title: Inhibitory effect of punicalagin on lipopolysaccharide-induced neuroinflammation, oxidative stress and memory impairment via inhibition of nuclear factor-kappaB.
abstract: Neuroinflammation is significant in the pathogenesis and development of Alzheimer's disease (AD). Previously, we showed lipopolysaccharide (LPS)-induced neuroinflammation caused memory impairment. We investigated the possible preventive effects of punicalagin (PUN), a component of pomegranate, on memory deficiency caused by LPS, along with the fundamental mechanisms. LPS-treated cultured astrocytes and microglial BV-2 cells were investigated for anti-neuroinflammatory effects of PUN. PUN (1.5 mg/kg) ameliorates LPS (250 μg/kg daily 7 times)-induced memory impairment as well as prevents the LPS-induced expression of inflammatory proteins. In in vitro study, we also found that PUN (1 μg/ml) inhibited the LPS-(10, 20 and 50 μM) induced expression of iNOS and Cox-2 as well as the production of ROS, NO, TNF-α and IL-1β. PUN also suppress activation of NF-κB via inhibition of IκB degradation as well as p50 and p65 translocation into the nucleus in LPS treated mouse brain and cultured astrocytes and microglial BV-2 cells. Consistent with the inhibitory effect on neuro inflammation, PUN inhibited LPS-induced Aβ1-42generation through down-regulation of APP and BACE1 expression in in vivo and in vitro study. Moreover, PUN directly binds to NF-κB subunit p50 evidenced by a docking model and pull down assay. These results suggest that PUN inhibits LPS-induced memory impairment via anti-inflammatory and anti-amylogenic mechanisms through inhibition of NF-κB activation.
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 28160, Republic of Korea.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 28160, Republic of Korea.
authors.forename: Chul Ju
authors.initials: CJ
authors.lastname: Hwang
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 28160, Republic of Korea.
authors.forename: Hee Pom
authors.initials: HP
authors.lastname: Lee
authors.affiliation: Bio-Interchange Co, 194-41, Osongsanengmyeong 1-ro, Heungdeock-gu, Cheongju, Chungbuk 28160, Republic of Korea.
authors.forename: Chun Sik
authors.initials: CS
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 28160, Republic of Korea.
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.affiliation: Department of Chemistry, Utah Valley University, 800 West University Parkway, Orem, UT 84508, USA.
authors.forename: Young Wan
authors.initials: YW
authors.lastname: Ham
authors.affiliation: Laboratory for Transplantation and Regenerative Medicine, Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Hellström
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 28160, Republic of Korea.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: Sustainable Bioresource Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gawhak-ro, Yuseoung, Daejeon 305-806, Republic of Korea.
authors.forename: Hee Sik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea, 64 Daeheung-ro, Jung-gu, Daejeon 34943, Republic of Korea. Electronic address: guevara614@catholic.ac.kr.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Park
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsangmyeong1-ro, Heungdeok-gu, Cheongju, Chungbuk 28160, Republic of Korea. Electronic address: jinthong@chungbuk.ac.kr.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D017628:Microglia / Q000187:drug effects; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats
chemical_list: D016564:Amyloid beta-Protein Precursor; D047348:Hydrolyzable Tannins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; C115642:punicalagin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer's disease; Amyloidogenesis; Lipopolysaccharide; Memory impairment; Neuroinflammation; Pomegranate; Punicalagin