Current Drug Targets

ISSN: 1389-4501

Current Drug Targets
Volume 9, Number 1, January 2008

Contents

Diabetic Neuropathy
Guest Editor: Eva L. Feldman


Editorial Pp. 1-2


Criteria for Creating and Assessing Mouse Models of Diabetic Neuropathy Pp. 3-13
K.A. Sullivan, S.I. Lentz, J.L. Roberts Jr. and E.L. Feldman
[Abstract]


Aldose Reductase, Still a Compelling Target for Diabetic Neuropathy Pp. 14-36
P.J. Oates
[Abstract]


Is C-Peptide Replacement the Missing Link for Successful Treatment of Neurological Complications in Type 1 Diabetes? Pp. 37-46
A.A.F. Sima and H. Kamiya
[Abstract]


Growth Factors as Therapeutics for Diabetic Neuropathy Pp. 47-59
N.A. Calcutt, C.G. Jolivalt and P. Fernyhough
[Abstract]


Pro-Inflammatory Mechanisms in Diabetic Neuropathy: Focus on the Nuclear Factor Kappa B Pathway Pp. 60-67
N.E. Cameron and M.A. Cotter
[Abstract]


Cyclooxygenase-2 Pathway as a Potential Therapeutic Target in Diabetic Peripheral Neuropathy Pp. 68-76
A.P. Kellogg, H.T. Cheng and R. Pop-Busui
[Abstract]


The Potential Role of Angiotensin Converting Enzyme and Vasopeptidase Inhibitors in the Treatment of Diabetic Neuropathy Pp. 77-84
M.A. Yorek
[Abstract]


Metabotropic Glutamate Receptors (mGluRs) and Diabetic Neuropathy Pp. 85-93
M. Anjaneyulu, A. Berent-Spillson and J.W. Russell
[Abstract]


The Antioxidant Response as a Drug Target in Diabetic Neuropathy Pp. 94-100
A.M. Vincent, J.L. Edwards, M. Sadidi and E.L. Feldman
[Abstract]




Abstracts

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Editorial

Diabetes and obesity have reached epidemic levels in the Western world. In the United States, 20 million people have diabetes, and this number is increasing annually. The morbidity of diabetes is secondary to the macrovascular and microvascular complications that develop in a patient’s lifetime. This edition of Current Drug Targets is focused on the most common microvascular complication of diabetes, neuropathy. More than half of all patients with diabetes develop neuropathy, a progressive loss of peripheral and autonomic nerve function. Diabetic neuropathy is the most common cause of foot ulcers and nontraumatic amputations in the United States; in his or her lifetime, a patient with diabetes and neuropathy has a greater than 15% likelihood of undergoing an amputation. Patients with neuropathy of autonomic nerves experience one or more symptoms of autonomic failure which can include dehabilitating loss of cardiac, gastrointestinal and/or genitourinary function.

Despite the morbidity of diabetic neuropathy, there are no approved treatments for the disease itself other than glucose control. In the last 25 years, animal and in vitro experiments have implicated multiple pathways of tissue damage which can result in the onset and progression of diabetic neuropathy. The first contribution by Sullivan and colleagues discusses the development of mouse models of diabetic neuropathy to provide a tool to screen the therapeutic efficacy of drugs. The authors point out that a murine model of diabetic neuropathy should mimic the human disorder and suggest phenotyping parameters for evaluating diabetic neuropathy in mouse models.

The remaining contributions focus on mechanism based drug development in diabetic neuropathy. While not all the pathways underlying the pathogenesis of diabetic neuropathy are presented in Fig. (1), pivotal pathways that serve as a framework for mechanism based drug design are presented in Fig. (1) and addressed in this special issue of Current Drug Targets. Oates begins with a review of the aldose reductase pathway. Excess glucose is converted to sorbitol by aldose reductase, leading to sorbitol and fructose accumulation, NAD(P)H-redox imbalance, and changes in multiple intracellular signaling cascades. The NAD(P)H-redox imbalance leads to depletion of necessary cellular antioxidants, such as glutathione, promoting accumulation of reactive oxygen species and oxidative damage. Previous trials of aldose reductase inhibitors have not proven efficacious, in part due to dose-related toxicity and accessibility to the nervous system. Newer aldose reductase inhibitors with a lower toxicity profile and improved nerve penetration may prove effective in the treatment of diabetic neuropathy. In the next contribution, Sima and Kamiya explore the evolving concept that the combined effects of insulin and C-peptide regulate essential metabolic processes in the nervous system, including key enzyme activity, nitric oxide release, and the production and activity of essential transcription factors, trophic factors and their receptors. Replacing C peptide can prevent and/or reverse diabetic neuropathy, supporting the essential role of C peptide in the pathogenesis of the disorder and identifying C peptide replacement as a new, promising therapy.

