Minocycline Reduces Spontaneous Hemorrhage in Mouse Models of Cerebral Amyloid Angiopathy. Issue 6 (June 2015)

• Record Type: Journal Article
• Authors: Yan, Ping; Zhu, Alec; Liao, Fan; Xiao, Qingli; Kraft, Andrew W.; Gonzales, Ernie; Perez, Ron; Greenberg, Steven M.; Holtzman, David M.; Lee, Jin-Moo
• Is Part Of: Stroke. Volume 46:Issue 6(2015)
• Publication Date: 2015-06
• Subjects: Cerebrovascular disease -- Periodicals; Cerebral circulation -- Periodicals; 616.81
• DOI: 10.1161/STROKEAHA.115.008582
• Languages: English
• ISSNs: 0039-2499

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background and Purpose—</title> <p>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.</p> </sec> <sec> <title>Methods—</title> <p>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.</p> </sec> <sec> <title>Results—</title> <p>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.</p> </sec> <sec> <title>Conclusions—</title> <p>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.</p> </sec> </abstract>