Therapeutic Effects of Aldose Reductase Inhibitor on Experimental Diabetic Neuropathy through Synthesis/Secretion of Nerve Growth Factor

T, Ohi; Saita, Kazuko; Furukawa, Shoei; Ohta, Mitsuhiro; Hayashi, Kyozo; Matsukura, Shigeru

doi:10.1006/exnr.1998.6821

Cited by 37 publications

(20 citation statements)

References 31 publications

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“…Early studies revealed that increased aldose reductase activity leads to sorbitol accumulation and resulting osmotic stress (16,36). Later, increased aldose reductase activity has also been found to result in a variety of biochemical abnormalities, including myo-inositol depletion and downregulation of Na/KATP-ase activity (32,37), NAD ϩ /NADH and NADP ϩ /NADPH redox imbalances (4,17), changes in fatty acid metabolism (38), impaired neurotrophic support (39), and upregulation of vascular endothelial growth factor (19). Some of these disturbances (myo-inositol depletion) are obviously related to and some [NAD(P) ϩ /NAD(P)H redox changes] are independent of intracellular osmotic stress.…”

Section: Resultsmentioning

confidence: 99%

Aldose Reductase Inhibition Counteracts Oxidative-Nitrosative Stress and Poly(ADP-Ribose) Polymerase Activation in Tissue Sites for Diabetes Complications

et al. 2005

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This study evaluated the effects of aldose reductase inhibition on diabetes-induced oxidative-nitrosative stress and poly(ADP-ribose) polymerase (PARP) activation. In animal experiments, control and streptozotocin-induced diabetic rats were treated with or without the aldose reductase inhibitor (ARI) fidarestat (16 mg ⅐ kg ؊1 ⅐ day ؊1 ) for 6 weeks starting from induction of diabetes. Sorbitol pathway intermediate, but not glucose, accumulation in sciatic nerve and retina was completely prevented in diabetic rats treated with fidarestat. Sciatic motor nerve conduction velocity, hindlimb digital sensory nerve conduction velocity, and sciatic nerve concentrations of two major nonenzymatic antioxidants, glutathione and ascorbate, were reduced in diabetic versus control rats, and these changes were prevented in diabetic rats treated with fidarestat. Fidarestat prevented the diabetes-induced increase in nitrotyrosine (a marker of peroxynitrite-induced injury) and poly(ADP-ribose) immunoreactivities in sciatic nerve and retina. Fidarestat counteracted increased superoxide formation in aorta and epineurial vessels and in in vitro studies using hyperglycemiaexposed endothelial cells, and the DCF test/flow cytometry confirmed the endothelial origin of this phenomenon. Fidarestat did not cause direct inhibition of PARP activity in a cell-free system containing PARP and NAD

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Section: Resultsmentioning

confidence: 99%

Aldose Reductase Inhibition Counteracts Oxidative-Nitrosative Stress and Poly(ADP-Ribose) Polymerase Activation in Tissue Sites for Diabetes Complications

et al. 2005

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“…Second, numerous findings suggest that increased AR activity is the major "upstream" mechanism that accounts for or provides the important contribution to numerous diabetes-induced abnormalities in peripheral nervous system and other tissue sites for diabetes complications. During the last 20 years, increased AR activity was found to result in myo-inositol depletion and decrease in Na ϩ /K ϩ ATP-ase activity (38), NAD ϩ / NADH redox changes (39), alterations in arachidonic acid metabolism (40), depletion of nerve growth factor and nerve growth factor-regulated neuropeptides (41,42), as well as ciliary neurotrophic factor (43), oxidative-nitrosative stress (44), and, recently, activation of mitogen- (4,5,19,39,46). Furthermore, several clinical trials with different AR inhibitors revealed that robust inhibition of the enzyme activity is accompanied by a statistically significant increase in nerve conduction velocity and myelinated fiber density, as well as improvement of subjective symptoms of PDN (including numbness, spontaneous pain, sensation of rigidity, paresthesia in the sole upon walking, heaviness in the foot, and hypesthesia) (47)(48)(49)(50).…”

Section: Diabetes Vol 55 December 2006mentioning

confidence: 99%

The Leptin-Deficient (ob/ob) Mouse

et al. 2006

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Whereas functional, metabolic, neurotrophic, and morphological abnormalities of peripheral diabetic neuropathy (PDN) have been extensively explored in streptozotocininduced diabetic rats and mice (models of type 1 diabetes), insufficient information is available on manifestations and pathogenetic mechanisms of PDN in type 2 diabetic models. The latter could constitute a problem for clinical trial design because the vast majority of subjects with diabetes have type 2 (non-insulin dependent) diabetes. This study was aimed at characterization of PDN in leptin-deficient (ob/ob) mice, a model of type 2 diabetes with relatively mild hyperglycemia and obesity. ob/ob mice (ϳ11 weeks old) clearly developed manifest sciatic motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable (ϳ78%) loss of intraepidermal nerve fibers. They also had increased sorbitol pathway activity in the sciatic nerve and increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion (DRG). Aldose reductase inhibition with fidarestat (16 mg ⅐ kg ؊1 ⅐ d ؊1 ), administered to ob/ob mice for 6 weeks starting from 5 weeks of age, was associated with preservation of normal MNCV and SNCV and alleviation of thermal hypoalgesia and intraepidermal nerve fiber loss but not tactile allodynia. Sciatic nerve nitrotyrosine immunofluorescence and the number of poly(ADP-ribose)-positive nuclei in sciatic nerve, spinal cord, and DRGs of fidarestattreated ob/ob mice did not differ from those in nondiabetic controls. In conclusion, the leptin-deficient ob/ob mouse is a new animal model that develops both large motor and sensory fiber and small sensory fiber PDN and responds to pathogenetic treatment. The results support the role for increased aldose reductase activity in functional and structural changes of PDN in type 2 diabetes. Diabetes 55: 3335-3343, 2006 P eripheral diabetic neuropathy (PDN) is a devastating complication of diabetes and a leading cause of foot amputation (1,2). Clinical indications of PDN include increased vibration and thermal perception thresholds that progress to sensory loss, occurring in conjunction with degeneration of all fiber types in the peripheral nerve. A proportion of patients with PDN also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain that sometimes coexist with loss of normal sensory function (3). Functional, metabolic, neurotrophic, and morphological abnormalities of PDN have extensively been explored in animal models of type 1 diabetes and, in particular, in streptozotocin-induced diabetic rats (4 -8) and mice (9,10). In contrast, manifestations and pathogenetic mechanisms of PDN in type 2 diabetic models remain remarkably understudied despite the fact that the vast majority of subjects with diabetes have type 2 (non-insulin dependent) diabetes.The epidemic of obesity in the developed countries is driving a ...

