Minocycline reduces spontaneous hemorrhage in mouse models of cerebral amyloid angiopathy.

Abstract

BACKGROUND AND PURPOSE:

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: Ping Yan, Alec Zhu, Fan Liao, Qingli Xiao, Andrew Kraft, Ernie Gonzales, Ron Perez, Steven M Greenberg, David Holtzman, Jin-Moo Lee
• Journal: Stroke (Stroke) Vol. 46 Issue 6 Pg. 1633-1640 (Jun 2015) ISSN: 1524-4628 [Electronic] United States
• PMID: 25944329 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Aif1 protein, mouse
• Anti-Bacterial Agents
• Calcium-Binding Proteins
• Glial Fibrillary Acidic Protein
• Microfilament Proteins
• Nerve Tissue Proteins
• S100 Calcium Binding Protein beta Subunit
• S100b protein, mouse
• glial fibrillary astrocytic protein, mouse
• NADPH Oxidase 4
• NADPH Oxidases
• Nox4 protein, mouse
• Leukocyte Common Antigens
• Ptprc protein, mouse
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse
• Minocycline

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Calcium-Binding Proteins (genetics, metabolism)
• Cerebral Amyloid Angiopathy (complications, drug therapy, genetics, metabolism, pathology)
• Cerebral Hemorrhage (etiology, genetics, metabolism, pathology, prevention & control)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Gene Expression Regulation (drug effects)
• Glial Fibrillary Acidic Protein
• Inflammation (drug therapy, genetics, metabolism, pathology)
• Leukocyte Common Antigens
• Matrix Metalloproteinase 9 (biosynthesis)
• Mice
• Mice, Transgenic
• Microfilament Proteins (genetics, metabolism)
• Minocycline (pharmacology)
• NADPH Oxidase 4
• NADPH Oxidases (biosynthesis)
• Nerve Tissue Proteins (genetics, metabolism)
• S100 Calcium Binding Protein beta Subunit (biosynthesis)