5-リポオキシゲナーゼ阻害剤は分泌型ホスホリパーゼA2の神経細胞毒性を抑制する

• Published in: 日本薬理学会年会要旨集 p. 3-P-205
• Main Authors: 矢上, 達郎, 山本, 泰弘, 高馬, 宏美
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2022
• Subjects: apoptosis; leukotriene; lipoxygenase; phospholipase
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.95.0_3-P-205

Mammalian secretory phospholipase A2 (sPLA2) is associated with neurological diseases including brain ischemia. Previously, we have reported the contribution of arachidonate (AA) metabolites via cyclooxygenase (COX) to the neurotoxicity of sPLA2. However, it has not yet been sufficiently clarified how arachidonate metabolites via 5-lipoxygenase (LOX) is involved in the neurotoxicity of sPLA2. In the present study, we evaluated protective effects of LOX inhibitors (phenidone and AA-868) against the group IB porcine sPLA2 (sPLA2-IB) in the primary culture of rat cortical neurons. sPLA2-IB-induced neuronal apoptosis had been established as the in vitro model for cerebral ischemia. sPLA2-IB generated reactive oxygen species and triggered the influx of Ca2+ into neurons via L-type voltage-dependent calcium channel (L-VDCC). We confirmed protective effects of a radical scavenger, vitamin E, and an L-VDCC blocker, nimodipine, on the neurotoxicity of sPLA2-IB. Before neuronal cell death, the enzyme produced AA metabolites via COX and LOX, prostaglandin (PG) D2 and leukotriene (LT) B4, respectively. As well as COX inhibitors, LOX inhibitors prevented neurons from the sPLA2-IB-induced cell death. A PGD2 receptor antagonist, BWA868C, did not exhibit protective effect on the neurotoxicity of sPLA2-IB. On the other hand, receptor antagonists for LTB4 (LY293111) and cysteinyl LTs (ONO-1078) suppressed the neurotoxicity of sPLA2-IB in a concentration-dependent manner. Furthermore, these LTR blockers ameliorated morphological alterations such as shrank neuronal cell bodies and shortened neurites in the sPLA2-IB-treated neurons. Thus, the present study suggested that AA metabolites via LOX might be involved in the sPLA2-IB-induced neuronal apoptosis.