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Salicylate-Based Anti-Inflammatory Drugs Inhibit the Early Lesion of Diabetic Retinopathy

¹ Department of Medicine, Case Western Reserve University, Cleveland, Ohio
² Department of Ophthalmology, Case Western Reserve University, Cleveland, Ohio
³ Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio

Address correspondence and reprint requests to Timothy S. Kern, PhD, Department of Medicine and Ophthalmology, 434 Biomedical Research Building, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. E-mail: tsk{at}case.edu

Abbreviations: C/EBP, CCAAT enhancer binding protein; COX, cyclooxygenase; DTT, dithiothreitol; EMSA, electrophoretic mobility shift assay; GCL, ganglion cell layer; ICAM, intracellular adhesion molecule; HPLC, high-performance liquid chromatography; INL, inner nuclear layer; iNOS, inducible nitric oxide synthase; NF-B, nuclear factor-B; PMSF, phenylmethylsulfonyl fluoride; TUNEL, transferase-mediated dUTP nick-end labeling; VCAM, vascular cell adhesion molecule

It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-B (NF-B). Diabetes of 9–10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2–4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-B DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-B) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-B, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. Salicylates, in doses administrated in our experiments, inhibited NF-B and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy.

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