Effect of the aldose reductase inhibitor fidarestat on experimental diabetic neuropathy in the rat

Kuzumoto, Yoshimasa; Kusunoki, Susumu; Kato, Noriaki; Kihara, Mikihiro; Low, Phillip A.

doi:10.1007/s00125-006-0400-7

Cited by 33 publications

(20 citation statements)

References 34 publications

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“…The observations are in accordance to the previous findings implicating lowered GSH levels in diabetes (Kuzumoto et al, 2006;Arora et al, 2008). Furthermore, abnormal GSH metabolism in diabetes may also enhance TNF-α expression (Sagara et al, 1994).…”

Section: Discussionsupporting

confidence: 92%

Protective effect of oryzanol isolated from crude rice bran oil in experimental model of diabetic neuropathy

Ghatak¹,

Panchal²

2012

Rev. bras. farmacogn.

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Several studies have implicated the involvement of poor glycemic control and oxidative/nitrosative stress in the development of diabetic neuropathic pain, an important microvascular complication affecting more than 50% of diabetic patients. However, lack of understanding of the underlying etiology, development of tolerance, inadequate relief and possible toxicity associated with classical analgesics warrant the investigation of the novel agents. Therefore, the present study was carried out to investigate the effect of oryzanol (OZ), a commercially-important potent antioxidant component isolated from from crude rice bran oil (cRBO), in streptozotocin (STZ)-induced diabetic neuropathy in rats. After eight weeks, diabetic rats developed neuropathy which was evident from decreased tail-flick latency (thermal hyperalgesia) and increased nociceptive behavior during the formalin test. This was accompanied by decreased motor coordination based on the evaluation of neuromuscular strength. Na + K + ATPase, a biochemical marker associated with the development of diabetic neuropathy, was significantly inhibited in the sciatic nerve of diabetic animals. The activities of antioxidant enzymes and lipid peroxidation levels were significantly elevated in diabetic rats, indicating the involvement of oxidative stress in diabetic neuropathy. Chronic treatment with oryzanol (OZ) (50 and 100 mg/kg) per oral (p.o.) and standard drug glibenclamide (Gl) (10 mg/ kg, p.o.) significantly attenuated the behavioral as well as biochemical changes associated with diabetic neuropathy. The findings provide experimental evidence to the protective effects of OZ on hyperglycemia-induced thermal hyperalgesia and oxidative stress which might be responsible for diabetes induced nerve damage.

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Section: Discussionsupporting

confidence: 92%

Protective effect of oryzanol isolated from crude rice bran oil in experimental model of diabetic neuropathy

Ghatak¹,

Panchal²

2012

Rev. bras. farmacogn.

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“…Fidarestat suppressed the increase in sorbitol and fructose, normalised reduced glutathione in sciatic nerve, and reduced the number of 8-hydroxy-2'-deoxyguanosine-positive cells in dorsal root ganglion neurons. This indicates that the fidarestat-improved neuropathy may be via an improvement in oxidative stress and supports a role for fidarestat in the treatment of diabetic neuropathy [95].…”

Section: Fidarestatsupporting

confidence: 57%

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

Zhu¹

2013

Diabetes Mellitus - Insights and Perspectives

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“…Furthermore, AR activation has been linked to multiple biochemical changes in tissue-sites for DPN including, but not limited to, mitochondrial and cytosolic NAD + /NADH redox imbalances and energy deficiency [8], oxidative-nitrosative stress [8,27,33–35], nerve growth factor deficit [54], activation or inhibition of PKC [12,51], and PARP [28,33], COX-2 [55], and p38 MAPK [14] activation. The relationship between AR and several of these biochemical alterations, and, in particular, oxidative-nitrosative stress, PKC inhibition as well as PARP and p38 MAPK activation has been described for DRG neurons [14,28,34,51]. …”

Section: Discussionmentioning

confidence: 99%

Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy

Stavniichuk

Shevalye

Hirooka³

et al. 2012

Biochemical Pharmacology

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The interactions among multiple pathogenetic mechanisms of diabetic peripheral neuropathy largely remain unexplored. Increased activity of aldose reductase, the first enzyme of the sorbitol pathway, leads to accumulation of cytosolic Ca++, essentially required for 12/15-lipoxygenase activation. The latter, in turn, causes oxidative-nitrosative stress, an important trigger of MAPK phosphorylation. This study therefore evaluated the interplay of aldose reductase, 12/15-lipoxygenase, and MAPKs in diabetic peripheral neuropathy. In experiment 1, male control and streptozotocin-diabetic mice were maintained with or without the aldose reductase inhibitor fidarestat, 16 mg kg−1 d−1, for 12 weeks. In experiment 2, male control and streptozotocin-diabetic wild-type (C57Bl6/J) and 12/15-lipoxygenase-deficient mice were used. Fidarestat treatment did not affect diabetes-induced increase in glucose concentrations, but normalized sorbitol and fructose concentrations (enzymatic spectrofluorometric assays) as well as 12(S) hydroxyeicosatetraenoic concentration (ELISA), a measure of 12/15-lipoxygenase activity, in the sciatic nerve and spinal cord. 12/15-lipoxygenase expression in these two tissues (Western blot analysis) as well as dorsal root ganglia (immunohistochemistry) was similarly elevated in untreated and fidarestat-treated diabetic mice. 12/15-lipoxygenase gene deficiency prevented diabetesassociated p38 MAPK and ERK, but not SAPK/JNK, activation in the sciatic nerve (Western blot analysis) and all three MAPK activation in the dorsal root ganglia (immunohistochemistry). In contrast, spinal cord p38 MAPK, ERK, and SAPK/JNK were similarly activated in diabetic wild-type and 12/15-lipoxygenase−/− mice. These findings identify the nature and tissue specificity of interactions among three major mechanisms of diabetic peripheral neuropathy, and suggest that combination treatments, rather than monotherapies, can sometimes be an optimal choice for its management.

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Effect of the aldose reductase inhibitor fidarestat on experimental diabetic neuropathy in the rat

Cited by 33 publications

References 34 publications

Protective effect of oryzanol isolated from crude rice bran oil in experimental model of diabetic neuropathy

Protective effect of oryzanol isolated from crude rice bran oil in experimental model of diabetic neuropathy

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy

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