Effects of a Novel Aldose Reductase Inhibitor, Fidarestat (SNK-860), on Vibration Perception Threshold and Subjective Symptoms in Patients with Diabetic Polyneuropathy

Hotta, Nigishi; Yasuda, Keigo; Y, Sumita; Sano, Takahisa; Kakuta, Hironobu; Nagashima, Makoto; Hayashi, Yoshinori; Yamamoto, Masahiro; Wakao, Takaaki; Okuyama, Makio; Kobayashi, Masato; Mori, Kouichi

doi:10.2165/00044011-200424110-00006

Cited by 15 publications

(14 citation statements)

References 19 publications

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“…The results, consistent with previous reports on the alleviation of diabetic complications with fidarestat treatment (63)(64)(65)(66), support a pathogenetic, rather than protective, role for increased aldose reductase activity in diabetic cataractogenesis and early retinopathy, and provide a rationale for the development of aldose reductase inhibitors, and, in particular, fidarestat, for their prevention and treatment.…”

Section: Discussionsupporting

confidence: 90%

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

Drel

Pacher²,

Ali³

et al. 2008

Int J Mol Med

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Abstract. This study was aimed at evaluating the potent and specific aldose reductase inhibitor fidarestat, on diabetesassociated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis. Control and streptozotocin-diabetic rats were treated with or without fidarestat (16 mg kg -1 d -1 ) for 10 weeks after an initial 2-week period without treatment. Lens changes were evaluated by indirect ophthalmoscopy and portable slit lamp. Nitrotyrosine, poly(ADP-ribose), and glial fibrillary acidic protein expression were assessed by immunohistochemistry. The rate of apoptosis was quantified in flat-mounted retinas by TUNEL assay with immunoperoxidase staining. To dissect the effects of high glucose exposure in retinal microvascular cells, primary bovine retinal pericytes and endothelial cells were cultured in 5 or 30 mM glucose, with or without fidarestat (10 μM) for 3-14 days. Apoptosis was assessed by TUNEL assay, nitrotyrosine and poly(ADP-ribose) by immunocytochemistry, and Bax and Bcl-2 expression by Western blot analyses. Fidarestat treatment prevented diabetic cataract formation and counteracted retinal nitrosative stress, and poly(ADP-ribose) polymerase activation, as well as glial activation. The number of TUNEL-positive nuclei (mean ± SEM) was increased approximately 4-fold in diabetic rats vs. controls (207±33 vs. 49±4, p<0.01), and this increase was partially prevented by fidarestat (106±34, p<0.05 vs. untreated diabetic group). The apoptotic cell number increased with the prolongation of exposure of both pericytes and endothelial cells to high glucose levels. Fidarestat counteracted nitrotyrosine and poly(ADP-ribose) accumulation and apoptosis in both cell types. Antiapoptotic effect of fidarestat in high glucose-exposed retinal pericytes was not associated with the inhibition of Bax or increase in Bcl-2 expression. In conclusion, the findings, i) support an important role for aldose reductase in diabetes-associated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis, and ii) provide a rationale for the development of aldose reductase inhibitors, and, in particular, fidarestat, for the prevention and treatment of diabetic ocular complications.

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Section: Discussionsupporting

confidence: 90%

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

Drel

Pacher²,

Ali³

et al. 2008

Int J Mol Med

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“…In addition, neuropathological lesions characterized by reduced axonal area (atrophy) of the peripheral meylinated nerve fibers have been reported in STZ-diabetic rats (14,22,23). Axonal deformity (decreased circularity index) due to Fig.…”

Section: Discussionmentioning

confidence: 96%

Long-Term Treatment With Ranirestat (AS-3201), a Potent Aldose Reductase Inhibitor, Suppresses Diabetic Neuropathy and Cataract Formation in Rats

et al. 2008

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Abstract. We investigated the chronic functional and histopathological changes in the sciatic nerve and lens of streptozotocin (STZ)-diabetic rats and evaluated the preventive effects of ranirestat (AS-3201), a potent aldose reductase inhibitor, on these changes. Sorbitol levels in the sciatic nerve and lens, motor nerve conduction velocity (MNCV), and development of cataracts were measured in STZ-diabetic rats given a ranirestat-admixed diet (0.0005%) for 35 weeks. Ranirestat reduced sorbitol accumulation in the sciatic nerve and improved the decrease in MNCV of STZ-diabetic rats. Morphological and morphometric examination of changes in sural nerve revealed that treatment with ranirestat prevented both the deformity of myelinated fibers and the decrease in their axonal and myelin areas (atrophy). Ranirestat also averted the changes in the size frequency histogram of myelinated fibers. Finally, STZ-diabetic rats developed early lens opacities 8 weeks after STZ injection and had cataract by the end of the experimental period. However, in the ranirestat-treated diabetic rats, no lens opacity was observed in any rat throughout the entire experimental period. This study suggests that the polyol pathway plays an important role in the progress of diabetic neuropathy and cataract formation in STZ-diabetic rats. Ranirestat should be a promising agent for the treatment of complications associated with diabetes, especially neuropathy.

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“…Short-term treatment with fidarestat (28 weeks) remarkably improved performance in arm and leg VPT (30), an indicator of sensory nerve disturbance (31). Raniresat also improved VPT at the first toe following 60 weeks of treatment (29).…”

Section: Safetymentioning

confidence: 99%

Long-Term Clinical Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Peripheral Neuropathy

Hotta

Akanuma²,

Kawamori³

et al. 2006

Diabetes Care

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322

164

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RESEARCH DESIGN AND METHODS -Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) Ն40 m/s, and HbA 1c Յ9% were enrolled in this open-label, multicenter study and randomized to 150 mg/day epalrestat or a control group. After excluding the withdrawals, 289 (epalrestat group) and 305 (control group) patients were included in the analyses. The primary end point was change from baseline in median MNCV at 3 years. Secondary end points included assessment of other somatic nerve function parameters (minimum F-wave latency [MFWL] of the median motor nerve and vibration perception threshold [VPT]), cardiovascular autonomic nerve function, and subjective symptoms.RESULTS -Over the 3-year period, epalrestat prevented the deterioration of median MNCV, MFWL, and VPT seen in the control group. The between-group difference in change from baseline in median MNCV was 1.6 m/s (P Ͻ 0.001). Although a benefit with epalrestat was observed in cardiovascular autonomic nerve function variables, this did not reach statistical significance compared with the control group. Numbness of limbs, sensory abnormality, and cramping improved significantly with epalrestat versus the control group. The effects of epalrestat on median MNCV were most evident in subjects with better glycemic control and with no or mild microangiopathies.CONCLUSIONS -Long-term treatment with epalrestat is well tolerated and can effectively delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease, particularly in subjects with good glycemic control and limited microangiopathy.

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Effects of a Novel Aldose Reductase Inhibitor, Fidarestat (SNK-860), on Vibration Perception Threshold and Subjective Symptoms in Patients with Diabetic Polyneuropathy

Cited by 15 publications

References 19 publications

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

Long-Term Treatment With Ranirestat (AS-3201), a Potent Aldose Reductase Inhibitor, Suppresses Diabetic Neuropathy and Cataract Formation in Rats

Long-Term Clinical Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Peripheral Neuropathy

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