title: Neuroprotective effects of α-iso-cubebenol on glutamate-induced neurotoxicity.
abstract: α-Iso-cubebenol is a natural compound isolated from Schisandra chinensis, and is reported to have beneficial bioactivity including anti-inflammatory and anti-tumor activities. Glutamate-induced oxidative neuronal damage has been implicated in a variety of neurodegenerative disorders. Here we investigated the mechanisms of α-iso-cubebenol protection of mouse hippocampus-derived neuronal cells (HT22 cells) from apoptotic cell death induced by the major excitatory neurotransmitter, glutamate. Pretreatment with α-iso-cubebenol markedly attenuated glutamate-induced loss of cell viability and release of lactate dehydrogenase), in a dose-dependent manner. α-Iso-cubebenol significantly reduced glutamate-induced intracellular reactive oxygen species and calcium accumulation. Strikingly, α-iso-cubebenol inhibited glutamate-induced mitochondrial depolarization, which releases apoptosis-inducing factor from mitochondria. α-Iso-cubebenol also suppressed glutamate-induced phosphorylation of extracellular-signal-regulated kinases. Furthermore, α-iso-cubebenol induced CREB phosphorylation and Nrf-2 nuclear accumulation and increased the promoter activity of ARE and CREB in HT22 cells. α-Iso-cubebenol also upregulated the expression of phase-II detoxifying/antioxidant enzymes such as HO-1 and NQO1. Subsequent studies revealed that the inhibitory effects of α-iso-cubebenol on glutamate-induced apoptosis were abolished by small interfering RNA-mediated knockdown of CREB and Nrf-2. These findings suggest that α-iso-cubebenol prevents excitotoxin-induced oxidative damage to neurons by inhibiting apoptotic cell death, and might be a potential preventive or therapeutic agent for neurodegenerative disorders.
authors: Bio-IT Fusion Technology Research Institute, Pusan National University, Busan 609-735, Republic of Korea.
authors: Sun Young
authors: SY
authors: Park
authors: Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, Republic of Korea.
authors: Yung Hyun
authors: YH
authors: Choi
authors: Department of Nanomaterials Engineering, Pusan National University, Busan 609-735, Republic of Korea. Electronic address: gtpark@pusan.ac.kr.
authors: Geuntae
authors: G
authors: Park
authors: Department of Horticultural Bioscience, Pusan National University, Miryang 627-706, Republic of Korea. Electronic address: ywchoi@pusan.ac.kr.
authors: Young-Whan
authors: YW
authors: Choi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000633:toxicity*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; C571662:alpha-iso-cubebenol; D018698:Glutamic Acid; D002118:Calcium
keywords: Apoptosis; CREB; Glutamate; Neuroprotection; Nrf-2; α-iso-Cubebenol