Open Access14,15‐epoxyeicosatrienoic acid produced by cytochrome P450s enhances neurite outgrowth of PC 12 and rat hippocampal neuronal cells
Author(s) -
Oguro Ami,
Inoue Takumi,
Kudoh Suguru N.,
Imaoka Susumu
Publication year - 2018
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.428
Subject(s) - neurite , arachidonic acid , hydroxyeicosatetraenoic acid , epoxyeicosatrienoic acid , chemistry , epoxygenase , biochemistry , microbiology and biotechnology , hippocampal formation , transient receptor potential channel , biology , in vitro , receptor , enzyme , endocrinology
Polyunsaturated fatty acids, such as arachidonic acid, are accumulated in brain and induce neuronal differentiation. Arachidonic acid is metabolized to epoxyeicosatrienoic acids ( EET s) and hydroxyeicosatetraenoic acids ( HETE s) by cytochrome P450s. In this study, we found that 14,15‐ EET and 20‐ HETE ‐enhanced NGF ‐induced rat pheochromocytoma PC 12 cell neurite outgrowth even at the concentration of 100 nmol L −1 . LC ‐ MS analysis revealed that 14,15‐ EET was effectively produced from arachidonic acid by rat CYP 2C11, 2C13, and 2C23, and these P450s were expressed in PC 12 cells. An inhibitor of these P450s, ketoconazole, inhibited neurite outgrowth, whereas inhibition of soluble epoxide hydrolase, which hydrolyzes EET s to their corresponding diols enhanced neurite outgrowth. To determine the mechanism of neurite formation enhancement by arachidonic acid metabolites, we focused on transient receptor potential ( TRP ) channels expressed in PC 12 cells. The TRPV 4 inhibitor HC 067047, but not the TRPV 1 inhibitor capsazepine, inhibited the effects of 14,15‐ EET on neurite outgrowth of PC 12. Furthermore, 14,15‐ EET increased the cytosolic calcium ion concentration and this increase was inhibited by HC 067047. 14,15‐ EET also enhanced neurite outgrowth of primary cultured neuron from rat hippocampus. This study suggests that arachidonic acid metabolites produced by P450 contribute to neurite outgrowth through calcium influx.