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“…As far as diabetic neuropathy is concerned, the role of polyol pathway hyperactivity has been most extensively investigated using different ARIs (22). The beneficial effect of ARIs on the development of diabetic neuropathy has been reported in diabetic animals (23)(24)(25)(26), and many clinical trials of ARIs on autonomic as well as somatic neuropathy have been performed, as summarized by Pfeifer et al (27). However, the efficacy of ARIs on human diabetic neuropathy has not been clearly established.…”

Section: Somatic Nerve Functionsmentioning

confidence: 99%

Aldose Reductase Inhibition Ameliorates Pupillary Light Reflex and F-Wave Latency in Patients With Mild Diabetic Neuropathy

et al. 2001

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OBJECTIVE -The present study was conducted to investigate the effect of an aldose reductase inhibitor, epalrestat, on autonomic and somatic neuropathy at an early stage in type 2 diabetic patients by assessing the pupillary light reflex and minimum latency of the F-wave. RESEARCH DESIGN AND METHODS-A total of 30 diabetic patients with subclinical or mild diabetic neuropathy were randomly allocated to a control group (n ϭ 15) and epalrestat (150 mg/day) group (n ϭ 15). After 24 weeks, the pupillary light reflex test, cardiovascular autonomic function tests, and nerve conduction study were performed.RESULTS -The beneficial effect of epalrestat on the pupillary light reflex was observed in the minimum diameter after light stimuli (P ϭ 0.044), constriction ratio (P ϭ 0.014), and maximum velocity of constriction (P ϭ 0.008). Among cardiovascular autonomic nerve functions, the ratio of the longest expiratory R-R interval to the shortest inspiratory R-R interval during deep breathing was significantly improved by epalrestat (P ϭ 0.037). Minimum latencies of F-wave of median and tibial motor nerves were significantly shortened by epalrestat (P ϭ 0.002 and P ϭ 0.001, respectively); however, no significant effects were observed in motor or sensory nerve conduction velocity.CONCLUSIONS -These observations suggest that epalrestat may have therapeutic value at the early stage of diabetic neuropathy and that the pupillary light reflex and minimum latency of F-wave may be useful indicators of diabetic neuropathy. Diabetes Care 24:1093-1098, 2001D iabetic neuropathy is generally classified into somatic and autonomic neuropathy. Although somatic neuropathy can be characterized by symptoms such as numbness, paresthesia, and abnormal sensation, the symptoms of autonomic neuropathy do not appear until the advanced stage.Diabetic autonomic neuropathy causes functional disorders of many organs, such as cardiovascular, gastrointestinal, genitourinary, metabolic, and pupillary dysfunctions. Among these, cardiovascular autonomic neuropathy may increase the risk of sudden death and affects the mortality of diabetic patients (1,2). Therefore, the diagnosis and treatment of autonomic neuropathy at an early stage is important for the management of diabetic patients.It is well known that diabetic autonomic neuropathy develops within a short duration of diabetes even when somatic neuropathy is not apparent (3,4). Furthermore, the abnormalities in pupillary functions can be detected earlier than those in cardiovascular autonomic functions and are considered the earliest signs of diabetic autonomic neuropathy (5-10). Therefore, the pupillary light reflex test has been used for evaluating diabetic autonomic neuropathy.It has been demonstrated that strict glycemic control can decrease the incidence of diabetic complications, including autonomic neuropathy (11). However, it is impossible to completely prevent the development of diabetic complications by glycemic control alone, except by performing a pancreas transplantation. Therefore, different t...

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Therapeutic Effects of Aldose Reductase Inhibitor on Experimental Diabetic Neuropathy through Synthesis/Secretion of Nerve Growth Factor

Cited by 37 publications

References 31 publications

Aldose Reductase Inhibition Counteracts Oxidative-Nitrosative Stress and Poly(ADP-Ribose) Polymerase Activation in Tissue Sites for Diabetes Complications

Aldose Reductase Inhibition Counteracts Oxidative-Nitrosative Stress and Poly(ADP-Ribose) Polymerase Activation in Tissue Sites for Diabetes Complications

The Leptin-Deficient (ob/ob) Mouse

Aldose Reductase Inhibition Ameliorates Pupillary Light Reflex and F-Wave Latency in Patients With Mild Diabetic Neuropathy

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