Fig. (1). Current Drug Targets in Diabetic Neuropathy. Interrelated defects in cellular metabolism and vascular tone occur in diabetes and lead to diabetic neuropathy. These defects provide the targets for the development of mechanism based drugs. These drugs are discussed in this special issue of Current Drug Targets.

The idea that altered neurotrophic support underlies the development of diabetic neuropathy is highlighted in the review by Calcutt and colleagues. Potential blunting of normal neurotrophic responses in the presence of persistent hyperglycemia may: 1) decrease growth factor synthesis by target organs; 2) disrupt retrograde transport of growth factors to the neuronal cell body; 3) affect the signal transduction mechanism of growth factors in neurons, or 4) alter the ability of neurons or Schwann cells to produce growth factors required for normal cell maintenance. Calcutt and colleagues discuss these ideas in the context of potential neurotrophic therapies. When deficits are identified, exogenous neurotrophic factors can represent a replacement therapy in diabetic neuropathy.

The pivotal role of inflammation in the development of diabetic neuropathy is discussed by both Cameron and Cotter with a focus on nuclear factor κ B (NFκB) and Pop-Busui and coworkers with a focus on glucose-mediated alteration of cyclooxygenase (COX) pathway activity with subsequent impaired production and function of prostaglandins (PGs). NFκB is produced in response to advanced glycation end product (AGE) activation of cell surface receptors for AGE. AGE activation leads to not only NFκB formation, as discussed by Cameron and Cotter, but also enhanced intracellular oxidative stress. NFκB activation can lead to blood flow abnormalities, aberrant angiogenesis, capillary occlusion and inflammation. In parallel, tumor necrosis factor (TNF) α is increased in acute and chronic inflammatory conditions including diabetes. Collectively, targeting the NFκB / TNFα axis leads to novel therapeutics for diabetic vascular complications, including diabetic neuropathy. Pop-Busui and coworkers continue on the theme of inflammation by targeting the inducible COX isoform, COX-2, in diabetic neuropathy. COX-2 is increased in the peripheral nervous system of animals with experimental diabetes and neuropathy and selective inhibition of COX-2 blocks the onset and progression of diabetic neuropathy. The contributions of Cameron and Cotter and Pop-Busui and coworkers emphasize the importance of inflammation in the pathogenesis of diabetic neuropathy, and providing a new area of investigation and potential drug targets.

Another adverse effective of continued hyperglycemia in diabetes is the increase in tissue angiotensin II. Yorek explains how angiotensin II induces oxidative stress, endothelial damage and other vascular pathologies including vasoconstriction, thrombosis, inflammation and vascular remodeling. Angiotensin converting enzyme inhibition and/or blocking of the angiotensin II receptor are established therapies in diabetic macrovascular disease and kidney disease. A new class of drugs has been developed based on the same mechanism to augment existing therapies. This drug class is known as the vasopeptidase inhibitors. The vasopeptidase inhibitors block both angiotensin converting enzyme activity and neutral endopeptidase, a protease that degrades vasoactive peptides. Yorek provides an informative discussion on the therapeutic potential of this new class of drugs in the treatment of diabetic neuropathy.

Russell and colleagues introduce the idea that excessive release of glutamate, and subsequent activation of ionotropic glutamate receptors (iGluRs) and some metabotropic glutamate receptors (mGluRs) underlie nervous system damage in diabetes. An understanding of the mGluRs appears particularly informative. Activation of group-II (mGluR2 and -3) or group-III metabotropic glutamate receptors (mGluR4, -6, -7 and -8) provides protection against nervous system injury. Of mechanistic interest, antagonism of group-I mGluRs (mGluR1 and -5) is also necessary for neuroprotection. This complex interplay between members of the metabotropic glutamate receptor family affords a unique opportunity for drug development and therapeutic intervention. Direct or indirect activation of mGluR2/3 protects again the development and progression of diabetic neuropathy in experimental animal models. Russell and colleagues suggest that select metabotropic glutamate receptor agonists provide a new class of drugs for the treatment of diabetic neuropathy.

