title: Concurrent Treatment with Taxifolin and Cilostazol on the Lowering of β-Amyloid Accumulation and Neurotoxicity via the Suppression of P-JAK2/P-STAT3/NF-κB/BACE1 Signaling Pathways.
abstract: Taxifolin is a potent flavonoid that exerts anti-oxidative effect, and cilostazol increases intracellular cAMP levels by inhibiting phosphodiesterase 3 that shows antiinflammatory actions. BACE1 (β-site APP cleaving enzyme 1) is the rate-limiting enzyme responsible for the β-cleavage of amyloid precursor proteins to Aβ peptides. In this study, endogenous Aβ and C99 accumulation was explored in N2a Swe cells exposed to 1% FBS medium. Increased Aβ and C99 levels were significantly attenuated by taxifolin alone and in combination with cilostazol. Increased phosphorylated JAK2 at Tyr1007/1008 (P-JAK), phosphorylated STAT3 at Tyr 705 (P-STAT3) expressions and increased expressions of BACE1 mRNA and protein in the activated N2a Swe cells were significantly attenuated by taxifolin (10~50 μM), cilostazol (10~50 μM) alone and in combination at minimum concentrations. In these cells, decreased cytosol IκBα expression was elevated, and increased nuclear NF-κB p65 level and nuclear NF-κB p65 DNA binding activity were significantly reduced by taxifolin and cilostazol in a similar manner. Following STAT3 gene (~70% reduction) knockdown in N2a cells, Aβ-induced nuclear NF-κB and BACE1 expressions were not observed. Taxifolin, cilostazol, or resveratrol significantly stimulated SIRT1 protein expression. In SIRT1 gene-silenced (~50%) N2a cells, taxifolin, cilostazol, and resveratrol all failed to suppress Aβ1-42-stimulated P-STAT3 and BACE1 expression. Consequently, taxifolin and cilostazol were found to significantly decrease lipopolysaccharide (1-10 μg/ml)-induced iNOS and COX-2 expressions, and nitrite production in cultured BV-2 microglia cells and to increase N2a cell viability. In conclusion, taxifolin and cilostazol strongly inhibited amyloidogenesis in a synergistic manner by suppressing P-JAK2/P-STAT3-coupled NF-κB-linked BACE1 expression via the up-regulation of SIRT1.
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Gyeongsangnam-do, Republic of Korea.|Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongsangnam-do, Republic of Korea.
authors.forename: So Youn
authors.initials: SY
authors.lastname: Park
authors.affiliation: Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongsangnam-do, Republic of Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongsangnam-do, Republic of Korea.
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Division of Meridian and Structural Medicine, Pusan National University, Gyeongsangnam-do, Republic of Korea.
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.affiliation: Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongsangnam-do, Republic of Korea.
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Gyeongsangnam-do, Republic of Korea.|Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongsangnam-do, Republic of Korea.
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002478:Cells, Cultured; D000077407:Cilostazol; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D050796:STAT3 Transcription Factor; D013777:Tetrazoles; D011794:Quercetin; C003377:taxifolin; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D000077407:Cilostazol