Contributions of Inflammatory Processes to the Development of the Early Stages of Diabetic Retinopathy

Abstract

Diabetes causes metabolic and physiologic abnormalities in the retina, and these changes suggest a role for inflammation in the development of diabetic retinopathy. These changes include upregulation of iNOS, COX-2, ICAM-1, caspase 1, VEGF, and NF-κB, increased production of nitric oxide, prostaglandin E2, IL-1β, and cytokines, as well as increased permeability and leukostasis. Using selective pharmacologic inhibitors or genetically modified animals, an increasing number of therapeutic approaches have been identified that significantly inhibit development of at least the early stages of diabetic retinopathy, especially occlusion and degeneration of retinal capillaries. A common feature of a number of these therapies is that they inhibit production of inflammatory mediators. The concept that localized inflammatory processes play a role in the development of diabetic retinopathy is relatively new, but evidence that supports the hypothesis is accumulating rapidly. This new hypothesis offers new insight into the pathogenesis of diabetic retinopathy, and offers novel targets to inhibit the ocular disease.

References

1. A. A. Sima, W.-X. Zhang, P. V. Cherian, and S. Chakrabarti, “Impaired visual evoked potential and primary axonopathy of the optic nerve in the diabetic BB/W-rat,” Diabetologia, vol. 35, no. 7, pp. 602–607, 1992. View at: Publisher Site | Google Scholar
2. M. Kamijo, P. V. Cherian, and A. A. F. Sima, “The preventive effect of aldose reductase inhibition on diabetic optic neuropathy in the BB/W-rat,” Diabetologia, vol. 36, no. 10, pp. 893–898, 1993. View at: Publisher Site | Google Scholar
3. H. P. Hammes, H. J. Federoff, and M. Brownlee, “Nerve growth factor prevents both neuroretinal programmed cell death and capillary pathology in experimental diabetes,” Molecular Medicine, vol. 1, no. 5, pp. 527–534, 1995. View at: Google Scholar
4. A. J. Barber, E. Lieth, S. A. Khin, D. A. Antonetti, A. G. Buchanan, and T. W. Gardner, “Neural apoptosis in the retina during experimental and human diabetes: early onset and effect of insulin,” Journal of Clinical Investigation, vol. 102, no. 4, pp. 783–791, 1998. View at: Google Scholar
5. X.-X. Zeng, Y.-K. Ng, and E.-A. Ling, “Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats,” Visual Neuroscience, vol. 17, no. 3, pp. 463–471, 2000. View at: Publisher Site | Google Scholar
6. E. Lieth, T. W. Gardner, A. J. Barber, and D. A. Antonetti, “Retinal neurodegeneration: early pathology in diabetes,” Clinical and Experimental Ophthalmology, vol. 28, no. 1, pp. 3–8, 2000. View at: Publisher Site | Google Scholar
7. Y. Aizu, K. Oyanagi, J. Hu, and H. Nakagawa, “Degeneration of retinal neuronal processes and pigment epithelium in the early stage of the streptozotocin-diabetic rats,” Neuropathology, vol. 22, no. 3, pp. 161–170, 2002. View at: Publisher Site | Google Scholar
8. V. Asnaghi, C. Gerhardinger, T. Hoehn, A. Adeboje, and M. Lorenzi, “A role for the polyol pathway in the early neuroretinal apoptosis and glial changes induced by diabetes in the rat,” Diabetes, vol. 52, no. 2, pp. 506–511, 2003. View at: Publisher Site | Google Scholar
9. S.-H. Park, J.-W. Park, S.-J. Park et al., “Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina,” Diabetologia, vol. 46, no. 9, pp. 1260–1268, 2003. View at: Publisher Site | Google Scholar
10. L. L. Kusner, V. P. Sarthy, and S. Mohr, “Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase: a role in high glucose-induced apoptosis in retinal Müller cells,” Investigative Ophthalmology & Visual Science, vol. 45, no. 5, pp. 1553–1561, 2004. View at: Publisher Site | Google Scholar
11. P. M. Martin, P. Roon, T. K. Van Ells, V. Ganapathy, and S. B. Smith, “Death of retinal neurons in streptozotocin-induced diabetic mice,” Investigative Ophthalmology & Visual Science, vol. 45, no. 9, pp. 3330–3336, 2004. View at: Publisher Site | Google Scholar
12. X. Ning, Q. Baoyu, L. Yuzhen, S. Shuli, E. Reed, and Q. Q. Li, “Neuro-optic cell apoptosis and microangiopathy in KKAY mouse retina,” International Journal of Molecular Medicine, vol. 13, no. 1, pp. 87–92, 2004. View at: Google Scholar
13. M. Seki, T. Tanaka, H. Nawa et al., “Involvement of brain-derived neurotrophic factor in early retinal neuropathy of streptozotocin-induced diabetes in rats: therapeutic potential of brain-derived neurotrophic factor for dopaminergic amacrine cells,” Diabetes, vol. 53, no. 9, pp. 2412–2419, 2004. View at: Publisher Site | Google Scholar
14. R. A. Feit-Leichman, R. Kinouchi, M. Takeda et al., “Vascular damage in a mouse model of diabetic retinopathy: relation to neuronal and glial changes,” Investigative Ophthalmology & Visual Science, vol. 46, no. 11, pp. 4281–4287, 2005. View at: Publisher Site | Google Scholar
15. D. Gaucher, J.-A. Chiappore, M. Pâques et al., “Microglial changes occur without neural cell death in diabetic retinopathy,” Vision Research, vol. 47, no. 5, pp. 612–623, 2007. View at: Publisher Site | Google Scholar
16. E. Lieth, A. J. Barber, B. Xu et al., “Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy,” Diabetes, vol. 47, no. 5, pp. 815–820, 1998. View at: Publisher Site | Google Scholar
17. M. Mizutani, C. Gerhardinger, and M. Lorenzi, “Müller cell changes in human diabetic retinopathy,” Diabetes, vol. 47, no. 3, pp. 445–449, 1998. View at: Publisher Site | Google Scholar
18. A. J. Barber, D. A. Antonetti, T. W. Gardner et al., “Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes,” Investigative Ophthalmology & Visual Science, vol. 41, no. 11, pp. 3561–3568, 2000. View at: Google Scholar
19. E. Rungger-Brändle, A. A. Dosso, and P. M. Leuenberger, “Glial reactivity, an early feature of diabetic retinopathy,” Investigative Ophthalmology & Visual Science, vol. 41, no. 7, pp. 1971–1980, 2000. View at: Google Scholar
20. E. Agardh, A. Bruun, and C.-D. Agardh, “Retinal glial cell immunoreactivity and neuronal cell changes in rats with STZ-induced diabetes,” Current Eye Research, vol. 23, no. 4, pp. 276–284, 2001. View at: Publisher Site | Google Scholar
21. T. S. Kern, C. M. Miller, Y. Du et al., “Topical administration of nepafenac inhibits diabetes-induced retinal microvascular disease and underlying abnormalities of retinal metabolism and physiology,” Diabetes, vol. 56, no. 2, pp. 373–379, 2007. View at: Publisher Site | Google Scholar
