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

<b>Aim:</b> This study aims to elucidate the regulatory role of extracellular vesicle (EV) release in glial cell activation, microglia-astrocyte interactions and neurological outcomes.<b>Materials & methods:</b> 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.<b>Results:</b> 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 <i>in vitro</i> and <i>in vivo</i>. 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.<b>Conclusion:</b> 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.