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Steven Abcouwer, Sumathi Shanmugam, Cheng-mao Lin, Heather Lindner, Alistair Barber, Arivalagan Muthusamy, David Antonetti; Minocycline Prevents Inflammatory Leukocyte Infiltration Following Retinal Ischemia-Reperfusion Injury. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3181.
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Retinal ischemia-reperfusion (IR) injury is an acute model of retinal neurodegeneration. The tetracycline derivative minocycline (Mino) exhibits anti-inflammatory and neuroprotective properties independent of its bacteriostatic function. We tested the ability of Mino to prevent the infiltration of leukocytes, neurodegeneration and gene expression changes following retinal IR injury.
Rats were treated with Mino by repeated intraperitoneal injection prior to and following IR. Retinas were made ischemic by elevation of intraocular pressure for 45 min and allowed to naturally reperfuse. Leukocyte infiltration was evaluated by flow cytometry of retinal cells after enzymatic-dissociation of pooled retinas, employing antibodies to the common leukocyte antigen CD45, the monocyte marker CD11b and major histocompatibility complex class II (MHC II). Microglia were identified as CD11b+/CD45low cells, invading monocytes and granulocytes as CD11b+/CD45high cells, and invading lymphocytes as CD11bneg/CD45high cells. Neuronal cell death and neurodegeneration was evaluated by caspase-3/7 activation, internucleosomal DNA cleavage and retinal layer thinning. Retinal mRNA expression was evaluated by qRT-PCR.
IR caused a marked and significant increase in the numbers of invading leukocytes present after 48 h of reperfusion, including those with high MHC class II expression indicative of an inflammatory and antigen presenting phenotype. Mino treatment inhibited the IR-induced infiltration of CD11b-positive and -negative leukocytes; this effect was greatest and most significant for MHC II-positive cells within each population (p<0.01). Surprisingly, Mino treatment had no effect on neuronal death or neurodegeneration following IR. Mino significantly inhibited the upregulation of several IR-responsive genes, including monocyte chemoattractant protein 1 (MCP-1, CCL2, p<0.05) and intracellular adhesion molecule 1 (ICAM-1, p<0.001).
Mino inhibited the infiltration of inflammatory leukocytes following IR injury and this effect was associated with prevention of neurodegeneration, but did coincide with inhibition of chemoattractant and adhesion molecule expression. Tetracycline derivatives may thus represent effective means to treat neural inflammation associated with retinal ischemic diseases by preventing the infiltration of inflammatory cells.
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