22. Y. Shirao and K. Kawasaki, “Electrical responses from diabetic retina,” Progress in Retinal and Eye Research, vol. 17, no. 1, pp. 59–76, 1998. View at: Publisher Site | Google Scholar
23. Q. Li, E. Zemel, B. Miller, and I. Perlman, “Early retinal damage in experimental diabetes: electroretinographical and morphological observations,” Experimental Eye Research, vol. 74, no. 5, pp. 615–625, 2002. View at: Publisher Site | Google Scholar
24. H. A. Hancock and T. W. Kraft, “Oscillatory potential analysis and ERGs of normal and diabetic rats,” Investigative Ophthalmology & Visual Science, vol. 45, no. 3, pp. 1002–1008, 2004. View at: Publisher Site | Google Scholar
25. G. R. Barile, S. I. Pachydaki, S. R. Tari et al., “The RAGE axis in early diabetic retinopathy,” Investigative Ophthalmology & Visual Science, vol. 46, no. 8, pp. 2916–2924, 2005. View at: Publisher Site | Google Scholar
26. J. A. Phipps, P. Yee, E. L. Fletcher, and A. J. Vingrys, “Rod photoreceptor dysfunction in diabetes: activation, deactivation, and dark adaptation,” Investigative Ophthalmology & Visual Science, vol. 47, no. 7, pp. 3187–3194, 2006. View at: Publisher Site | Google Scholar
27. P. G. Winyard and D. R. Blake, “Antioxidants, redox-regulated transcription factors, and inflammation,” Advances in Pharmacology, vol. 38, pp. 403–421, 1997. View at: Google Scholar
28. D. Jourd'heuil, Z. Morise, E. M. Conner, and M. B. Grisham, “Oxidants, transcription factors, and intestinal inflammation,” Journal of Clinical Gastroenterology, vol. 25, 1, pp. S61–S72, 1997. View at: Publisher Site | Google Scholar
29. I. Rahman, “Oxidative stress, transcription factors and chromatin remodelling in lung inflammation,” Biochemical Pharmacology, vol. 64, no. 5-6, pp. 935–942, 2002. View at: Publisher Site | Google Scholar
30. L. Escoubet-Lozach, C. K. Glass, and S. I. Wasserman, “The role of transcription factors in allergic inflammation,” Journal of Allergy and Clinical Immunology, vol. 110, no. 4, pp. 553–564, 2002. View at: Publisher Site | Google Scholar
31. V. J. Quagliarello, B. Wispelwey, W. J. Long Jr., and W. M. Scheld, “Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat: characterization and comparison with tumor necrosis factor,” Journal of Clinical Investigation, vol. 87, no. 4, pp. 1360–1366, 1991. View at: Google Scholar
32. R. A. Kowluru and S. Odenbach, “Role of interleukin-1$\beta$ in the pathogenesis of diabetic retinopathy,” British Journal of Ophthalmology, vol. 88, no. 10, pp. 1343–1347, 2004. View at: Publisher Site | Google Scholar
33. Y. Du, V. P. Sarthy, and T. S. Kern, “Interaction between NO and COX pathways in retinal cells exposed to elevated glucose and retina of diabetic rats,” American Journal of Physiology, vol. 287, pp. R735–R741, 2004. View at: Publisher Site | Google Scholar
34. J. A. Vincent and S. Mohr, “Inhibition of caspase-1/interleukin-1$\beta$ signaling prevents degeneration of retinal capillaries in diabetes and galactosemia,” Diabetes, vol. 56, no. 1, pp. 224–230, 2007. View at: Publisher Site | Google Scholar
35. S. Schroder, W. Palinski, and G. W. Schmid-Schonbein, “Activated monocytes and granulocytes, capillary nonperfusion, and neovascularization in diabetic retinopathy,” American Journal of Pathology, vol. 139, no. 1, pp. 81–100, 1991. View at: Google Scholar
36. A. G. Harris, T. C. Skalak, and D. L. Hatchell, “Leukocyte-capillary plugging and network resistance are increased in skeletal muscle of rats with streptozotocin-induced hyperglycemia,” International Journal of Microcirculation, Clinical and Experimental, vol. 14, no. 3, pp. 159–166, 1994. View at: Google Scholar
37. D. L. Hatchell, C. A. Wilson, and P. Saloupis, “Neutrophils plug capillaries in acute experimental retinal ischemia,” Microvascular Research, vol. 47, no. 3, pp. 344–354, 1994. View at: Publisher Site | Google Scholar
38. K. Miyamoto, S. Khosrof, S.-E. Bursell et al., “Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 19, pp. 10836–10841, 1999. View at: Publisher Site | Google Scholar
39. A. Nonaka, J. Kiryu, A. Tsujikawa et al., “PKC-$ß$ inhibitor (LY333531) attenuates leukocyte entrapment in retinal microcirculation of diabetic rats,” Investigative Ophthalmology & Visual Science, vol. 41, no. 9, pp. 2702–2706, 2000. View at: Google Scholar
40. A. M. Joussen, T. Murata, A. Tsujikawa, B. Kirchhof, S.-E. Bursell, and A. P. Adamis, “Leukocyte-mediated endothelial cell injury and death in the diabetic retina,” American Journal of Pathology, vol. 158, no. 1, pp. 147–152, 2001. View at: Google Scholar
41. A. M. Joussen, V. Poulaki, N. Mitsiades et al., “Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-$a$ suppression,” The FASEB Journal, vol. 16, no. 3, pp. 438–440, 2002. View at: Publisher Site | Google Scholar
42. N. Kinoshita, A. Kakehashi, S. Inoda et al., “Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide,” Diabetologia, vol. 45, no. 5, pp. 735–739, 2002. View at: Publisher Site | Google Scholar
43. F. Mori, T. Hikichi, T. Nagaoka, J. Takahashi, N. Kitaya, and A. Yoshida, “Inhibitory effect of losartan, an AT1 angiotensin II receptor antagonist, on increased leucocyte entrapment in retinal microcirculation of diabetic rats,” British Journal of Ophthalmology, vol. 86, no. 10, pp. 1172–1174, 2002. View at: Publisher Site | Google Scholar
44. T. C. Moore, J. E. Moore, Y. Kaji et al., “The role of advanced glycation end products in retinal microvascular leukostasis,” Investigative Ophthalmology & Visual Science, vol. 44, no. 10, pp. 4457–4464, 2003. View at: Publisher Site | Google Scholar
45. R. Tadayoni, M. Paques, A. Gaudric, and E. Vicaut, “Erythrocyte and leukocyte dynamics in the retinal capillaries of diabetic mice,” Experimental Eye Research, vol. 77, no. 4, pp. 497–504, 2003. View at: Publisher Site | Google Scholar
46. A. M. Joussen, V. Poulaki, M. L. Le et al., “A central role for inflammation in the pathogenesis of diabetic retinopathy,” The FASEB Journal, vol. 18, no. 12, pp. 1450–1452, 2004. View at: Publisher Site | Google Scholar
47. H. Tamura, K. Miyamoto, J. Kiryu et al., “Intravitreal injection of corticosteroid attenuates leukostasis and vascular leakage in experimental diabetic retina,” Investigative Ophthalmology & Visual Science, vol. 46, no. 4, pp. 1440–1444, 2005. View at: Publisher Site | Google Scholar
