title: Metabolites of sesamin, a major lignan in sesame seeds, induce neuronal differentiation in PC12 cells through activation of ERK1/2 signaling pathway.
abstract: Sesamin, a major lignan in sesame seeds, exhibits various health benefits. Here, we investigated effects of sesamin, its stereoisomer episesamin, and their metabolites on neuronal differentiation in rat pheochromocytoma PC12 cells. Among all compounds tested, primary metabolites of sesamin and episesamin, SC-1 and EC-1 {S- and R-epimer of 2-(3,4-methylenedioxyphenyl)-6-(3,4-dihydroxyphenyl)-3,7-dioxabicyclo [3.3.0]octane}, were the most potent to induce neuronal differentiation. SC-1 alone induced neuronal differentiation through extracellular signal-regulated kinase (ERK) 1/2 activation that is essential for nerve growth factor (NGF)-induced neuronal differentiation, as shown by the suppression with MEK1/2 inhibitors, PD98059 and U0126. However, SC-1 did not increase phosphorylation of TrkA, a high-affinity NGF receptor, and a TrkA inhibitor, K252a, did not affect SC-1-induced neuronal differentiation. Furthermore, SC-1 potentiated neuronal differentiation in cells co-treated with NGF, which was associated with enhanced ERK1/2 activation and increased expression of neuronal differentiation markers. Interestingly, when treated with SC-1 and a high dose of NGF, formation of synaptic connections and synaptophysin accumulation at the neurite terminals were markedly enhanced. These results indicate that (1) SC-1 alone induces neuronal differentiation, (2) SC-1 potentiates neuronal differentiation in NGF-treated cells, (3) SC-1 enhances formation of synaptic connections in cells treated with a high dose of NGF, all of which are associated with ERK1/2 activation. It is therefore concluded that SC-1 may promote neuronal differentiation by tapping into the ERK1/2-MAPK (mitogen-activated protein kinase) signaling pathway downstream from the TrkA receptor in PC12 cells.
authors.affiliation: Department of Longevity and Aging Research, Gifu International Institute of Biotechnology, 1-1 Naka-fudogaoka, Kakamigahara, Gifu 504-0838, Japan.
authors.forename: Nanako
authors.initials: N
authors.lastname: Hamada
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fujita
authors.forename: Arisa
authors.initials: A
authors.lastname: Tanaka
authors.forename: Makoto
authors.initials: M
authors.lastname: Naoi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nozawa
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Ono
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kitagawa
authors.forename: Namino
authors.initials: N
authors.lastname: Tomimori
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Kiso
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D004149:Dioxoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D017705:Lignans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects* / Q000378:metabolism; D020932:Nerve Growth Factor / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D020917:Receptor, trkA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D016708:Synaptophysin / Q000187:drug effects / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004149:Dioxoles; D017705:Lignans; D016708:Synaptophysin; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D048052:Mitogen-Activated Protein Kinase 3; C054125:sesamin