title: The non-antibiotic properties of tetracyclines: clinical potential in ophthalmic disease.
abstract: BACKGROUND
  Beyond their decades of long use as broad-spectrum antibiotics, tetracyclines and their derivatives have been shown to exhibit non-antimicrobial properties including their ability to interact with matrix metalloproteinases (MMP), tissue inhibitors of MMPs, growth factors and cytokines. As such, they are capable of affecting inflammation, immunomodulation, cell proliferation, and angiogenesis. Although they have been used to treat a variety of conditions including acne, cutaneous sarcoid, and rheumatoid arthritis, amongst others, their use in treating ophthalmologic disease is in its infancy.
  
  
  METHODS
  A literature review on the role of non-antimicrobial properties of tetracyclines, semisynthetic tetracyclines, and chemically modified non-antibacterial tetracyclines (CMTs) and their clinical properties was performed. The effects of these compounds in relation to ophthalmic disease are presented.
  
  
  RESULTS
  Due to their non-antimicrobial properties, tetracyclines and their derivatives are capable of influencing a wide variety of ocular diseases in animal models. By affecting expression of MMP-9 and tumor necrosis factor (TNF)-α, these compounds decrease corneal permeability, improve corneal smoothness, and reduce meibomian gland dysfunction; this improves the tear film which in turn restores the optical quality of the tear film and cornea. Sterile corneal ulceration may be inhibited via anticollagenase activity; this has been demonstrated in both animal models and case reports. CMTs suppress cataractogenesis in a diabetic rat model, possibly by affecting MMPs. With respect to retinal disease, tetracyclines can inhibit both microglial-mediated cell death and retinal cell apoptosis as well as prevent retinal capillary damage via caspase inhibition thus preventing retinal neovascularization. Experimental choroidal neovascularization is reduced by inhibition of MMP-2 and MMP-9, elevation of pigment epithelial derived growth factor (PEDF), and reduction of vascular endothelial growth factor (VEGF) expression via Fas ligand.
  
  
  CONCLUSIONS
  Due to their non-antimicrobial properties, tetracyclines and their derivatives are capable of influencing a wide variety of ocular disease in animal models. Research suggests that they are able to reduce inflammation in the eyelid meibomian glands, improve optical clarity of the cornea, retard cataract formation, and limit ocular angiogenesis. They may have a role in treating the leading causes of vision loss: cataract, age-related macular degeneration, and diabetic retinopathy, all of which are anticipated to increase in incidence due to the aging population.
  
  
  CONCLUSIONS
  Tetracyclines, semisynthetic tetracyclines, and CMTs may have a role in the treatment of several important ophthalmologic diseases; however, further research is required, including prospective multicenter clinical trials.
authors.affiliation: State University of New York, Department of Ophthalmology, Health Science Center, Level 2, Room 152, Stony Brook, NY 11794, USA. tfederici@gmail.com
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Federici
mesh_terms: D000818:Animals; D061945:Caspase Inhibitors; D016207:Cytokines / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005128:Eye Diseases / Q000188:drug therapy*; D005136:Eye Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D015843:Serpins; D013754:Tetracyclines / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D061945:Caspase Inhibitors; D016207:Cytokines; D004791:Enzyme Inhibitors; D005136:Eye Proteins; D061965:Matrix Metalloproteinase Inhibitors; D009414:Nerve Growth Factors; D009569:Nitric Oxide; D015843:Serpins; D013754:Tetracyclines; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor