Ginkgo biloba extract 50 alleviates memory and synaptic plasticity deficits by inhibiting neuroinflammation via the blockage of ATP-P2X7R axis in presenilin 1/2 conditional double knockout mice.

内容摘要

Ginkgo biloba L. has been widely utilized in traditional Chinese medicine for its potential to enhance memory-related functions. In traditional medical practices, it is also commonly prescribed for conditions associated with cognitive decline and age-related disorders. These ethnopharmacological uses are closely linked to neurodegenerative disorders, in which neuroinflammation plays a central role. Ginkgo biloba has shown anti-inflammatory and neuroprotective properties, yet its underlying mechanisms in modulating neuroinflammation are still not fully understood. Neuroinflammation is critically involved in cognitive impairment and neurodegenerative diseases, while therapeutic options remain limited. Ginkgo biloba extract 50 (GBE50) is a standardized formulation with potential neuroprotective properties. This study aimed to assess its effects on neuroinflammation-associated cognitive dysfunction and to clarify the mechanisms involved. Presenilin 1/2 conditional double knockout mice served as a cognitive impairment model, with behavioral tests used to evaluate cognitive function. The constituents of GBE50 were identified by UPLC-Q-TOF-MS, and ATP content was quantified using biochemical assays. The expression of P2X7 receptor, NLRP3 inflammasome-related proteins, inflammatory cytokines, and synaptic markers was determined at both mRNA and protein levels using qRT-PCR and Western blotting. Microglial activation and P2X7R distribution were assessed via immunofluorescence, and hippocampal synaptic plasticity was examined using electrophysiological recordings. Using UPLC-Q-TOF-MS, 51 compounds were characterized in GBE50, mainly flavonoids and terpene lactones, which are likely responsible for its biological activities. Treatment with GBE50 markedly alleviated cognitive impairment in PS cDKO mice. It downregulated P2X7R and key components of the NLRP3 inflammasome (NLRP3, NEK7, Caspase-1, and ASC), while also reducing the transcription of pro-inflammatory cytokines including Il-1β, Il-18, and Tnf-α. In parallel, GBE50 restored synaptic protein levels and improved long-term potentiation deficits. Collectively, our findings suggest that modulation of the ATP-P2X7R-NLRP3 axis contributes to the neuroprotective effects of GBE50 in AD, highlighting this pathway as a promising therapeutic target for preventing AD-related neurodegeneration.