title: Protection by cilostazol against amyloid-β(1-40)-induced suppression of viability and neurite elongation through activation of CK2α in HT22 mouse hippocampal cells.
abstract: Amyloid-β peptide (Aβ) deposits in the brain are critical in the neurotoxicity induced by Aβ. This study elucidates the underlying signaling pathway by which cilostazol protects HT22 neuronal cells from Aβ(1-40) (3-30 μM)-induced deterioration of cell proliferation, viability, and neurite elongation. Cilostazol rescued HT22 cells from the apoptotic cell death induced by Aβ toxicity through the downregulation of phosphorylated p53 (Ser15), Bax, and caspase-3 and the upregulation of Bcl-2 expression, which improved neuronal cell proliferation and viability. Furthermore, Aβ(1-40) suppressed both phosphorylated CK2α protein expression and CK2 activity in the cytosol; these were concentration dependently recovered by cilostazol (3-30 μM). Cilostazol significantly increased the levels of GSK-3β phosphorylation at Ser9 and β-catenin phosphorylation at Ser675 in the cytosol and nucleus. Cilostazol effects were reversed by KT5720 (1 μM, PKA inhibitor) and TBCA (40 μM, inhibitor of CK2) and CK2α knockdown by siRNA transfection. Likewise, Aβ-stimulated GSK-3β phosphorylation at Tyr 216 was decreased by cilostazol in the control but not in the CK2α siRNA-transfected cells. Furthermore, the Aβ (10 μM)-induced suppression of neurite elongation was recovered by cilostazol; this recovery was attenuated by inhibitors such as KT5720 and TBCA and blocked by CK2α knockdown. In conclusion, increased cAMP-dependent protein kinase-linked CK2α activation underlies the pharmacological effects of cilostazol in downregulating p53 phosphorylation at Ser15 and upregulating GSK-3β phosphorylation at Ser9/β-catenin phosphorylation at Ser675, thereby suppressing Aβ(1-40)-induced neurotoxicity and improving neurite elongation.
authors.affiliation: Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Beomeo-ri, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, Korea.
authors.forename: Hye Rin
authors.initials: HR
authors.lastname: Lee
authors.forename: So Youn
authors.initials: SY
authors.lastname: Park
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.forename: Won Suk
authors.initials: WS
authors.lastname: Lee
authors.forename: Byung Yong
authors.initials: BY
authors.lastname: Rhim
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D047390:Casein Kinase II / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077407:Cilostazol; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D013777:Tetrazoles; D047390:Casein Kinase II; D000077407:Cilostazol