title: Minocycline reduces spontaneous hemorrhage in mouse models of cerebral amyloid angiopathy.
abstract: OBJECTIVE
  Cerebral amyloid angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine whether spontaneous intracerebral hemorrhage could be reduced.
  
  
  METHODS
  Tg2576 (n=16) and 5xFAD/ApoE4 knockin mice (n=16), aged 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, IP) or saline every other day for 2 months. Brains were extracted and stained with X-34 (to quantify amyloid), Perls' blue (to quantify hemorrhage), and immunostained to examined β-amyloid peptide load, gliosis (glial fibrillary acidic protein [GFAP], Iba-1), and vascular markers of blood-brain barrier integrity (zonula occludins-1 [ZO-1] and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes.
  
  
  RESULTS
  Minocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5xFAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (matrix metalloproteinase-9, NOX4, CD45, S-100b, and Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls.
  
  
  CONCLUSIONS
  Minocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in 2 different mouse models of CAA, supporting the importance of matrix metalloproteinase-related and inflammatory pathways in intracerebral hemorrhage pathogenesis. As a Food and Drug Administration-approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related intracerebral hemorrhage.
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Yan
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Alec
authors.initials: A
authors.lastname: Zhu
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Liao
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Qingli
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kraft
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ernie
authors.initials: E
authors.lastname: Gonzales
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Perez
authors.affiliation: Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: David
authors.initials: D
authors.lastname: Holtzman
authors.affiliation: Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jin-Moo
authors.initials: JM
authors.lastname: Lee
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016657:Cerebral Amyloid Angiopathy / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017493:Leukocyte Common Antigens; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit / Q000096:biosynthesis
chemical_list: C491049:Aif1 protein, mouse; D000900:Anti-Bacterial Agents; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D064568:S100 Calcium Binding Protein beta Subunit; C579159:S100b protein, mouse; C528900:glial fibrillary astrocytic protein, mouse; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D008911:Minocycline
keywords: apolipoproteins E; cerebral amyloid angiopathy; cerebral hemorrhage; gliosis; matrix metalloproteinase-9; minocycline