The issue ends by a review by Vincent and coworkers on the use of antioxidants in the treatment of diabetic neuropathy. Extensive animal and in vitro experiments suggest that a series of interrelated defects in protein structure and function and/or in vascular tone lead to diabetic neuropathy. One unifying mechanism of nervous system injury lies in the ability of both metabolic and vascular insults to increase cellular oxidative stress and impair the function of mitochondria. Antioxidants that target different components of the oxidative stress pathways have been used and are currently in clinical trials for the treatment of diabetic neuropathy. The known efficacy of these therapies is discussed, along with their future promise as effective therapies in disease treatment.

In summary, this issue provides a timely review of established theories on the pathogenesis of diabetic neuropathy leading to continued drug development as well as introducing novel concepts of disease pathogenesis that provide new classes of drug targets for mechanism-based therapies.


Eva L. Feldman
University of Michigan,
Department of Neurology,
Room 5017 BSRB, 109 Zina Pitcher Place,
Ann Arbor, Michigan 48109,
USA;
E-mail: efeldman@umich.edu


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Criteria for Creating and Assessing Mouse Models of Diabetic Neuropathy
K.A. Sullivan, S.I. Lentz, J.L. Roberts Jr. and E.L. Feldman

Diabetic neuropathy (DN) is a serious and debilitating complication of both type 1 and type 2 diabetes. Despite intense research efforts into multiple aspects of this complication, including both vascular and neuronal metabolic derangements, the only treatment remains maintenance of euglycemia. Basic research into the mechanisms responsible for DN relies on using the most appropriate animal model. The advent of genetic manipulation has moved mouse models of human disease to the forefront. The ability to insert or delete genes affected in human patients offers unique insight into disease processes; however, mice are still not humans and difficulties remain in interpreting data derived from these animals. A number of studies have investigated and described DN in mice but it is difficult to compare these studies with each other or with human DN due to experimental differences including background strain, type of diabetes, method of induction and duration of diabetes, animal age and gender. This review describes currently used DN animal models. We followed a standardized diabetes induction protocol and designed and implemented a set of phenotyping parameters to classify the development and severity of DN. By applying standard protocols, we hope to facilitate the comparison and characterization of DN across different background strains in the hope of discovering the most human like model in which to test potential therapies.


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Aldose Reductase, Still a Compelling Target for Diabetic Neuropathy
P.J. Oates

Aldose reductase (AR) enzymatically transforms cytosolic glucose into sorbitol, a molecule that poorly penetrates cell membranes and is sometimes slowly metabolized. Hyperglycemia can cause intracellular accumulation of sorbitol and its metabolite, fructose, which can create osmotic swelling and cell dysfunction. Driven by this simple paradigm, the “Osmotic Hypothesis,” and armed with positive pre-clinical results on prototype AR inhibitors (ARIs), researchers worldwide have targeted diabetic neuropathy with ARIs for four decades. However, most double-blind placebo-controlled ARI diabetic neuropathy trial outcomes have been disappointing. Ironically, scientific evidence that AR plays a key pathogenic role in diabetic neuropathy has continued to mount. Diabetic mice lacking AR exhibit strong protection of nerve function. Diabetic mice overexpressing AR have accelerated nerve dysfunction and damage. Human diabetics with "high AR expression" alleles shows faster loss of maximum pupillary constriction velocity, an indicator of autonomic neuropathy, while those with "low AR expression" alleles have slower loss of foot hot thermal threshold, an indicator of sensory neuropathy. Evidence is now strong that the Osmotic Hypothesis and the nerve sorbitol endpoint were misleading. Reliance on nerve sorbitol to assess AR inhibition likely caused underestimation of doses needed for clinical efficacy and overestimation of drug safety margins. Current recognition of the pathogenic importance of oxidative stress and its strong link to metabolic flux through AR have led to a revitalized "Metabolic Flux Hypothesis" emphasizing cofactor turnover rather than polyol accumulation. Hopefully, these new insights will lead to novel ARIs that will effectively and safely slow the progression of diabetic neuropathy.


