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I. G. Obrosova, Y. Maksimchyk, E. Agardh, M.-L. Smith, U. Julius, A. B. El-Remessy, C.-D. Agardh; Aldose Reductase Inhibition Counteracts Retinal Ischemia-Reperfusion Injury. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4703.
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© ARVO (1962-2015); The Authors (2016-present)
Evidence for the important role of increased activity of the sorbitol pathway of glucose metaboism in ischemia-reperfusion injury is emerging. We evaluated the effects of retinal ischemia-reperfusion injury and aldose reductase (AR) inhibition with the potent and specific AR inhibitor fidarestat (F) on apoptosis, aldose reductase (AR) and sorbitol dehydrogenase (SDH) protein expressions, sorbitol pathway intermediate concentrations, and oxidative-nitrosative stress.
The experiments were performed on female Wistar rats, body weight 200-250 g, divided into groups pre-treated with either vehicle (V, N-methyl-D-glucamine), or F. Both V and F were administered for 3 consecutive days at the dose of 32 mgkg-1d-1 i.v., via the right jugular vein. Part of V- and F-treated rats were subjected to 45-min retinal ischemia (I) followed by 24 h of reperfusion. Ischemia was induced 30 min after 3-d V or F administrations. Retinal changes were evaluated by immunohistochemistry, Western blot analysis, and enzymatic spectrofluorometric assays.
Retinal ischemia-reperfusion resulted in a remarkable increase in retinal cell dealth. The number of TUNEL-positive nuclei increased 48-fold in I+V compared with V (p < 0.01), and this increase was partially prevented in I+F (6-fold lower vs I+V, but still 8-fold higher than in V, p< 0.01 for both comparisons).AR protein expression was increased by 19% in I+V vs V (p < 0.05), and this increase was prevented by F. SDH and nitrated protein expressions were similar among the four groups. Retinal sorbitol concentrations tended to increase in I+V but the difference with V did not achieve statistical significance (p = 0.08). Retinal fructose concentrations were 2.2-fold greater in I+V vs V (p < 0.05). Pre-treatment with F of rats subjected to ischemia reduced retinal sorbitol concentration to the levels in V. Retinal fructose concentrations were reduced by 41% in I+F vs I+V (p=0.0517), but remained 30% higher in I+F vs V.
Increased sorbitol pathway activity is implicated in retinal ischemia-reperfuison injury. Fidarestat suppresses ischemia-reperfusion related retinal cell death by mechanism(s) that involves inhibition of increased sorbitol pathway activity, but appears independent from oxidative-nitrosative stress. The results provide rationale for development of AR inhibitors for treatment of retinal ischemia-reperfusion injury.
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