48. L. W. Kelly, C. A. Barden, J. S. Tiedeman, and D. L. Hatchell, “Alterations in viscosity and filterability of whole blood and blood cell subpopulations in diabetic cats,” Experimental Eye Research, vol. 56, no. 3, pp. 341–347, 1993. View at: Publisher Site | Google Scholar
49. D. J. Lefer, D. S. McLeod, C. Merges, and G. A. Lutty, “Immunolocalization of ICAM-1 (CD54) in the posterior eye of sickle cell and diabetic patients,” Investigative Ophthalmology & Visual Science, vol. 34, p. 1206, 1993. View at: Google Scholar
50. D. Boeri, M. Maiello, and M. Lorenzi, “Increased prevalence of microthromboses in retinal capillaries of diabetic individuals,” Diabetes, vol. 50, no. 6, pp. 1432–1439, 2001. View at: Publisher Site | Google Scholar
51. D. A. Antonetti, A. J. Barber, S. Khin et al., “Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells,” Diabetes, vol. 47, no. 12, pp. 1953–1959, 1998. View at: Publisher Site | Google Scholar
52. D. A. Antonetti, E. Lieth, A. J. Barber, and T. W. Gardner, “Molecular mechanisms of vascular permeability in diabetic retinopathy,” Seminars in Ophthalmology, vol. 14, no. 4, pp. 240–248, 1999. View at: Google Scholar
53. J. L. Wilkinson-Berka, “Vasoactive factors and diabetic retinopathy: vascular endothelial growth factor, cycoloxygenase-2 and nitric oxide,” Current Pharmaceutical Design, vol. 10, no. 27, pp. 3331–3348, 2004. View at: Publisher Site | Google Scholar
54. N. S. Harhaj, E. A. Felinski, E. B. Wolpert, J. M. Sundstrom, T. W. Gardner, and D. A. Antonetti, “VEGF activation of protein kinase C stimulates occludin phosphorylation and contributes to endothelial permeability,” Investigative Ophthalmology & Visual Science, vol. 47, no. 11, pp. 5106–5115, 2006. View at: Publisher Site | Google Scholar
55. A. Carmo, J. G. Cunha-Vaz, A. P. Carvalho, and M. C. Lopes, “Nitric oxide synthase activity in retinas from non-insulin-dependent diabetic Goto-Kakizaki rats: correlation with blood-retinal barrier permeability,” Nitric Oxide, vol. 4, no. 6, pp. 590–596, 2000. View at: Publisher Site | Google Scholar
56. A. M. Joussen, V. Poulaki, A. Tsujikawa et al., “Suppression of diabetic retinopathy with angiopoietin-1,” American Journal of Pathology, vol. 160, no. 5, pp. 1683–1693, 2002. View at: Google Scholar
57. A. B. El-Remessy, M. A. Behzadian, G. Abou-Mohamed, T. Franklin, R. W. Caldwell, and R. B. Caldwell, “Experimental diabetes causes breakdown of the blood-retina barrier by a mechanism involving tyrosine nitration and increases in expression of vascular endothelial growth factor and urokinase plasminogen activator receptor,” American Journal of Pathology, vol. 162, no. 6, pp. 1995–2004, 2003. View at: Google Scholar
58. X. Xu, Q. Zhu, X. Xia, S. Zhang, Q. Gu, and D. Luo, “Blood-retinal barrier breakdown induced by activation of protein kinase C via vascular endothelial growth factor in streptozotocin-induced diabetic rats,” Current Eye Research, vol. 28, no. 4, pp. 251–256, 2004. View at: Publisher Site | Google Scholar
59. B. A. Berkowitz, R. Roberts, H. Luan, J. Peysakhov, X. Mao, and K. A. Thomas, “Dynamic contrast-enhanced MRI measurements of passive permeability through blood retinal barrier in diabetic rats,” Investigative Ophthalmology & Visual Science, vol. 45, no. 7, pp. 2391–2398, 2004. View at: Publisher Site | Google Scholar
60. R. G. Tilton, K. Chang, G. Pugliese et al., “Prevention of hemodynamic and vascular albumin filtration changes in diabetic rats by aldose reductase inhibitors,” Diabetes, vol. 38, no. 10, pp. 1258–1270, 1989. View at: Publisher Site | Google Scholar
61. L. P. Aiello, S.-E. Bursell, A. Clermont et al., “Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective $ß$-isoform-selective inhibitor,” Diabetes, vol. 46, no. 9, pp. 1473–1480, 1997. View at: Publisher Site | Google Scholar
62. R. G. Tilton, K. C. Chang, W. S. Lejeune, C. C. Stephan, T. A. Brock, and J. R. Williamson, “Role for nitric oxide in the hyperpermeability and hemodynamic changes induced by intravenous VEGF,” Investigative Ophthalmology & Visual Science, vol. 40, no. 3, pp. 689–696, 1999. View at: Google Scholar
63. K. Miyamoto, S. Khosrof, S.-E. Bursell et al., “Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1),” American Journal of Pathology, vol. 156, no. 5, pp. 1733–1739, 2000. View at: Google Scholar
64. M. Nakajima, M. J. Cooney, A. H. Tu et al., “Normalization of retinal vascular permeability in experimental diabetes with genistein,” Investigative Ophthalmology & Visual Science, vol. 42, no. 9, pp. 2110–2114, 2001. View at: Google Scholar
65. M. Takeda, F. Mori, A. Yoshida et al., “Constitutive nitric oxide synthase is associated with retinal vascular permeability in early diabetic rats,” Diabetologia, vol. 44, no. 8, pp. 1043–1050, 2001. View at: Publisher Site | Google Scholar
66. D. A. Antonetti, E. B. Wolpert, L. DeMaio, N. S. Harhaj, and R. C. Scaduto Jr., “Hydrocortisone decreases retinal endothelial cell water and solute flux coincident with increased content and decreased phosphorylation of occludin,” Journal of Neurochemistry, vol. 80, no. 4, pp. 667–677, 2002. View at: Publisher Site | Google Scholar
67. S. P. Ayalasomayajula and U. B. Kompella, “Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model,” European Journal of Pharmacology, vol. 458, no. 3, pp. 283–289, 2003. View at: Publisher Site | Google Scholar
68. M. Cukiernik, D. Hileeto, T. Evans, S. Mukherjee, D. Downey, and S. Chakrabarti, “Vascular endothelial growth factor in diabetes induced early retinal abnormalities,” Diabetes Research and Clinical Practice, vol. 65, no. 3, pp. 197–208, 2004. View at: Publisher Site | Google Scholar
69. K. Musashi, J. Kiryu, K. Miyamoto et al., “Thrombin inhibitor reduces leukocyte-endothelial cell interactions and vascular leakage after scatter laser photocoagulation,” Investigative Ophthalmology & Visual Science, vol. 46, no. 7, pp. 2561–2566, 2005. View at: Publisher Site | Google Scholar
70. K. Muranaka, Y. Yanagi, Y. Tamaki et al., “Effects of peroxisome proliferator-activated receptor $?$ and its ligand on blood-retinal barrier in a streptozotocin-induced diabetic model,” Investigative Ophthalmology & Visual Science, vol. 47, no. 10, pp. 4547–4552, 2006. View at: Publisher Site | Google Scholar