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Is C-Peptide Replacement the Missing Link for Successful Treatment of Neurological Complications in Type 1 Diabetes?
A.A.F. Sima and H. Kamiya

In this review we will describe the interaction between insulin and C-peptide which enhances and attenuates insulin-signaling functions. We will describe how replenishment of C-peptide prevents and reverses the early metabolic abnormalities in type 1 diabetic polyneuropathy, such as Na⁺/K⁺-ATPase activity and endoneurial vascular NO release, resulting in prevention and reversal of early nerve dysfunction. The effects on expression of neurotrophic factors and their receptors, mediated by corrections of early gene responses and transcription factors, have downstream beneficial effects on cytoskeletal protein mRNAs and protein expression. Similar effects probably underlie corrections of cell adhesive molecules. The end-effects are prevention and reversal of myelinated and unmyelinated axonal degeneration, atrophy, and loss. Similarly, progressive degeneration of the node and paranode is prevented and repaired by C-peptide replacement with normalization of the molecular constituents of these functionally important structures. Cognitive dysfunction is now recognized as a complication of type 1 diabetes. Experimentally it is linked to impaired synaptic plasticity and eventually apoptotic neuronal loss caused by impaired insulin action and neurotrophic support. C-peptide replacement partially prevents hippocampal neuronal apoptosis and cognitive deficits. It is therefore becoming increasingly clear that C-peptide has major functions in supporting insulin action with a multitude of beneficial effects on diabetic polyneuropathy and primary diabetic encephalopathy in type 1 diabetes.


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Growth Factors as Therapeutics for Diabetic Neuropathy
N.A. Calcutt, C.G. Jolivalt and P. Fernyhough

There has been a rapid growth in appreciation of the diverse array of neurotrophic factors, growth factors and other biological molecules that have the capacity to support adult neurons and direct reparative processes after injury to the nervous system. Understanding the mechanisms by which these factors operate offers the opportunity to use either the factors themselves or other agents that manipulate relevant signal transduction pathways as therapeutics for a wide range of neurodegenerative diseases, including diabetic neuropathy. In this review, we aim to summarize current knowledge of the extent to which loss of neurotrophic support contributes to the pathogenesis of diabetic neuropathy, present pre-clinical evidence that supports the potential efficacy of growth factors or their mimetics against indices of diabetic neuropathy and highlight the emerging approaches to manipulating neuronal support mechanisms that show potential for translation to clinical use. Recent advances in directly assessing the progression of nerve damage in diabetic patients will hopefully facilitate renewed clinical evaluation of treatments for degenerative diabetic neuropathy and provide the framework for advancing the potential of growth factors as a therapy for this widespread and currently untreatable condition.


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Pro-Inflammatory Mechanisms in Diabetic Neuropathy: Focus on the Nuclear Factor Kappa B Pathway
N.E. Cameron and M.A. Cotter

Neuropathy is a common complication of diabetes mellitus, which reduces the quality of life and may be life-threatening. The etiology is complex and multifactorial: hyperglycemia and dyslipidemia give rise to oxidative stress and formation of advanced glycation and lipoxidation end products. These stimulate inflammatory processes, nuclear factor κB (NFκB) activation being of central importance. Many of the drugs that have been developed for treatment of diabetic complication at least in part work through suppressing either NFκB activation itself, or the production of cytokines that stimulate NFκB, such as tumor necrosis factor (TNF) α. To date there have been few tests of drugs that are specific inhibitors of the NFκB / TNFα axis. However preliminary results in animal models are encouraging and go some way in establishing the NFκB cascade as an important therapeutic target for diabetic vascular complications in general, and neuropathy in particular.


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Cyclooxygenase-2 Pathway as a Potential Therapeutic Target in Diabetic Peripheral Neuropathy
A.P. Kellogg, H.T. Cheng and R. Pop-Busui

