The pharmacology of diabetic neuropathy

Tomlinson, David R.

doi:10.1002/dmr.5610080107

Cited by 36 publications

(12 citation statements)

References 155 publications

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“…Over the years many studies from several laboratories have demonstrated the beneficial effects of different pharmacotherapeutic agents in experimental diabetic neuropathy (Tomlinson, 1992;Bravenboer et al, 1992;. The present study confirms and extends the results of previous STZdiabetic rat studies (Robertson et al, 1992;Kappelle et al, 1993a,b) in which Ca2" antagonists improved existing experimental diabetic neuropathy.…”

Section: Discussionsupporting

confidence: 90%

Beneficial effect of the Ca²⁺ antagonist, nimodipine, on existing diabetic neuropathy in the BB/Wor rat

Kappelle¹,

Biessels²,

Bravenboer³

et al. 1994

British J Pharmacology

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1 Neuropathy is a frequently diagnosed complication of diabetes mellitus. Effective pharmacotherapy is not available. 2 The spontaneously diabetic BB/Wor rats develop secondary complications like neuropathy as do human diabetic patients. 3 BB/Wor rats treated with insulin via a subcutaneous implant show a significant impairment of sensory and motor nerve conduction velocity 6 weeks after the onset of diabetes mellitus. 4 Intraperitoneal treatment of diabetic BB/Wor rats with the Ca2+ antagonist, nimodipine (20 mg kg-'), from week 6 onwards every 48 h for a period of 6 weeks resulted in a significant increase of sensory and motor nerve conduction velocity. 5 Twelve weeks after the onset of diabetes mellitus BB/Wor rats show a 40% impairment of sciatic nerve blood flow as compared to the non-diabetic age-matched controls. Treatment with nimodipine (20 mg kg-') from week 6 onwards significantly increased the sciatic nerve blood flow as compared to placebo-treated diabetic BB/Wor rats. 6 The adrenergic responsiveness of the vasa nervorum of the sciatic nerve to tyramine and phenylephrine was investigated as a parameter for autonomic neuropathy. 7 The fact that nimodipine treatment restored the reduced response to tyramine independently of the reduced postsynaptic phenylephrine responsiveness indicates that nimodipine improves adrenergic responsiveness mainly at the presynaptic level.

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Section: Discussionsupporting

confidence: 90%

Beneficial effect of the Ca²⁺ antagonist, nimodipine, on existing diabetic neuropathy in the BB/Wor rat

Kappelle¹,

Biessels²,

Bravenboer³

et al. 1994

British J Pharmacology

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“…Therefore, the role of myo-inositol deficiency in the development of diabetic neuropathy remains controversial [61]. Clinically, myoinositol supplementation has proved disappointing and no trials have shown any improvement in nerve function [62].…”

Section: Discussionmentioning

confidence: 99%

Effect of Treating Streptozotocin‐Induced Diabetic Rats With Sorbinil, Myo‐Inositol or Aminoguanidine on Endoneurial Blood Flow, Motor Nerve Conduction Velocity and Vascular Function of Epineurial Arterioles of the Sciatic Nerve

Coppey

Gellett

Davidson

et al. 2001

Journal of Diabetes Research

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Previously we have demonstrated that diabetes causes impairment in vascular function of epineurial vessels, which precedes the slowing of motor nerve conduction velocity. Treatment of diabetic rats with aldose reductase inhibitors, aminoguanidine or myo-inositol supplementation have been shown to improve motor nerve conduction velocity and/or decreased endoneurial blood flow. However, the effect these treatments have on vascular reactivity of epineurial vessels of the sciatic nerve is unknown. In these studies we examined the effect of treating streptozotocininduced rats with sorbinil, aminoguanidine or myo-inositol on motor nerve conduction velocity, endoneurial blood flow and endotheliumdependent vascular relaxation of arterioles that provide circulation to the region of the sciatic nerve. Treating diabetic rats with sorbinil, aminoguanidine or myo-inositol improved the reduction of endoneurial blood flow and motor nerve conduction velocity. However, only sorbinil treatment significantly improved the diabetes-induced impairment of acetylcholinemediated vasodilation of epineurial vessels of the sciatic nerve. All three treatments were efficacious in preventing the appropriate metabolic derangements associated with either activation of the polyol pathway or increased nonenzymatic glycation. In addition, sorbinil was shown to prevent the diabetes-induced decrease in lens glutathione level. However, other mark-____________________ *Corresponding author: 3 E 17 Veterans Affairs Medical Center, Iowa City, IA 52246; tel: (319) 338-0581 ext. 7629; fax: (319) 339-7025; e-mail: myorek@icva.gov Int. Jnl. Experimental Diab. Res., 3:21-36, 2002 © 2002 Taylor and Francis 1560 ers of oxidative stress were not vividly improved by these treatments. These studies suggest that sorbinil treatment may be more effective in preventing neural dysfunction in diabetes than either aminoguanidine or myoinositol.Key words: diabetes, diabetic neuropathy, endothelium, vascular reactivity, aldose reductase inhibitor, aminoguanidine INTRODUCTIONDiabetic neuropathy is a multifactorial problem likely due to the poor control of hyperglycemia. Two of these perturbations are the activation of the polyol pathway by which glucose is metabolized to sorbitol via aldose reductase contributing to an alteration in the redox balance and a decrease in myo-inositol uptake and content and an increase in non-enzymatic glycation leading to the abnormal glycation of proteins [1,2]. In animal models of diabetes prevention of these defects by treatment with aldose reductase inhibitors, aminoguanidine or supplementation with myo-inositol has been shown to improve peripheral neuropathy.Studies from numerous laboratories have shown that treating diabetic rats with an aldose reductase inhibitor improves nerve function as well as endoneurial blood flow [3][4][5][6][7][8][9][10][11][12]. This has led to wide speculation regarding the potential benefit of aldose reductase inhibitor treatment of diabetic complications [10][11][12][13][14][15][16]. However, clinical tri...