71. R. A. Kowluru, P. Koppolu, S. Chakrabarti, and S. Chen, “Diabetes-induced activation of nuclear transcriptional factor in the retina, and its inhibition by antioxidants,” Free Radical Research, vol. 37, no. 11, pp. 1169–1180, 2003. View at: Publisher Site | Google Scholar
72. L. Zheng, C. Szabó, and T. S. Kern, “Poly(ADP-ribose) polymerase is involved in the development of diabetic retinopathy via regulation of nuclear factor-$\kappa$B,” Diabetes, vol. 53, no. 11, pp. 2960–2967, 2004. View at: Publisher Site | Google Scholar
73. G. Romeo, W.-H. Liu, V. Asnaghi, T. S. Kern, and M. Lorenzi, “Activation of nuclear factor-$\kappa$B induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes,” Diabetes, vol. 51, no. 7, pp. 2241–2248, 2002. View at: Publisher Site | Google Scholar
74. L. Zheng, S. J. Howell, D. A. Hatala, K. Huang, and T. S. Kern, “Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy,” Diabetes, vol. 56, no. 2, pp. 337–345, 2007. View at: Publisher Site | Google Scholar
75. R. A. Kowluru, J. Tang, and T. S. Kern, “Abnormalities of retinal metabolism in diabetes and experimental galactosemia: VII. Effect of long-term administration of antioxidants on the development of retinopathy,” Diabetes, vol. 50, no. 8, pp. 1938–1942, 2001. View at: Publisher Site | Google Scholar
76. A. M. Abu El-Asrar, S. Desmet, A. Meersschaert, L. Dralands, L. Missotten, and K. Geboes, “Expression of the inducible isoform of nitric oxide synthase in the retinas of human subjects with diabetes mellitus,” American Journal of Ophthalmology, vol. 132, no. 4, pp. 551–556, 2001. View at: Publisher Site | Google Scholar
77. R. A. Kowluru, R. L. Engerman, G. L. Case, and T. S. Kern, “Retinal glutamate in diabetes and effect of antioxidants,” Neurochemistry International, vol. 38, no. 5, pp. 385–390, 2001. View at: Publisher Site | Google Scholar
78. Y. Du, M. A. Smith, C. M. Miller, and T. S. Kern, “Diabetes-induced nitrative stress in the retina, and correction by aminoguanidine,” Journal of Neurochemistry, vol. 80, no. 5, pp. 771–779, 2002. View at: Publisher Site | Google Scholar
79. A. do Carmo, C. Lopes, M. Santos, R. Proença, J. Cunha-Vaz, and A. P. Carvalho, “Nitric oxide synthase activity and $\text{L}$-arginine metabolism in the retinas from streptozotocin-induced diabetic rats,” General Pharmacology, vol. 30, no. 3, pp. 319–324, 1998. View at: Publisher Site | Google Scholar
80. R. A. Kowluru, R. L. Engerman, and T. S. Kern, “Abnormalities of retinal metabolism in diabetes or experimental galactosemia VIII. Prevention by aminoguanidine,” Current Eye Research, vol. 21, no. 4, pp. 814–819, 2000. View at: Publisher Site | Google Scholar
81. R. A. Kowluru, “Retinal metabolic abnormalities in diabetic mouse: comparison with diabetic rat,” Current Eye Research, vol. 24, no. 2, pp. 123–128, 2002. View at: Publisher Site | Google Scholar
82. R. A. Kowluru, “Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats,” Diabetes, vol. 52, no. 3, pp. 818–823, 2003. View at: Publisher Site | Google Scholar
83. A. M. Joussen, V. Poulaki, W. Qin et al., “Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo,” American Journal of Pathology, vol. 160, no. 2, pp. 501–509, 2002. View at: Google Scholar
84. J.-W. Park, S.-J. Park, S.-H. Park et al., “Up-regulated expression of neuronal nitric oxide synthase in experimental diabetic retina,” Neurobiology of Disease, vol. 21, no. 1, pp. 43–49, 2006. View at: Publisher Site | Google Scholar
85. R. G. Tilton, G. Pugliese, L. S. LaRose et al., “Discordant effects of the aldose reductase inhibitor, sorbinil, on vascular structure and function in chronically diabetic and galactosemic rats,” Journal of Diabetic Complications, vol. 5, no. 4, pp. 230–237, 1991. View at: Publisher Site | Google Scholar
86. J. A. Corbett, R. G. Tilton, K. Chang et al., “Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction,” Diabetes, vol. 41, no. 4, pp. 552–556, 1992. View at: Publisher Site | Google Scholar
87. K. Hasan, B.-J. Heesen, J. A. Corbett et al., “Inhibition of nitric oxide formation by guanidines,” European Journal of Pharmacology, vol. 249, no. 1-2, pp. 101–106, 1993. View at: Publisher Site | Google Scholar
88. T. P. Misko, W. M. Moore, T. P. Kasten et al., “Selective inhibition of the inducible nitric oxide synthase by aminoguanidine,” European Journal of Pharmacology, vol. 233, no. 1, pp. 119–125, 1993. View at: Publisher Site | Google Scholar
89. T. S. Kern and R. L. Engerman, “Pharmacological inhibition of diabetic retinopathy: aminoguanidine and aspirin,” Diabetes, vol. 50, no. 7, pp. 1636–1642, 2001. View at: Publisher Site | Google Scholar
90. H.-P. Hammes, S. Martin, K. Federlin, K. Geisen, and M. Brownlee, “Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 24, pp. 11555–11558, 1991. View at: Publisher Site | Google Scholar
91. H.-P. Hammes, M. Brownlee, D. Edelstein, M. Saleck, S. Martin, and K. Federlin, “Aminoguanidine inhibits the development of accelerated diabetic retinopathy in the spontaneous hypertensive rat,” Diabetologia, vol. 37, no. 1, pp. 32–35, 1994. View at: Google Scholar
92. T. S. Kern, J. Tang, M. Mizutani et al., “Response of capillary cell death to aminoguanidine predicts the development of retinopathy: comparison of diabetes and galactosemia,” Investigative Ophthalmology & Visual Science, vol. 41, no. 12, pp. 3972–3978, 2000. View at: Google Scholar
93. Y. Kobayashi and D. V. Maudsley, “Inhibition of histidine decarboxylase in rat stomach by aminoguanidine,” British Journal of Pharmacology, vol. 43, no. 2, p. 426P, 1971. View at: Google Scholar
94. M. Brownlee, H. Vlassara, A. Kooney, P. Ulrich, and A. Cerami, “Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking,” Science, vol. 232, no. 4758, pp. 1629–1632, 1986. View at: Publisher Site | Google Scholar
95. T. Rokkas, S. Vaja, G. M. Murphy, and R. H. Dowling, “Aminoguanidine blocks intestinal diamine oxidase (DAO) activity and enhances the intestinal adaptive response to resection in the rat,” Digestion, vol. 46, 2, pp. 447–457, 1990. View at: Google Scholar
96. P. Ou and S. P. Wolff, “Aminoguanidine: a drug proposed for prophylaxis in diabetes inhibits catalase and generates hydrogen peroxide in vitro,” Biochemical Pharmacology, vol. 46, no. 7, pp. 1139–1144, 1993. View at: Publisher Site | Google Scholar
97. G. Jerums, T. Soulis-Liparota, S. Panagiotopoulos, and M. E. Cooper, In vivo Effects of Aminoguanidine, Royal Society of Chemistry, Cambridge, UK, 1994.
