Vol. 61, Issue 1, 114-126, January 2002

Human Group IIA Secretory Phospholipase A₂ Induces Neuronal Cell Death via Apoptosis

Tatsurou Yagami, Keiichi Ueda, Kenji Asakura, Satoshi Hata, Takayuki Kuroda, Toshiyuki Sakaeda, Nobuo Takasu, Kazushige Tanaka, Takefumi Gemba, and Yozo Hori

Discovery Research Laboratories (T.Y., K.U., K.A., S.H., T.K., T.S., K.T., T.G., Y.H.), and Developmental Research Laboratories (N.T.), Shionogi and Co., Ltd., Osaka, Japan

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.