title: Neuroprotective effects of α-iso-cubebene against glutamate-induced damage in the HT22 hippocampal neuronal cell line.
abstract: Since oxidative stress is critically involved in excitotoxic damage, we sought to determine whether the activation of the transcription factors, cAMP-responsive element binding protein (CREB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2, also known as NFE2L2), by α-iso-cubebene is involved in its protective effects against glutamate-induced neuronal cell death. Pre-treatment with α-iso-cubebene significantly attenuated glutamate-induced cytotoxicity in mouse hippocampus-derived neuronal cells. α-iso-cubebene also reduced the glutamate-induced generation of reactive oxygen species and calcium influx, thus preventing apoptotic cell death. α-iso-cubebene inhibited glutamate-induced mitochondrial membrane depolarization and, consequently, inhibited the release of the apoptosis-inducing factor from the mitochondria. Immunoblot anlaysis revealed that the phosphorylation of extracellular signal-regulated kinase (ERK) by glutamate was reduced in the presence of α-iso-cubebene. α-iso-cubebene activated protein kinase A (PKA), CREB and Nrf2, which mediate the expression of the antioxidant enzymes, heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1), involved in neuroprotection. In addition, α-iso-cubebene induced the expression of antioxidant responsive element and CRE transcriptional activity, thus conferring neuroprotection against glutamate-induced oxidative injury. α-iso-cubebene also induced the expression of Nrf2-dependent genes encoding HO-1 and NQO1. Furthermore, the knockdown of CREB and Nrf2 by small interfering RNA attenuated the neuroprotective effects of α-iso-cubebene. Taken together, our results indicate that α-iso-cubebene protects HT22 cells from glutamate-induced oxidative damage through the activation of Nrf2/HO-1/NQO-1, as well as through the PKA and CREB signaling pathways.
authors.affiliation: Bio-IT Fusion Technology Research Institute, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Horticultural Bioscience, Pusan National University, Miryang 627-706, Republic of Korea.
authors.forename: Won Jung
authors.initials: WJ
authors.lastname: Jung
authors.affiliation: Department of Horticultural Bioscience, Pusan National University, Miryang 627-706, Republic of Korea.
authors.forename: Jum Soon
authors.initials: JS
authors.lastname: Kang
authors.affiliation: Research Center for Anti-Aging Technology Development, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Cheol-Min
authors.initials: CM
authors.lastname: Kim
authors.affiliation: Bio-IT Fusion Technology Research Institute, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Geuntae
authors.initials: G
authors.lastname: Park
authors.affiliation: Department of Horticultural Bioscience, Pusan National University, Miryang 627-706, Republic of Korea.
authors.forename: Young-Whan
authors.initials: YW
authors.lastname: Choi
mesh_terms: D000818:Animals; D002460:Cell Line; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D012717:Sesquiterpenes; C539088:alpha-iso-cubebene; D018698:Glutamic Acid