98. J. R. Rumble, M. E. Cooper, T. Soulis et al., “Aminoguanidine attenuates mesenteric vascular hypertrophy and TGF-$ß$ 1 mRNA in diabetic rats,” Diabetologia, vol. 39, suupplement 1, p. A70, 1996. View at: Google Scholar
99. Y. Al-Abed and R. Bucala, “Efficient scavenging of fatty acid oxidation products by aminoguanidine,” Chemical Research in Toxicology, vol. 10, no. 8, pp. 875–879, 1997. View at: Publisher Site | Google Scholar
100. P. H. Yu and D. M. Zuo, “Aminoguanidine inhibits semicarbazide-sensitive amine oxidase activity: implications for advanced glycation and diabetic complications,” Diabetologia, vol. 40, no. 11, pp. 1243–1250, 1997. View at: Publisher Site | Google Scholar
101. L. Zheng, Y. Du, C. Miller et al., “Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes,” Diabetologia, vol. 50, no. 9, pp. 1987–1996, 2007. View at: Publisher Site | Google Scholar
102. N. Naveh-Floman, C. Weissman, and M. Belkin, “Arachidonic acid metabolism by retinas of rats with streptozotocin-induced diabetes,” Current Eye Research, vol. 3, no. 9, pp. 1135–1139, 1984. View at: Google Scholar
103. E. I. M. Johnson, M. E. Dunlop, and R. G. Larkins, “Increased vasodilatory prostaglandin production in the diabetic rat retinal vasculature,” Current Eye Research, vol. 18, no. 2, pp. 79–82, 1999. View at: Publisher Site | Google Scholar
104. S. P. Ayalasomayajula, A. C. Amrite, and U. B. Kompella, “Inhibition of cyclooxygenase-2, but not cyclooxygenase-1, reduces prostaglandin ${\text{E}}_2$ secretion from diabetic rat retinas,” European Journal of Pharmacology, vol. 498, no. 1–3, pp. 275–278, 2004. View at: Publisher Site | Google Scholar
105. S. Ishida, K. Yamashiro, T. Usui et al., “Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease,” Nature Medicine, vol. 9, no. 6, pp. 781–788, 2003. View at: Publisher Site | Google Scholar
106. A. J. Barber, D. A. Antonetti, T. S. Kern et al., “The $\text{Ins}{2}^{\text{Akita}}$ mouse as a model of early retinal complications in diabetes,” Investigative Ophthalmology & Visual Science, vol. 46, no. 6, pp. 2210–2218, 2005. View at: Publisher Site | Google Scholar
107. M. Lu, V. L. Perez, N. Ma et al., “VEGF increases retinal vascular ICAM-1 expression in vivo,” Investigative Ophthalmology & Visual Science, vol. 40, no. 8, pp. 1808–1812, 1999. View at: Google Scholar
108. A. K. Hubbard and R. Rothlein, “Intercellular adhesion molecule-1 (ICAM-1) expression and cell signaling cascades,” Free Radical Biology and Medicine, vol. 28, no. 9, pp. 1379–1386, 2000. View at: Publisher Site | Google Scholar
109. W. Chen, D. B. Jump, M. B. Grant, W. J. Esselman, and J. V. Busik, “Dyslipidemia, but not hyperglycemia, induces inflammatory adhesion molecules in human retinal vascular endothelial cells,” Investigative Ophthalmology & Visual Science, vol. 44, no. 11, pp. 5016–5022, 2003. View at: Publisher Site | Google Scholar
110. H. Sone, Y. Kawakami, Y. Okuda et al., “Ocular vascular endothelial growth factor levels in diabetic rats are elevated before observable retinal proliferative changes,” Diabetologia, vol. 40, no. 6, pp. 726–730, 1997. View at: Publisher Site | Google Scholar
111. C. Gerhardinger, L. F. Brown, S. Roy, M. Mizutani, C. L. Zucker, and M. Lorenzi, “Expression of vascular endothelial growth factor in the human retina and in nonproliferative diabetic retinopathy,” American Journal of Pathology, vol. 152, no. 6, pp. 1453–1462, 1998. View at: Google Scholar
112. Y. Segawa, Y. Shirao, S.-I. Yamagishi et al., “Upregulation of retinal vascular endothelial growth factor mRNAs in spontaneously diabetic rats without ophthalmoscopic retinopathy. A possible participation of advanced glycation end products in the development of the early phase of diabetic retinopathy,” Ophthalmic Research, vol. 30, no. 6, pp. 333–339, 1998. View at: Publisher Site | Google Scholar
113. M. J. Tolentino, J. W. Miller, E. S. Gragoudas et al., “Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate,” Ophthalmology, vol. 103, no. 11, pp. 1820–1828, 1996. View at: Google Scholar
114. M. J. Tolentino, D. S. McLeod, M. Taomoto, T. Otsuji, A. P. Adamis, and G. A. Lutty, “Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate,” American Journal of Ophthalmology, vol. 133, no. 3, pp. 373–385, 2002. View at: Publisher Site | Google Scholar
115. J. F. Arevalo, J. Fromow-Guerra, H. Quiroz-Mercado et al., “Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: results from the Pan-American Collaborative Retina Study Group at 6-month follow-up,” Ophthalmology, vol. 114, no. 4, pp. 743–750, 2007. View at: Publisher Site | Google Scholar
116. C. Starita, M. Patel, B. Katz, and A. P. Adamis, “Vascular endothelial growth factor and the potential therapeutic use of pegaptanib (macugen®) in diabetic retinopathy,” Developments in Ophthalmology, vol. 39, pp. 122–148, 2007. View at: Publisher Site | Google Scholar
117. R. Jorge, R. A. Costa, D. Calucci, L. P. Cintra, and I. U. Scott, “Intravitreal bevacizumab (Avastin) for persistent new vessels in diabetic retinopathy (IBEPE study),” Retina, vol. 26, no. 9, pp. 1006–1013, 2006. View at: Publisher Site | Google Scholar
118. E. W. M. Ng and A. P. Adamis, “Anti-VEGF aptamer (pegaptanib) therapy for ocular vascular diseases,” Annals of the New York Academy of Sciences, vol. 1082, pp. 151–171, 2006. View at: Publisher Site | Google Scholar
119. R. L. Avery, J. Pearlman, D. J. Pieramici et al., “Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy,” Ophthalmology, vol. 113, no. 10, pp. 1695–1705.e6, 2006. View at: Publisher Site | Google Scholar
