Abstract

Expression of group IIA secretory phospholipase A₂(sPLA₂-IIA) is documented in the cerebral cortex (CTX) after ischemia, suggesting that sPLA₂-IIA is associated with neurodegeneration. However, how sPLA₂-IIA is involved in the neurodegeneration remains obscure. To clarify the pathologic role of sPLA₂-IIA, we examined its neurotoxicity in rats that had the middle cerebral artery occluded and in primary cultures of cortical neurons. After occlusion, sPLA₂ activity was increased in the CTX. An sPLA₂ inhibitor, indoxam, significantly ameliorated not only the elevated activity of the sPLA₂ but also the neurodegeneration in the CTX. The neuroprotective effect of indoxam was observed even when it was administered after occlusion. In primary cultures, sPLA₂-IIA caused marked neuronal cell death. Morphologic and ultrastructural characteristics of neuronal cell death by sPLA₂-IIA were apoptotic, as evidenced by condensed chromatin and fragmented DNA. Before apoptosis, sPLA₂-IIA liberated arachidonic acid (AA) and generated prostaglandin D₂ (PGD₂), an AA metabolite, from neurons. Indoxam significantly suppressed not only AA release, but also PGD₂ generation. Indoxam prevented neurons from sPLA₂-IIA–induced neuronal cell death. The neuroprotective effect of indoxam was observed even when it was administered after sPLA₂-IIA treatment. Furthermore, a cyclooxygenase-2 inhibitor significantly prevented neurons from sPLA₂-IIA–induced PGD₂ generation and neuronal cell death. In conclusion, sPLA₂-IIA induces neuronal cell death via apoptosis, which might be associated with AA metabolites, especially PGD₂. Furthermore, sPLA₂ contributes to neurodegeneration in the ischemic brain, highlighting the therapeutic potential of sPLA₂-IIA inhibitors for stroke.