AbstractMicroglia are the macrophages that reside in the brain. Activated microglia induces further activation of astrocytes and neuronal cells for mounting an immune response. However, activated microglia release neurotoxic mediators causing neuroinflammation, which is associated with chronic etiology of neurodegenerative diseases. We investigated the effect of ethanol extract of Physalis alkekengi L. var. francheti fruit (PAFE) on neuronal cell death mediated by activated microglia. PAFE decreased NO production and IL-6 secretion in LPS-stimulated BV-2 and primary microglial cells without reducing cell viability. Consistently, treatment with PAFE decreased iNOS and COX-2 expression and ERK phosphorylation in LPS-stimulated BV-2 cells. Finally, apoptosis of N2a cells grown in conditioned media prepared from LPS-stimulated BV-2 cells containing PAFE was inhibited via downregulation of the Bax/Bcl-2 ratio. Taken together, PAFE alleviates neuronal cell death by reducing neurotoxic mediators such as NO and IL-6 from activated microglia. Therefore, it could be a potential candidate to treat neurodegenerative diseases caused by chronic neuroinflammation.