New insights on targeting extracellular vesicle release by GW4869 to modulate lipopolysaccharide-induced neuroinflammation in mice model

Aim: This study aims to elucidate the regulatory role of extracellular vesicle (EV) release in glial cell activation, microglia–astrocyte interactions and neurological outcomes. Materials & methods: We employed a pharmacological intervention using GW4869 to modulate EV release, investigating its impact on primary cultures of microglia and astrocytes, microglia–astrocyte interactions, neuroinflammation and behavioral changes in lipopolysaccharide (LPS)-induced cell and animal models. Results: We isolated the EVs from glial cells and confirmed their positivity for CD9, CD63 and CD81. Our findings demonstrate that GW4869 significantly reduced EV protein concentrations secreted by glial cells within 6–12 h. Utilizing ELISA, immunostaining and western blot analyses, we observed that treatment with GW4869 attenuated glial cell activation and inflammatory responses both in vitro and in vivo. Transwell assays indicated that controlled EV release from activated microglia and astrocytes mitigated neurotoxic reactivity in normal astrocytes and microglia, respectively. Furthermore, GW4869 administration in LPS-injected mice resulted in notable improvements in spatial memory, anxiety-like behaviors and exploratory activity compared with vehicles. Conclusion: Our study suggests that modulating glia-derived EV dynamics effectively reduce neuroinflammation and enhance behavioral outcomes in mice. These findings underscore the potential of targeting EV release as a novel therapeutic approach for neurological disorders. Targeting extracellular vesicle (EV) release: This study explores the use of GW4869 to modulate EV release, offering a potentially more targeted and side effect-free therapeutic strategy for neuroinflammation and neurological disorders. Microglia–astrocyte Interactions: By clarifying extracellular vesicle roles in microglia–astrocyte communication, the research provides essential insights for developing interventions to modulate these interactions for therapeutic benefits. Behavioral outcomes: The study establishes a connection between cellular and molecular changes and behavioral improvements in animal models, thereby enhancing the translational relevance for clinical applications. Broad applications: The findings have implications for a range of neurological disorders, such as Alzheimer’s, Parkinson’s and multiple sclerosis, where neuroinflammation is a key factor.