Arachidonic acid induces neuronal death through lipoxygenase and cytochrome P450 rather than cyclooxygenase.
Arachidonic acid (AA) is released from membrane phospholipids during normal and pathologic processes such as neurodegeneration. AA is metabolized via lipoxygenase (LOX)-, cyclooxygenase (COX)-, and cytochrome P450 (CYP450)-catalyzed pathways. We investigated the relative contributions of these pathways in AA-induced neuronal death. Exposure of cultured cortical neurons to AA (50 microM) yielded significantly apoptotic neuronal death, which was attenuated greatly by LOX inhibitors (nordihydroguaiaretic acid, AA861, and baicalein), or CYP450 inhibitors (SKF525A and metyrapone), rather than COX inhibitors (indomethacin and NS398). AA (10 microM)-induced neurotoxicity was prevented by all kinds of inhibitors. Compared, the neurotoxic effects of three pathway metabolites, 12-hydroxyeicosatetraenoic acid (12-HETE), a major LOX metabolite, induced a significant neurotoxicity. AA also produced reactive oxygen species within 30 min, which was reduced by all inhibitors tested, including COX inhibitors, and AA neurotoxicity was abolished by the antioxidant Trolox. AA treatment also depleted glutathione levels; this depletion was reduced by the LOX or CYP450 inhibitors rather than by the COX inhibitors. Taken together, our data suggested that the LOX pathway likely plays a major role in AA-induced neuronal death with the modification of intracellular free radical levels.
Kwon
Kyoung Ja
KJ
Department of Physiology, Ajou University School of Medicine, Suwon, Korea.
Jung
Yi-Sook
YS
Lee
Soo Hwan
SH
Moon
Chang-Hyun
CH
Baik
Eun Joo
EJ
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016718:Arachidonic Acid / Q000008:administration & dosage / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology; D018920:Coculture Techniques; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008084:Lipoxygenase / Q000378:metabolism*; D051379:Mice; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000201:enzymology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D018709:Statistics, Nonparametric
D017382:Reactive Oxygen Species; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases