Minocycline prevents retinal inflammation and vascular permeability following ischemia-reperfusion injury

Abstract

BackgroundMany retinal diseases are associated with vascular dysfunction accompanied by neuroinflammation. We examined the ability of minocycline (Mino), a tetracycline derivative with anti-inflammatory and neuroprotective properties, to prevent vascular permeability and inflammation following retinal ischemia-reperfusion (IR) injury, a model of retinal neurodegeneration with breakdown of the blood-retinal barrier (BRB).MethodsMale Sprague–Dawley rats were subjected to 45 min of pressure-induced retinal ischemia, with the contralateral eye serving as control. Rats were treated with Mino prior to and following IR. At 48 h after reperfusion, retinal gene expression, cellular inflammation, Evan’s blue dye leakage, tight junction protein organization, caspase-3 activation, and DNA fragmentation were measured. Cellular inflammation was quantified by flow-cytometric evaluation of retinal tissue using the myeloid marker CD11b and leukocyte common antigen CD45 to differentiate and quantify CD11b+/CD45low microglia, CD11b+/CD45hi myeloid leukocytes and CD11bneg/CD45hi lymphocytes. Major histocompatibility complex class II (MHCII) immunoreactivity was used to determine the inflammatory state of these cells.ResultsMino treatment significantly inhibited IR-induced retinal vascular permeability and disruption of tight junction organization. Retinal IR injury significantly altered mRNA expression for 21 of 25 inflammation- and gliosis-related genes examined. Of these, Mino treatment effectively attenuated IR-induced expression of lipocalin 2 (LCN2), serpin peptidase inhibitor clade A member 3 N (SERPINA3N), TNF receptor superfamily member 12A (TNFRSF12A), monocyte chemoattractant-1 (MCP-1, CCL2) and intercellular adhesion molecule-1 (ICAM-1). A marked increase in leukostasis of both myeloid leukocytes and lymphocytes was observed following IR. Mino treatment significantly reduced retinal leukocyte numbers following IR and was particularly effective in decreasing the appearance of MHCII+ inflammatory leukocytes. Surprisingly, Mino did not significantly inhibit retinal cell death in this model.ConclusionsIR induces a retinal neuroinflammation within hours of reperfusion characterized by inflammatory gene expression, leukocyte adhesion and invasion, and vascular permeability. Despite Mino significantly inhibiting these responses, it failed to block neurodegeneration.

Silybin reduces obliterated retinal capillaries in experimental diabetic retinopathy in rats

“…The concept of ICAM-1 inhibition has become a potential therapeutic strategy for the prevention of diabetic retinopathy (Joussen et al, 2001;Miyamoto et al, 1999). Some flavonoid compounds, such as hesperidin, trans-chalcone, and minocycline, were reported to possess properties to inhibit diabetic-induced (Lamoke et al, 2011) or ischemia-induced (Abcouwer et al, 2013;Shi et al, 2012) ICAM-1 expression in retina. Our immunofluorescence and Western blot analysis also clearly supported that silybin effectively inhibited the up-regulated ICAM-1 protein (Fig.…”

TLR4 regulates insulin-resistant proteins to increase apoptosis in the mouse retina

“…Retinal damage in type 2 diabetes results from insulin resistance [1]. There is ample evidence that inhibition of various inflammatory pathways can protect the diabetic retina [2–5]. A key question then arises, is there a common link between insulin resistance and inflammation?…”

Angiogenic and Inflammatory Vitreous Biomarkers Associated With Increasing Levels of Retinal Ischemia

“…One nonglucocorticoid and nonmolecular approach could be the use of minocycline, which has recently been investigated for its anti-inflammatory properties in the retina during ischemiareperfusion and branch retinal vein occlusion (BRVO) via the inhibition of microglial activation and apoptosis inhibition. 58,59 Minocycline has also been shown to reduce many of the side effects of diabetic ischemic disease thought to be associated with the aforementioned inflammatory cascade. 60,61 Specifically targeting inflammatory cytokines, whether through any of the above mechanisms, may yield improved clinical outcomes in severe ischemic disease.…”