120. J. O. Mason III, P. A. Nixon, and M. F. White, “Intravitreal Injection of bevacizumab (Avastin) as adjunctive treatment of proliferative diabetic retinopathy,” American Journal of Ophthalmology, vol. 142, no. 4, pp. 685–688, 2006. View at: Publisher Site | Google Scholar
121. A. P. Adamis, M. Altaweel, N. M. Bressler et al., “Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals,” Ophthalmology, vol. 113, no. 1, pp. 23–28, 2006. View at: Publisher Site | Google Scholar
122. R. A. Kowluru and S. Odenbach, “Role of interleukin-1$\beta$ in the development of retinopathy in rats: effect of antioxidants,” Investigative Ophthalmology & Visual Science, vol. 45, no. 11, pp. 4161–4166, 2004. View at: Publisher Site | Google Scholar
123. J. K. Krady, A. Basu, C. M. Allen et al., “Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy,” Diabetes, vol. 54, no. 5, pp. 1559–1565, 2005. View at: Publisher Site | Google Scholar
124. S. Mohr, A. Xi, J. Tang, and T. S. Kern, “Caspase activation in retinas of diabetic and galactosemic mice and diabetic patients,” Diabetes, vol. 51, no. 4, pp. 1172–1179, 2002. View at: Publisher Site | Google Scholar
125. A. B. El-Remessy, M. Al-Shabrawey, Y. Khalifa, N.-T. Tsai, R. B. Caldwell, and G. I. Liou, “Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes,” American Journal of Pathology, vol. 168, no. 1, pp. 235–244, 2006. View at: Publisher Site | Google Scholar
126. L. M. Le, V. Poulaki, K. Koizumi, S. Fauser, B. Kirchhof, and A. M. Joussen, “Reduced histopathological alterations in long-term diabetic TNF-R deficient mice,” Investigative Ophthalmology & Visual Science, vol. 44, 2, p. 3894, 2003. View at: Publisher Site | Google Scholar
127. C. Harada, A. Okumura, K. Namekata et al., “Role of monocyte chemotactic protein-1 and nuclear factor $?$B in the pathogenesis of proliferative diabetic retinopathy,” Diabetes Research and Clinical Practice, vol. 74, no. 3, pp. 249–256, 2006. View at: Publisher Site | Google Scholar
128. A. M. Joussen, V. Poulaki, N. Mitsiades et al., “Suppression of Fas-FasL-induced endothelial cell apoptosis prevents diabetic blood-retinal barrier breakdown in a model of streptozotocin-induced diabetes,” The FASEB Journal, vol. 17, no. 1, pp. 76–78, 2003. View at: Publisher Site | Google Scholar
129. J. Zhang, C. Gerhardinger, and M. Lorenzi, “Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy,” Diabetes, vol. 51, no. 12, pp. 3499–3504, 2002. View at: Publisher Site | Google Scholar
130. J. Acosta, J. Hettinga, R. Flückiger et al., “Molecular basis for a link between complement and the vascular complications of diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 10, pp. 5450–5455, 2000. View at: Publisher Site | Google Scholar
131. C. S. Davies, C. L. Harris, and B. P. Morgan, “Glycation of CD59 impairs complement regulation on erythrocytes from diabetic subjects,” Immunology, vol. 114, no. 2, pp. 280–286, 2005. View at: Publisher Site | Google Scholar
132. X. Qin, A. Goldfine, N. Krumrei et al., “Glycation inactivation of the complement regulatory protein CD59: a possible role in the pathogenesis of the vascular complications of human diabetes,” Diabetes, vol. 53, no. 10, pp. 2653–2661, 2004. View at: Publisher Site | Google Scholar
133. J. R. Gamble, J. Drew, and L. Trezise, “Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions,” Circulation Research, vol. 87, no. 7, pp. 603–607, 2000. View at: Google Scholar
134. S. Chakrabarti and A. A. F. Sima, “Effect of aldose reductase inhibition and insulin treatment on retinal capillary basement membrane thickening in BB rats,” Diabetes, vol. 38, no. 9, pp. 1181–1186, 1989. View at: Publisher Site | Google Scholar
135. R. A. Kowluru and S. Odenbach, “Effect of long-term administration of $\alpha$-lipoic acid on retinal capillary cell death and the development of retinopathy in diabetic rats,” Diabetes, vol. 53, no. 12, pp. 3233–3238, 2004. View at: Publisher Site | Google Scholar
136. H. P. Hammes, A. Bartmann, L. Engel, and P. Wülfroth, “Antioxidant treatment of experimental diabetic retinopathy in rats with nicanartine,” Diabetologia, vol. 40, no. 6, pp. 629–634, 1997. View at: Publisher Site | Google Scholar
137. H.-P. Hammes, X. Du, D. Edelstein et al., “Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy,” Nature Medicine, vol. 9, no. 3, pp. 294–299, 2003. View at: Publisher Site | Google Scholar
138. A. Bierhaus, D. M. Stern, and P. P. Nawroth, “RAGE in inflammation: a new therapeutic target?” Current Opinion in Investigational Drugs, vol. 7, no. 11, pp. 985–991, 2006. View at: Google Scholar
139. A. Goldin, J. A. Beckman, A. M. Schmidt, and M. A. Creager, “Advanced glycation end products: sparking the development of diabetic vascular injury,” Circulation, vol. 114, no. 6, pp. 597–605, 2006. View at: Publisher Site | Google Scholar
140. M. Alves, V. C. Calegari, D. A. Cunha, M. J. A. Saad, L. A. Velloso, and E. M. Rocha, “Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor $\kappa$B in lacrimal glands of diabetic rats,” Diabetologia, vol. 48, no. 12, pp. 2675–2681, 2005. View at: Publisher Site | Google Scholar
141. L. Gu, S. Hagiwara, Q. Fan et al., “Role of receptor for advanced glycation end-products and signalling events in advanced glycation end-product-induced monocyte chemoattractant protein-1 expression in differentiated mouse podocytes,” Nephrology Dialysis Transplantation, vol. 21, no. 2, pp. 299–313, 2006. View at: Publisher Site | Google Scholar
142. K.-M. Haslbeck, A. Bierhaus, S. Erwin et al., “Receptor for advanced glycation endproduct (RAGE)-mediated nuclear factor-$?$B activation in vasculitic neuropathy,” Muscle & Nerve, vol. 29, no. 6, pp. 853–860, 2004. View at: Publisher Site | Google Scholar
