title: Omega-3 fatty acid supplement prevents development of intracranial atherosclerosis.
abstract: OBJECTIVE
  Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and, in particular, has been implicated as a leading cause of recurrent ischemic stroke. We adapted a rat model of atherosclerosis to study brain intracranial atherosclerosis, and further investigated the effect of omega-3 fatty acids (O3FA) in attenuating development of ICAS.
  
  
  METHODS
  Adult male Sprague-Dawley rats were divided into control normal-cholesterol or high-cholesterol diet groups with or without O3FA for up to 6weeks. During the first 2weeks, NG-nitro-l-arginine methyl ester (l-NAME, 3mg/mL) was added to the drinking water of the high-cholesterol groups. The rats received supplementation with O3FA (5mg/kg/day) by gavages. Blood lipids including low density lipoprotein (LDL), cholesterol (CHO), triglycerides (TG) and high density lipoprotein (HDL) were measured at 3 and 6weeks. The lumen of middle cerebral artery (MCA) and the thickness of the vessel wall were assessed. Inflammatory molecular markers were assessed by Western blot.
  
  
  RESULTS
  A high-cholesterol diet exhibited a significant increase in the classic blood markers (LDL, CHO, and TG) for atherosclerosis, as well as a decrease in HDL. These markers were found to be progressively more severe with time. Lumen stenosis and intimal thickening were increased in MCA. O3FA showed attenuation of blood lipids with an absence of morphological changes. O3FA significantly reduced the inflammatory marker CD68 in MCA and prevented monocyte chemotactic protein (MCP-1) and interferon-γ (IFN-γ) expression in the brain. O3FA similarly decreased inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6), markers affiliated with monocyte activity in atherosclerosis. Furthermore, O3FA significantly inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1), a marker for endothelial activation. Lastly, O3FA increased ATP-binding cassette transporter A1 (ABCA1) protein expression via silent information regulator 1 (SIRT1) activation, thus increasing cholesterol efflux from macrophages to HDL.
  
  
  CONCLUSIONS
  Long-term O3FA dietary supplementation prevents the development of intracranial atherosclerosis. This O3FA effect appears to be mediated by its prevention of macrophage infiltration into the vessel wall, therefore reducing inflammation and intimal thickening. While similar effects in humans need to be determined, O3FA dietary supplement shows promising results in the prevention of ICAS.
authors: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, China; Department of Neurosurgery, Wayne State University School of Medicine, USA. Electronic address: shenjiameide@163.com.
authors: Jiamei
authors: J
authors: Shen
authors: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, China; Department of Neurosurgery, Wayne State University School of Medicine, USA. Electronic address: ahafeez313@gmail.com.
authors: Adam
authors: A
authors: Hafeez
authors: Department of Neurosurgery, Wayne State University School of Medicine, USA. Electronic address: jamsteve@med.wayne.edu.
authors: James
authors: J
authors: Stevenson
authors: Department of Pathology, Beijing Luhe Hospital, Capital Medical University, China. Electronic address: yjj197651@sina.com.
authors: Jianjie
authors: J
authors: Yang
authors: Department of Clinical Laboratory, Beijing Luhe Hospital, Capital Medical University, China. Electronic address: yincb26@163.com.
authors: Changbin
authors: C
authors: Yin
authors: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, China. Electronic address: fengwulijlu@126.com.
authors: Fengwu
authors: F
authors: Li
authors: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, China. Electronic address: 13901314157@126.com.
authors: Sainan
authors: S
authors: Wang
authors: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, China; Department of Neurology, Beijing Luhe Hospital, Capital Medical University, China. Electronic address: dhs13106@126.com.
authors: Huishan
authors: H
authors: Du
authors: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, China. Electronic address: jixunming@vip.163.com.
authors: Xunming
authors: X
authors: Ji
authors: Department of Anatomy and Cell Biology, Wayne State University School of Medicine, USA. Electronic address: jrafols@med.wayne.edu.
authors: Jose A
authors: JA
authors: Rafols
authors: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, China; Department of Neurosurgery, Wayne State University School of Medicine, USA; Department of Neurology, Beijing Luhe Hospital, Capital Medical University, China. Electronic address: xgeng@ccmu.edu.cn.
authors: Xiaokun
authors: X
authors: Geng
authors: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, China; Department of Neurosurgery, Wayne State University School of Medicine, USA. Electronic address: yding@med.wayne.edu.
authors: Yuchuan
authors: Y
authors: Ding
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D002784:Cholesterol / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D003251:Constriction, Pathologic / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D059305:Diet, High-Fat / Q000009:adverse effects; D019587:Dietary Supplements; D004195:Disease Models, Animal; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage*; D015850:Interleukin-6 / Q000378:metabolism; D002537:Intracranial Arteriosclerosis / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020768:Middle Cerebral Artery / Q000473:pathology; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D064286:ATP Binding Cassette Transporter 1; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018932:Chemokine CCL2; D002784:Cholesterol; D015525:Fatty Acids, Omega-3; D015850:Interleukin-6; D056564:Sirtuin 1; D019010:Vascular Cell Adhesion Molecule-1; C577834:Abca1 protein, rat; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C491766:Ccl2 protein, rat; C488368:Sirt1 protein, rat
keywords: ATP-binding cassette transporter A1 (ABCA1); cholesterol; intracranial atherosclerosis; l-NAME; silent information regulator 1 (SIRT1)