Abstract
The purpose of this study was to investigate the effects of minocycline on alkali burn-induced corneal neovascularization (CNV). A total of 105 mice treated with alkali burns were randomly divided into three groups to receive intraperitoneal injections of either phosphate buffered saline (PBS) or minocycline twice a day (60 mg/kg or 30 mg/kg) for 14 consecutive days. The area of CNV and corneal epithelial defects was measured on day 4, 7, 10, and14 after alkali burns. On day 14, a histopathological examination was performed to assess morphological change and the infiltration of polymorphonuclear neutrophils (PMNs). The mRNA expression levels of vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), basic fibroblast growth factor (bFGF), matrix metalloproteinases (MMPs), interleukin-1α, 1β, 6 (IL-1α, IL-1β, IL-6) were analyzed using real-time quantitative polymerase chain reaction. The expression of MMP-2 and MMP-9 proteins was determined by gelatin zymography. In addition, enzyme-linked immunosorbent assay was used to analyze the protein levels of VEGFR1, VEGFR2, IL-1β and IL-6. Minocycline at a dose of 60 mg/kg or 30 mg/kg significantly enhanced the recovery of the corneal epithelial defects more than PBS did. There were significant decreases of corneal neovascularization in the group of high-dosage minocycline compared with the control group at all checkpoints. On day 14, the infiltrated PMNs was reduced, and the mRNA expression of VEGFR1, VEGFR2, bFGF, IL-1β, IL-6, MMP-2, MMP-9, -13 as well as the protein expression of VEGFR2, MMP-2, -9, IL-1β, IL-6 in the corneas were down-regulated with the use of 60 mg/kg minocycline twice a day. Our results showed that the intraperitoneal injection of minocycline (60 mg/kg b.i.d.) can significantly inhibit alkali burn-induced corneal neovascularization in mice, possibly by accelerating corneal wound healing and by reducing the production of angiogenic factors, inflammatory cytokines and MMPs.
Highlights
Corneal neovascularization (CNV) is a sight-threatening condition usually associated with inflammatory or infectious disorders of the ocular surface
The area of corneal neovascularization (CNV) increased over time in all three groups, while shorter and fewer new corneal vessels were found in the highdosage group than in the other groups at every checkpoint (Fig. 1A)
The results showed that the recovery of corneal epithelial defect was faster in the minocycline-treated groups
Summary
Corneal neovascularization (CNV) is a sight-threatening condition usually associated with inflammatory or infectious disorders of the ocular surface. It was just demonstrated successful in inhibiting tumorinduced rabbit CNV [13] Both doxycycline and minocycline have similar effects on inhibiting human aortic smooth muscle cell migration, Yao’s experiments showed that minocycline seemed to have more versatile effects because it inhibited MMPs and down-regulated ERK1/2 and Akt pathways [14].minocycline can readily cross the blood–brain barrier with a rate of at least fivefold higher than doxycycline in rodents [15]. In order to determine whether these multi-targets of minocycline will function in alkali burned-induced CNV, we treated mice with intraperitoneal minocycline in this study
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