143. J. C. Mamputu and G. Renier, “Advanced glycation end-products increase monocyte adhesion to retinal endothelial\ cells through vascular endothelial growth factor-induced ICAM-1 expression: inhibitory effect of antioxidants,” Journal of Leukocyte Biology, vol. 75, no. 6, pp. 1062–1069, 2004. View at: Publisher Site | Google Scholar
144. R. Tammali, K. V. Ramana, S. S. Singhal, S. Awasthi, and S. K. Srivastava, “Aldose reductase regulates growth factor-induced cyclooxygenase-2 expression and prostaglandin ${\text{E}}_2$ production in human colon cancer cells,” Cancer Research, vol. 66, no. 19, pp. 9705–9713, 2006. View at: Publisher Site | Google Scholar
145. K. V. Ramana, B. Friedrich, S. Srivastava, A. Bhatnagar, and S. K. Srivastava, “Activation of nulcear factor-$\kappa$B by hyperglycemia in vascular smooth muscle cells is regulated by aldose reductase,” Diabetes, vol. 53, no. 11, pp. 2910–2920, 2004. View at: Publisher Site | Google Scholar
146. K. V. Ramana, A. Bhatnagar, and S. K. Srivastava, “Inhibition of aldose reductase attenuates TNF-$\alpha$-induced expression of adhesion molecules in endothelial cells,” The FASEB Journal, vol. 18, no. 11, pp. 1209–1218, 2004. View at: Publisher Site | Google Scholar
147. W. Sun, C. Gerhardinger, Z. Dagher, T. Hoehn, and M. Lorenzi, “Aspirin at low-intermediate concentrations protects retinal vessels in experimental diabetic retinopathy through non-platelet-mediated effects,” Diabetes, vol. 54, no. 12, pp. 3418–3426, 2005. View at: Publisher Site | Google Scholar
148. L. Zheng and T. S. Kern, “Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit development of early stages of diabetic retinopathy,” Diabetes, 2005, Abstract 929-P. View at: Google Scholar
149. J. J. Steinle, “Sympathetic neurotransmission modulates expression of inflammatory markers in the rat retina,” Experimental Eye Research, vol. 84, no. 1, pp. 118–125, 2007. View at: Publisher Site | Google Scholar
150. T. Abiko, A. Abiko, A. C. Clermont et al., “Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes: role of oxidants and protein kinase-C activation,” Diabetes, vol. 52, no. 3, pp. 829–837, 2003. View at: Publisher Site | Google Scholar
151. E. A. Felinski and D. A. Antonetti, “Glucocorticoid regulation of endothelial cell tight junction gene expression: novel treatments for diabetic retinopathy,” Current Eye Research, vol. 30, no. 11, pp. 949–957, 2005. View at: Publisher Site | Google Scholar
152. A. K. Dubey, “Intravitreal injection of triamcinolone acetonide for diabetic macular edema: principles and practice,” Indian Journal of Ophthalmology, vol. 54, no. 4, pp. 290–291, 2006. View at: Google Scholar
153. A. Ramezani, H. Ahmadieh, and H. Tabatabaei, “Intravitreal triamcinolone reinjection for refractory diabetic macular edema,” Korean Journal of Ophthalmology, vol. 20, no. 3, pp. 156–161, 2006. View at: Google Scholar
154. N. Miyamoto, D. Iossifov, F. Metge, and F. Behar-Cohen, “Early effects of intravitreal triamcinolone on macular edema: mechanistic implication,” Ophthalmology, vol. 113, no. 11, pp. 2048–2053, 2006. View at: Publisher Site | Google Scholar
155. J. B. Jonas, B. A. Kamppeter, B. Harder, U. Vossmerbaeumer, G. Sauder, and U. H. M. Spandau, “Intravitreal triamcinolone acetonide for diabetic macular edema: a prospective, randomized study,” Journal of Ocular Pharmacology and Therapeutics, vol. 22, no. 3, pp. 200–207, 2006. View at: Publisher Site | Google Scholar
156. J. B. Jonas, “Intravitreal triamcinolone acetonide for diabetic retinopathy,” Developments in Ophthalmology, vol. 39, pp. 96–110, 2007. View at: Publisher Site | Google Scholar
157. R. A. Greenwald and L. M. Golub, “Biologic properties of non-antibiotic, chemically modified tetracyclines (CMTs): as structured, annotated bibliography,” Current Medicinal Chemistry, vol. 8, no. 3, pp. 237–242, 2001. View at: Google Scholar
158. A. R. Amin, M. G. Attur, G. D. Thakker et al., “A novel mechanism of action of tetracyclines: effects on nitric oxide synthases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 24, pp. 14014–14019, 1996. View at: Publisher Site | Google Scholar
159. J. Yrjänheikki, T. Tikka, R. Keinänen, G. Goldsteins, P. H. Chan, and J. Koistinaho, “A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 23, pp. 13496–13500, 1999. View at: Publisher Site | Google Scholar
160. S. Zhu, I. G. Stavrovskaya, M. Drozda et al., “Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice,” Nature, vol. 417, no. 6884, pp. 74–78, 2002. View at: Publisher Site | Google Scholar
161. C. X. Wang, T. Yang, and A. Shuaib, “Effects of minocycline alone and in combination with mild hypothermia in embolic stroke,” Brain Research, vol. 963, no. 1-2, pp. 327–329, 2003. View at: Publisher Site | Google Scholar
162. R. Pi, W. Li, N. T. K. Lee et al., “Minocycline prevents glutamate-induced apoptosis of cerebellar granule neurons by differential regulation of p38 and Akt pathways,” Journal of Neurochemistry, vol. 91, no. 5, pp. 1219–1230, 2004. View at: Publisher Site | Google Scholar
163. R. M. Bonelli, A. K. Hödl, P. Hofmann, and H.-P. Kapfhammer, “Neuroprotection in Huntington’s disease: a 2-year study on minocycline,” International Clinical Psychopharmacology, vol. 19, no. 6, pp. 337–342, 2004. View at: Publisher Site | Google Scholar
164. P. A. LeWitt, “Clinical trials of neuroprotection for Parkinson’s disease,” Neurology, vol. 63, no. 7, supplement 2, pp. S23–S31, 2004. View at: Google Scholar
