title: Apigenin protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis.
abstract: Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson disease, and cerebral ischemia. In this study, we investigated the effects of apigenin on ER stress-induced apoptosis in murine HT22 hippocampal neuronal cells. Apigenin reduced apoptotic cell death of HT22 cells induced by thapsigargin (TG) and brefeldin A (BFA), two representative ER stress inducers. Consistent with these findings, apigenin blocked TG- and BFA-induced activation of caspase-12 and -3 and cleavage of poly (ADP-ribose) polymerase. Apigenin also reduced the TG- and BFA-induced expression of ER stress-associated proteins, including C/EBP homologous protein (CHOP), glucose-regulated protein (GRP) 78 and GRP94, the cleavage of activating transcription factor 6alpha, the phosphorylation of eukaryotic initiation factor 2alpha and inositol-requiring enzyme 1alpha, and the activation of mitogen-activated protein kinases, such as p38, c-Jun NH(2)-terminal kinase, and extracellular-regulated kinase. We also found that antioxidants such as N-acetylcysteine and glutathione blocked TG- and BFA-induced cell death and the expression of CHOP and GRP78. These results suggest that TG- and BFA-induced reactive oxygen species (ROS) accumulation plays an important role in ER stress-induced apoptosis. Apigenin also reduced TG- and BFA-induced ROS accumulation, suggesting that it exerts an antioxidant effect against ER stress inducers. Moreover, apigenin recovered TG- and BFA-induced reduction of the mitochondrial membrane potential in HT22 cells. Taken together, these results suggest that apigenin could protect HT22 neuronal cells against ER stress-induced apoptosis by reducing CHOP induction as well as ROS accumulation and mitochondrial damage.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: A Young
authors.initials: AY
authors.lastname: Choi
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Jung Yeon
authors.initials: JY
authors.lastname: Lee
authors.forename: Kyung-Sik
authors.initials: KS
authors.lastname: Yoon
authors.forename: Wonchae
authors.initials: W
authors.lastname: Choe
authors.forename: Joohun
authors.initials: J
authors.lastname: Ha
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Yeo
authors.forename: Insug
authors.initials: I
authors.lastname: Kang
mesh_terms: D000818:Animals; D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020126:Brefeldin A / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005434:Flow Cytometry; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006868:Hydrolysis; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D020126:Brefeldin A; D019284:Thapsigargin; D047310:Apigenin; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D020782:Matrix Metalloproteinases