An internal fragment of the human neuroprotective polypeptide DSEP (Diffusible Survival Evasion Peptide) was delivered at 0.4 mg/kg (subcutaneously) 20-30 min after stab wound lesions in the parietal cortex of anesthetized rats. The peptide, CHEASAAQC or CHEC-9, inhibited the inflammatory response to the lesion and the degeneration of neurons adjacent to the wound. Four days after surgery, peptide-treated animals (n = 6) had 75% fewer reactive ameboid microglia/brain macrophages in the cortical parenchyma surrounding the lesion compared to vehicle-injected control rats (n = 6, p = 0.004). The cortical laminae in area 2 adjacent to the lesion were completely obscured in controls because of the increase in inflammatory cells and frank degeneration of neurons, while there was preservation of the neurons and cytoarchitecture after peptide treatment. In parallel experiments, CHEC-9 was found to inhibit the enzymatic activity of secreted phospholipase A2 (sPLA2), including activity present in the serum of peptide-injected rats. Kinetic analysis revealed the peptide increased the average Km for serum by 318% when tested 45 min after treatment (peptide-treated, n = 6; control-treated, n = 6; p = 0.0087), suggesting the principal effect of the peptide was to lower the affinity of serum sPLA2 for substrate. The sPLA2 inhibition by this particular peptide sequence appeared to be highly specific since inversion of a single pair of amino acids eliminated the inhibitory effect. Phorbol-12-myristate-13-acetate stimulated platelet aggregation, a PLA2-regulated activity, was also inhibited by the peptide. The discovery of CHEC-9 makes it possible to study in vivo the long appreciated contribution made by PLA2-directed inflammation to both acute and chronic neurodegeneration and may be helpful in designing therapies to limit neuron death in these conditions.