Effect of an aldose reductase inhibitor, SNK‐860, on deficits in the electroretinogram of diabetic rats

Hotta, Nigishi; Koh, Naoki; Sakakibara, Fumihiko; Nakamura, Jiro; Hamada, Yoji; Naruse, Keiji; Sasaki, Hodaka; Mizuno, Kazuo; Matsubara, Akiko; Kakuta, Hironobu

doi:10.1113/expphysiol.1995.sp003909

Cited by 10 publications

(7 citation statements)

References 31 publications

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“…Therefore, we can conclude from these preliminary studies that the ERG changes are associated with AR activity and sorbitol accumulation. Similar inhibition of AR in diabetic rats with either fiderestat (SNK-860) or TAT has also been reported to ameliorate ERG changes in b-wave oscillatory potentials [61], [62].…”

Section: Discussionmentioning

confidence: 59%

Novel Diabetic Mouse Models as Tools for Investigating Diabetic Retinopathy

et al. 2012

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ObjectiveMouse models possessing green fluorescent protein (GFP) and/or human aldose reductase (hAR) in vascular tissues have been established and crossed with naturally diabetic Akita mice to produce new diabetic mouse models.Research Design and MethodsColonies of transgenic C57BL mice expressing GFP (SMAA-GFP), hAR (SMAA-hAR) or both (SMAA-GFP-hAR) in vascular tissues expressing smooth muscle actin were established and crossbred with C57BL/6-Ins2Akita/J (AK) mice to produce naturally diabetic offspring AK-SMAA-GFP and AK-SMAA-GFP-hAR. Aldose reductase inhibitor AL1576 (ARI) was administered in chow. Retinal and lenticular sorbitol levels were determined by HPLC. Retinal functions were evaluated by electroretinography (ERGs). Growth factor and signaling changes were determined by Western Blots using commercially available antibodies. Retinal vasculatures were isolated from the neural retina by enzymatic digestion. Flat mounts were stained with PAS-hematoxylin and analyzed.ResultsAkita transgenics developed DM by 8 weeks of age with blood glucose levels higher in males than females. Sorbitol levels were higher in neural retinas of AK-SMAA-GFP-hAR compared to AK-SMAA-GFP mice. AK-SMAA-GFP-hAR mice also had higher VEGF levels and reduced ERG scotopic b-wave function, both of which were normalized by AL1576. AK-SMAA-GFP-hAR mice showed induction of the retinal growth factors bFGF, IGF-1, and TGFβ, as well as signaling changes in P-Akt, P-SAPK/JNK and P-44/42 MAPK that were also reduced by ARI treatment. Quantitative analysis of flat mounts in 18 week AK-SMAA-GFP-hAR mice revealed increased loss of nuclei/capillary length and a significant increase in the percentage of acellular capillaries present which was not seen in AK-SMAA-GFP-hAR treated with ARI.Conclusions/SignificanceThese new mouse models of early onset diabetes may be valuable tools for assessing both the role of hyperglycemia and AR in the development of retinal lesions associated with diabetic retinopathy.

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Section: Discussionmentioning

confidence: 59%

Novel Diabetic Mouse Models as Tools for Investigating Diabetic Retinopathy

et al. 2012

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“…The ERG b-wave is known to be related to Mü ller cell, bipolar cell, amacrine cell and ganglion cell function. 23,24 Amacrine cell-generated OPs consist of four-to-six wavelets that are present on the rising phase of the bwave. 25 OPs arise in the IPL, and are reflective of inner retinal functioning.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen-Rich Saline Prevents Early Neurovascular Dysfunction Resulting from Inhibition of Oxidative Stress in STZ-Diabetic Rats

Feng¹,

Wang

et al. 2012

Current Eye Research

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“…The present study explored the clinical utility of a novel AR inhibitor, fidarestat (SNK-860; Sanwa Kagaku Kenkyusho, Nagoya, Japan) (5)(6)(7)(8)(9)(10)(11)(12), in patients with diabetic neuropathy. In animal models of diabetic neuropathy, fidarestat was demonstrated to be one of the most potent AR inhibitors yet identified.…”

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confidence: 99%

Clinical Efficacy of Fidarestat, a Novel Aldose Reductase Inhibitor, for Diabetic Peripheral Neuropathy

Hotta

Toyota²,

Matsuoka³

et al. 2001

Diabetes Care

211

112

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A 52-week multicenter placebo-controlled double-blind parallel group study OBJECTIVE -The purpose of this study was to evaluate the efficacy of fidarestat, a novel aldose reductase (AR) inhibitor, in a double-blind placebo controlled study in patients with type 1 and type 2 diabetes and associated peripheral neuropathy.RESEARCH DESIGN AND METHODS -A total of 279 patients with diabetic neuropathy were treated with placebo or fidarestat at a daily dose of 1 mg for 52 weeks. The efficacy evaluation was based on change in electrophysiological measurements of median and tibial motor nerve conduction velocity, F-wave minimum latency, F-wave conduction velocity (FCV), and median sensory nerve conduction velocity (forearm and distal), as well as an assessment of subjective symptoms.RESULTS -Over the course of the study, five of the eight electrophysiological measures assessed showed significant improvement from baseline in the fidarestat-treated group, whereas no measure showed significant deterioration. In contrast, in the placebo group, no electrophysiological measure was improved, and one measure significantly deteriorated (i.e., median nerve FCV). At the study conclusion, the fidarestat-treated group was significantly improved compared with the placebo group in two electrophysiological measures (i.e., median nerve FCV and minimal latency). Subjective symptoms (including numbness, spontaneous pain, sensation of rigidity, paresthesia in the sole upon walking, heaviness in the foot, and hypesthesia) benefited from fidarestat treatment, and all were significantly improved in the treated versus placebo group at the study conclusion. At the dose used, fidarestat was well tolerated, with an adverse event profile that did not significantly differ from that seen in the placebo group.CONCLUSIONS -The effects of fidarestat-treatment on nerve conduction and the subjective symptoms of diabetic neuropathy provide evidence that this treatment alters the progression of diabetic neuropathy. Diabetes Care 24:1776 -1782, 2001D iabetic neuropathy is a degenerative disorder triggered by persistent hyperglycemia. The degenerative changes, consisting of axonal atrophy, demyelination, nerve fiber loss, and disordered nerve fiber repair, develop and progress even in the early stage of diabetes. Axonal atrophy, demyelination, and disordered repair can be clinically assessed as a decline in nerve conduction velocity. During hyperglycemia, nerve maturation secondary to nerve fiber loss is also disturbed. Abnormal excitement of these immaturely regenerated nerve fibers causes spontaneous pain, numbness, and paresthesia (1-3). In the majority of patients, these changes, characteristic of diabetic neuropathy, considerably deteriorate the quality of life.After the onset of subjective symptoms, only palliative treatments are currently available. Accordingly, early diagnosis and treatment before the onset of subjective symptoms is considered essential. Diabetic neuropathy is a long-term complication of diabetes that should not be underestimated, bec...

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Effect of an aldose reductase inhibitor, SNK‐860, on deficits in the electroretinogram of diabetic rats

Cited by 10 publications

References 31 publications

Novel Diabetic Mouse Models as Tools for Investigating Diabetic Retinopathy

Novel Diabetic Mouse Models as Tools for Investigating Diabetic Retinopathy

Hydrogen-Rich Saline Prevents Early Neurovascular Dysfunction Resulting from Inhibition of Oxidative Stress in STZ-Diabetic Rats

Clinical Efficacy of Fidarestat, a Novel Aldose Reductase Inhibitor, for Diabetic Peripheral Neuropathy

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