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“…Neuropathy in these two rat models mimics clinical diabetic neuropathy in several aspects. As in diabetic patients, early neurological dystkction in both STZ-and BB/Wor diabetic rats is characterised by reductions in motor and sensory nerve conduction velocities (33). These early reductions in conduction velocity are mostly rapidly reversible (34).…”

Section: Diabetic Neuronathymentioning

confidence: 99%

The calcium hypothesis of brain aging and neurodegenerative disorders: Significance in diabetic neuropathy

Biessels

Gispen

1996

Life Sciences

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SummaryIn this paper we discuss the possible role of disturbed neuronal calcium homeostasis in brain aging and diabetic neuropathy. Disturbances in the homeostasis of cytosolic calcium concentration have been implicated in the pathogenesis of various acute and chronic neurodegenerative disorders and in brain aging. Obviously, these disorders do not all share the same pathogenetic mechanisms. However, a number of the pathogenetic mechanisms involved have in common that they may ultimately cause loss of calcium homeostasis, leading to neuronal damage. By identifying the possible role of calcium, treatment strategies can be developed that may be effective in a variety of neurodegenerative disorders, despite differences in their pathogenesis. Our aim is to explore some of the similarities that exist between a number of processes that have been implicated in the pathogenesis of brain aging and diabetic neuropathy, including ischemia, oxidative stress and non-enzymatic protein glycosylation. Each of these factors might impair neuronal calcium homeostasis, and ultimately lead to neurodegenerative changes. By discussing the putative role of these specific factors in two apparently dissimilar disorders, such as brain aging and diabetic neuropathy, we obviously do not intend to suggest that their pathogenesis is one and the same. Instead, by examining the relative role of these factors in two different types of neurodegenerative disorders we would like to emphasize the importance of disturbances in celh&.r calcium homeostasis as a final common pathway in neuronal damage resulting Corn various noxious events.Key Worris: calcium, diabetic neuropathy, aging, neurodegenerationThe calcium hypothesis of brain aging and neurodegenerative disorders postulates that cellular mechanisms for maintaining the cellular homeostasis of cytosolic calcium concentration play a key role in aging, and that sustained changes in calcium homeostasis could provide the final common pathway for the neuropathological changes associated with brain aging and various neurodegenerative disorders (1,2). In this paper we will review the putative role of disturbed calcium homeostasis in the pathogenesis of diabetic neuropathy, one of the most common of neurodegenerative disorders in man. In particular, we will try to explore some of the similarities that exist between a number of processes that have been implicated in the pathogenesis of diabetic neuropathy and factors that have been implicated in brain aging. These factors include ischemia, oxidative stress and non-enzymatic protein glycosylation. Each of these factors might impair neuronal calcium homeostasis, and ultimately lead to neurodegenerative changes.

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The pharmacology of diabetic neuropathy

Cited by 36 publications

References 155 publications

Beneficial effect of the Ca²⁺ antagonist, nimodipine, on existing diabetic neuropathy in the BB/Wor rat

Beneficial effect of the Ca²⁺ antagonist, nimodipine, on existing diabetic neuropathy in the BB/Wor rat

Effect of Treating Streptozotocin‐Induced Diabetic Rats With Sorbinil, Myo‐Inositol or Aminoguanidine on Endoneurial Blood Flow, Motor Nerve Conduction Velocity and Vascular Function of Epineurial Arterioles of the Sciatic Nerve

The calcium hypothesis of brain aging and neurodegenerative disorders: Significance in diabetic neuropathy

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The pharmacology of diabetic neuropathy

Cited by 36 publications

References 155 publications

Beneficial effect of the Ca2+ antagonist, nimodipine, on existing diabetic neuropathy in the BB/Wor rat

Beneficial effect of the Ca2+ antagonist, nimodipine, on existing diabetic neuropathy in the BB/Wor rat

Effect of Treating Streptozotocin‐Induced Diabetic Rats With Sorbinil, Myo‐Inositol or Aminoguanidine on Endoneurial Blood Flow, Motor Nerve Conduction Velocity and Vascular Function of Epineurial Arterioles of the Sciatic Nerve

The calcium hypothesis of brain aging and neurodegenerative disorders: Significance in diabetic neuropathy

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Beneficial effect of the Ca²⁺ antagonist, nimodipine, on existing diabetic neuropathy in the BB/Wor rat

Beneficial effect of the Ca²⁺ antagonist, nimodipine, on existing diabetic neuropathy in the BB/Wor rat