165. D. C. Baptiste, A. T. E. Hartwick, C. A. B. Jollimore, W. H. Baldridge, G. M. Seigel, and M. E. M. Kelly, “An investigation of the neuroprotective effects of tetracycline derivatives in experimental models of retinal cell death,” Molecular Pharmacology, vol. 66, no. 5, pp. 1113–1122, 2004. View at: Publisher Site | Google Scholar
166. N. Reynolds, “Revisiting safety of minocycline as neuroprotection in Huntington’s disease,” Movement Disorders, vol. 22, no. 2, p. 292, 2007. View at: Publisher Site | Google Scholar
167. H. F. Elewa, R. Hilali, D. C. Hess, L. S. Machado, and S. C. Fagan, “Minocycline for short-term neuroprotection,” Pharmacotherapy, vol. 26, no. 4, pp. 515–521, 2006. View at: Publisher Site | Google Scholar
168. A. Y. Lai and K. G. Todd, “Hypoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclines,” GLIA, vol. 53, no. 8, pp. 809–816, 2006. View at: Publisher Site | Google Scholar
169. J. Neumann, M. Gunzer, H. O. Gutzeit, O. Ullrich, K. G. Reymann, and K. Dinkel, “Microglia provide neuroprotection after ischemia,” The FASEB Journal, vol. 20, no. 6, pp. 714–716, 2006. View at: Publisher Site | Google Scholar
170. M. Chen, V. O. Ona, M. Li et al., “Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease,” Nature Medicine, vol. 6, no. 7, pp. 797–801, 2000. View at: Publisher Site | Google Scholar
171. M. Domercq and C. Matute, “Neuroprotection by tetracyclines,” Trends in Pharmacological Sciences, vol. 25, no. 12, pp. 609–612, 2004. View at: Publisher Site | Google Scholar
172. L. W. Ai, A. C. H. Yu, T. L. Lau et al., “Minocycline inhibits LPS-induced retinal microglia activation,” Neurochemistry International, vol. 47, no. 1-2, pp. 152–158, 2005. View at: Publisher Site | Google Scholar
173. K. Kojima, H. Matsubara, T. Harada et al., “Effects of aldose reductase inhibitor on retinal microangiopathy in streptozotocin-diabetic rats,” Japanese Journal of Ophthalmology, vol. 29, no. 1, pp. 99–109, 1985. View at: Google Scholar
174. W. Sun, P. J. Oates, J. B. Coutcher, C. Gerhardinger, and M. Lorenzi, “A selective aldose reductase inhibitor of a new structural class prevents or reverses early retinal abnormalities in experimental diabetic retinopathy,” Diabetes, vol. 55, no. 10, pp. 2757–2762, 2006. View at: Publisher Site | Google Scholar
175. Sorbinil Retinopathy Trial Research Group, “A randomized trial of sorbinil, an aldose reductase inhibitor, in diabetic retinopathy,” Archives of Ophthalmology, vol. 108, no. 9, pp. 1234–1244, 1990. View at: Google Scholar
176. C. Arauz-Pacheco, L. C. Ramirez, L. Pruneda, G. E. Sanborn, J. Rosenstock, and P. Raskin, “The effect of the aldose reductase inhibitor, ponalrestat, on the progression of diabetic retinopathy,” Journal of Diabetes and Its Complications, vol. 6, no. 2, pp. 131–137, 1992. View at: Publisher Site | Google Scholar
177. K. V. Ramana, M. S. Willis, M. D. White et al., “Endotoxin-induced cardiomyopathy and systemic inflammation in mice is prevented by aldose reductase inhibition,” Circulation, vol. 114, no. 17, pp. 1838–1846, 2006. View at: Publisher Site | Google Scholar
178. C. Li, Y. Xu, D. Jiang et al., “The expression of HIF-1 in the early diabetic NOD mice,” Yan Ke Xue Bao, vol. 22, no. 2, pp. 107–111, 2006. View at: Google Scholar
179. T. Yuuki, T. Kanda, Y. Kimura et al., “Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy,” Journal of Diabetes and Its Complications, vol. 15, no. 5, pp. 257–259, 2001. View at: Publisher Site | Google Scholar
180. M. Myśliwiec, K. Zorena, A. Balcerska, J. Myśliwska, P. Lipowski, and K. Raczyńska, “The activity of N-acetyl-beta-D-glucosaminidase and tumor necrosis factor-alpha at early stage of diabetic retinopathy development in type 1 diabetes mellitus children,” Clinical Biochemistry, vol. 39, no. 8, pp. 851–856, 2006. View at: Publisher Site | Google Scholar
181. N. Demircan, B. G. Safran, M. Soylu, A. A. Ozcan, and S. Sizmaz, “Determination of vitreous interleukin-1(IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy,” Eye, vol. 20, no. 12, pp. 1366–1369, 2006. View at: Publisher Site | Google Scholar
182. J.-M. González-Clemente, D. Mauricio, C. Richart et al., “Diabetic neuropathy is associated with activation of the TNF-$a$ system in subjects with type 1 diabetes mellitus,” Clinical Endocrinology, vol. 63, no. 5, pp. 525–529, 2005. View at: Publisher Site | Google Scholar
183. S. Doganay, C. Evereklioglu, H. Er et al., “Comparison of serum NO, TNF-$a$, IL-1$ß$, sIL-2R, IL-6 and IL-8 levels with grades of retinopathy in patients with diabetes mellitus,” Eye, vol. 16, no. 2, pp. 163–170, 2002. View at: Publisher Site | Google Scholar
184. G. Zoppini, G. Faccini, M. Muggeo, L. Zenari, G. Falezza, and G. Targher, “Elevated plasma levels of soluble receptors of TNF-$\alpha$ and their association with smoking and microvascular complications in young adults with type I diabetes,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 8, pp. 3805–3808, 2001. View at: Publisher Site | Google Scholar
185. J. Tang, S. Mohr, Y.-P. Du, and T. S. Kern, “Non-uniform distribution of lesions and biochemical abnormalities within the retina of diabetic humans,” Current Eye Research, vol. 27, no. 1, pp. 7–13, 2003. View at: Publisher Site | Google Scholar
186. C. Baudoin, P. Passa, P. Sharp, and E. Kohner, “Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy: a multicenter randomized controlled clinical trial,” Diabetes, vol. 38, no. 4, pp. 491–498, 1989. View at: Publisher Site | Google Scholar
187. Early Treatment Diabetic Retinopathy Research Group, “Effects of aspirin treatment on diabetic retinopathy,” Ophthalmol, vol. 98, 5, pp. 757–765, 1991. View at: Google Scholar

Copyright

Copyright © 2007 Timothy S. Kern. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.