RESEARCH ARTICLE


Aldose Reductase Inhibitor Fidarestat Prevents Diabetic Ocular Complications in Spontaneously Diabetic Torii Rats



Akihiro Kakehashi*, 1, Mikiko Takezawa1, Fumihiko Toyoda1, Nozomi Kinoshita1, Chiho Kambara1, Hiroko Yamagami1, Noriaki Kato2, San-e Ishikawa3, Masanobu Kawakami3, Yasunori Kanazawa4
1 Department of Ophthalmology, Jichi Medical University, Saitama Medical Center, Japan.
2 Department of Pharmacology, Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Japan
3 Department of Integrated Medicine I, Jichi Medical University, Saitama Medical Center, Japan.
4 Japanese Diabetes Foundation, Tokyo, Japan.


© Kakehashi et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Ophthalmology, Jichi Medical University, Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama-shi, 330-8503, Japan. Tel: +81-48-647-2111; Fax: +81- 648-5188; E-mail: kakeaki@omiya.jichi.ac.jp


Abstract

We evaluated the effect of an aldose reductase inhibitor, fidarestat, on diabetic retinopathy (DR) and cataract in spontaneously diabetic Torii (SDT) rats. Four rat groups were included: untreated, low- and high-dose (8 and 32 mg/kg/day) fidarestat-treated SDT rats, and nondiabetic control Sprague-Dawley rats. DR and cataract were evaluated and retinal and lens sorbitol, reduced glutathione (GSH), ocular fluid vascular endothelial growth factor (VEGF), and urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG) was measured. The incidence rates of DR and cataract were significantly lower in the low- and high-dose fidarestat groups vs the untreated group (p<0.001/p<0.001). Retinal and lens sorbitol levels were lower in the control (1.1±0.1/3.1±0.2 nmol/mg protein) (p<0.05/p<0.01) and low- (2.7±1.1/30.0±3.3 nmol/mg protein) (p<0.01/p<0.01) and high-dose groups (0.7±0.2/5.9±0.6 nmol/mg protein) (p<0.001/p<0.001) vs the untreated group (23.2±4.7/123.9±29.6 nmol/mg protein). Retinal and lens GSH levels were higher in the nondiabetic control (52.2±5.8/29.0±2.7 􀀁mol/mg protein) (p<0.01/p<0.001) and the low- (46.8±8.2/24.7±2.8 􀀁mol/mg protein) (not significant (NS)/p<0.001) and high-dose groups (63.3±14.6/26.9±3.6 􀀁mol/mg protein) (p<0.05/p<0.001) vs the untreated group (30.3±2.0/1.6±0.4 􀀁mol/mg protein). VEGF levels were lower in the nondiabetic control (40.4±10.0 pg/ml) (p<0.01) and low- (65.3±4.5 pg/ml) (p<0.05) and high-dose groups (47.7±10 pg/ml) (p<0.001) vs the untreated group (324.7±76.4 pg/ml). 8-OHdG levels were lower in the nondiabetic control (0.73±0.11 ng/mg creatinine) (p<0.01) and low- (4.57±0.42 ng/mg creatinine) (NS) and high-dose groups (3.58±0.70 ng/mg creatinine) (NS) vs the untreated group (6.04±1.28 ng/ml). Fidarestat inhibited activation of the polyol pathway, reduced oxidative stress and VEGF, and prevented DR and cataract in SDT rats.

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