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This is the first study showing that a 6-h delayed posttreatment with PaPE-1 inhibited hypoxia\/ischemia-induced neuronal death, as indicated by neutral red uptake in mouse primary cell cultures in vitro. The effect was accompanied by substantial decreases in neurotoxicity and neurodegeneration in terms of LDH release and Fluoro-Jade C staining of damaged cells, respectively. The mechanisms of the neuroprotective action of PaPE-1 also involved apoptosis inhibition demonstrated by normalization of both mitochondrial membrane potential and expression levels of apoptosis-related genes and proteins such as <jats:italic>Fas<\/jats:italic>, <jats:italic>Fasl<\/jats:italic>, <jats:italic>Bcl2<\/jats:italic>, FAS, FASL, BCL2, BAX, and GSK3\u03b2. Furthermore, PaPE-1-evoked neuroprotection was mediated through a reduction in ROS formation and restoration of cellular metabolic activity that had become dysregulated due to hypoxia and ischemia. 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