protein (ERK/CREB) signaling, accompanied by increased neural stem cell proliferation, neuronal and astrocytic differentiation, and protection against ischemic injury. These effects were attenuated by TrkA inhibition, supporting TrkA-dependent signaling. In a rat model of ischemic stroke, mangiferin reduced cerebral infarct volume, improved neurobehavioral outcomes, and increased cellular and histological markers associated with endogenous neural repair in the peri-infarct region. These findings identify mangiferin as a TrkA-targeting natural compound with neuroprotective and neurorestorative potential for poststroke neural repair.