Diabetic peripheral neuropathy (DPN) is the most common diabetic complication and is the leading cause of diabetes-related hospital admissions and non-traumatic amputations. DPN is also associated with a poor quality of life and high economic costs for both type 1 and type 2 diabetic patients. An effective treatment for DPN, besides tight glycemic control, is not yet available. The pathogenesis of DPN is complex and involves an intertwined array of mechanisms. Glucose-mediated alteration of cyclooxygenase (COX) pathway activity with subsequent impaired production and function of prostaglandins (PGs) is one mechanism that is implicated in the pathogenesis of DPN. COX-2, the inducible COX isoform, is upregulated in a variety of pathophysiological conditions including diabetes. COX-2 upregulation has tissue-specific consequences and is associated with activation of downstream inflammatory reactions. We have previously reported that COX-2 is upregulated in the peripheral nerves and dorsal root ganglia neurons in experimental diabetes and that COX-2 gene inactivation and/or selective COX-2 inhibition provides protection against various DPN deficits. This review will summarize current evidence supporting the role of COX-2 activation in inducing diabetic neurovascular dysfunction and that modulation of the COX-2 pathway is a potential therapeutic target for DPN.


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The Potential Role of Angiotensin Converting Enzyme and Vasopeptidase Inhibitors in the Treatment of Diabetic Neuropathy
M.A. Yorek

Diabetic neuropathy is a debilitating disorder that occurs in more than 50 percent of patients with diabetes. Evidence suggests that there are at least five major pathways involved in the development of diabetic neuropathy: metabolic, vascular, immunologic, neurohormonal growth factor deficiency, and extracellular matrix remodeling. In light of the complicated etiologies, an effective treatment for diabetic neuropathy has not yet been identified. Hyperglycemia increases tissue angiotensin II, which induces oxidative stress, endothelial damage and other pathologies including vasoconstriction, thrombosis, inflammation and vascular remodeling. Angiotensin converting enzyme inhibition and/or blocking of the angiotensin II receptor are recognized as first line treatment for nephropathy and cardiovascular disease in diabetes patients. A new class of drug in late stages of development is vasopeptidase inhibitors. This drug inhibits both angiotensin converting enzyme activity and neutral endopeptidase. Neutral endopeptidase is a protease that degrades a number of biologically active peptides including vasoactive peptides. However, little information is available about the potential benefits of these drugs on diabetic neuropathy. Pre-clinical studies suggest that these drugs may be useful in treating diabetic complications involving vascular tissue. The purpose of this review is to evaluate the use of angiotensin converting enzyme and vasopeptidase inhibitors in the treatment of diabetic neuropathy.


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Metabotropic Glutamate Receptors (mGluRs) and Diabetic Neuropathy
M. Anjaneyulu, A. Berent-Spillson and J.W. Russell

Multiple in vivo and in vitro studies show that excessive release of glutamate, and subsequent activation of ionotropic glutamate receptors (iGluRs) and some metabotropic glutamate receptors (mGluRs) cause neuronal cell death through either necrosis or apoptosis. However, recently alternative evidence has shown that mGluRs have modulatory effects on excitotoxicity and neuronal cell death. Metabotropic glutamate receptors form a family of eight subtypes (mGluR1-8), subdivided into three groups (I-III) that initiate their biological effects by G protein-linked intracellular signal transduction. Their expression throughout the mammalian nervous system implicates these receptors as essential mediators of a cell's fate during injury to the nervous system. Activation of group-II (mGluR2 and -3) or group-III metabotropic glutamate receptors (mGluR4, -6, -7 and -8) has been established to be neuroprotective in vitro and in vivo. In contrast, group-I mGluRs (mGluR1 and -5) need to be antagonized in order to evoke protection. The pathological signaling pathways associated with diabetic neuropathy are complex and this influences development of appropriate therapies. The Group II mGluRs target several signaling pathways affected in diabetic neuropathy, prevent cellular injury in the peripheral nervous system, and may provide a novel mechanism for treatment of diabetic neuropathy. Direct or indirect activation of mGluR2/3 in animal models protects against development of diabetic neuropathy. The potential mechanisms and role of mGluRs in protection against diabetic neuropathy will be reviewed.


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The Antioxidant Response as a Drug Target in Diabetic Neuropathy
A.M. Vincent, J.L. Edwards, M. Sadidi and E.L. Feldman

While increasing antioxidant potential is an attractive treatment strategy for diabetic neuropathy, many years of trials using high-dose oral antioxidants have not produced therapeutic results. An increasing understanding of the innate antioxidant response and the pharmacological agents that can regulate this mechanism may open new avenue for drug development. This review describes the current state of antioxidant trials and the potential for targeting the antioxidant response. In combination with antihyperglycemic agents, agents that regulate the antioxidant response may afford superior protection against cellular oxidative injury in diabetes.