title: Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice.
abstract: OBJECTIVE
  Increasing evidence suggests that probucol, a lipid-lowering agent with anti-oxidant activities, may be useful for the treatment of ischemic stroke with hyperlipidemia via reduction in cholesterol and neuroinflammation. In this study we examined whether probucol could protect against brain ischemic injury via anti-neuroinflammatory action in normal and hyperlipidemic mice.
  
  
  METHODS
  Primary mouse microglia and murine BV2 microglia were exposed to lipopolysaccharide (LPS) for 3 h, and the release NO, PGE2, IL-1β and IL-6, as well as the changes in NF-κB, MAPK and AP-1 signaling pathways were assessed. ApoE KO mice were fed a high-fat diet containing 0.004%, 0.02%, 0.1% (wt/wt) probucol for 10 weeks, whereas normal C57BL/6J mice received probucol (3, 10, 30 mg·kg(-1)·d(-1), po) for 4 d. Then all the mice were subjected to focal cerebral ischemia through middle cerebral artery occlusion (MCAO). The neurological deficits were scored 24 h after the surgery, and then brains were removed for measuring the cerebral infarct size and the production of pro-inflammatory mediators.
  
  
  RESULTS
  In LPS-treated BV2 cells and primary microglial cells, pretreatment with probucol (1, 5, 10 μmol/L) dose-dependently inhibited the release of NO, PGE2, IL-1β and IL-6, which occurred at the transcription levels. Furthermore, the inhibitory actions of probucol were associated with the downregulation of the NF-κB, MAPK and AP-1 signaling pathways. In the normal mice with MCAO, pre-administration of probucol dose-dependently decreased the infarct volume and improved neurological function. These effects were accompanied by the decreased production of pro-inflammatory mediators (iNOS, COX-2, IL-1, IL-6). In ApoE KO mice fed a high-fat diet, pre-administration of 0.1% probucol significantly reduced the infarct volume, improved the neurological deficits following MCAO, and decreased the total- and LDL-cholesterol levels.
  
  
  CONCLUSIONS
  Probucol inhibits LPS-induced microglia activation and ameliorates cerebral ischemic injury in normal and hyperlipidemic mice via its anti-neuroinflammatory actions, suggesting that probucol has potential for the treatment of patients with or at risk for ischemic stroke and hyperlipidemia.
authors.affiliation: Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Yeon Suk
authors.initials: YS
authors.lastname: Jung
authors.affiliation: Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.|Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Park
authors.affiliation: Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.|Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Hyunha
authors.initials: H
authors.lastname: Kim
authors.affiliation: Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.|Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Hwang
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
authors.affiliation: Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.|Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.|Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Byung Tae
authors.initials: BT
authors.lastname: Choi
authors.affiliation: Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.|Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.|Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.|Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D002545:Brain Ischemia / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D059305:Diet, High-Fat; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006949:Hyperlipidemias / Q000150:complications* / Q000378:metabolism; D007238:Infarction / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D061251:Primary Cell Culture; D011341:Probucol / Q000494:pharmacology* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D015232:Dinoprostone; D011341:Probucol