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Phosphodiesterase 4 (PDE4) inhibition has been shown to reduce neuroinflammation and improve neurological outcomes in several neurodegenerative diseases, such as multiple sclerosis. Especially the PDE4B gene is known to contribute to the inflammatory reaction. Therefore, we investigated the effects of PDE4 and PDE4B inhibition in ischemic stroke. We used the distal middle cerebral artery occlusion (dMCAO) mouse model to assess inflammatory cell infiltration and lesion size, and complemented the data with in vitro studies on neutrophils. Our results show that prophylactic PDE4 and PDE4B inhibition reduced the lesion size and neutrophil infiltration in vivo, whereas post-stroke administration of these inhibitors did not show an effect. In vitro, neutrophil activation was decreased following PDE4 and PDE4B inhibition. Furthermore, spatial proteomics analysis of the ischemic brain identified C1QBP as a potential contributing factor to the beneficial effects of prophylactic PDE4B inhibition. 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