Elsevier

Biochemical Pharmacology

Volume 83, Issue 7, 1 April 2012, Pages 932-940
Biochemical Pharmacology

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

https://doi.org/10.1016/j.bcp.2012.01.015Get rights and content

Abstract

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 Ca2+, essentially required for 12/15-lipoxygenase activation. The latter, in turn, causes oxidative–nitrosative stress, an important trigger of mitogen activated protein kinase (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 diabetes-associated 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.

Introduction

Diabetic peripheral neuropathy (DPN) affects at least 50% of patients with both Type 1 and Type 2 diabetes, and is a leading cause of foot amputation [1], [2], [3]. DPN is manifested by nerve blood flow and motor (MNCV) and sensory (SNCV) nerve conduction velocity deficits as well as by increased vibration and thermal perception thresholds that progress to sensory loss, occurring in conjunction with degeneration of all fiber types in the peripheral nerve [4]. A significant proportion of patients with DPN also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain [3], [4], [5].

The pathogenesis of DPN has extensively been studied in animal models of diabetes, and involves complex interactions between vascular and non-vascular mechanisms [6], [7]. Multiple biochemical changes including, but not limited to, increased activity of the sorbitol pathway of glucose metabolism [8], [9], non-enzymatic glycation/glycoxidation [10], [11], activation of protein kinase C (PKC) and mitogen activated protein kinases (MAPKs) [12], [13], [14], [15], oxidative–nitrosative stress [16], [17], [18], [19], impaired neurotrophism [20], activation of poly(ADP-ribose) polymerase (PARP [21], [22]) as well as of the enzymes of arachidonic acid metabolism, cyclooxygenase-2 [23] and 12/15-lipoxygenase (LO [24], [25]), participate in the development of nerve conduction velocity deficits and small sensory nerve fiber dysfunction. Increased sorbitol pathway activity [26], [27], [28], impaired neurotrophic support [29], [30], oxidative–nitrosative stress [31], PARP [32], cyclooxygenase-2 [23], and LO [25] activation have also been implicated in axonal atrophy of large myelinated fibers and/or small sensory nerve fiber degeneration. The interactions among some of biochemical mechanisms, e.g. (1) increased activity of the sorbitol pathway and oxidative–nitrosative stress [8], [27], [28], [33], [34], [35], PKC [12], p38 MAPK [14], and PARP [33] activation; (2) oxidative stress and impaired neurotrophic support [36]; (3) oxidative–nitrosative stress and PARP activation [19], [32], in DPN have been identified, but many others remain largely unexplored. Diabetes-induced increase in activity of aldose reductase (AR), the first enzyme of the sorbitol pathway, has been reported to lead to accumulation of cytosolic Ca2+ [37], essentially required for LO activation [38], [39]. The latter, in turn, causes oxidative–nitrosative stress [24], an important trigger of MAPK phosphorylation [40]. The present study therefore evaluated the interplay of AR, LO, and MAPKs in tissue sites for DPN including peripheral nerve, spinal cord, and dorsal root ganglion (DRG) neurons. The experiments were performed in C57Bl6/J mice, a robust animal model of DPN, that is manifested by MNCV and SNCV deficits, small sensory nerve fiber dysfunction and degeneration, and axonal atrophy of large myelinated fibers [9], [19], [24], [25], [27], and is amenable to treatment with AR [9], [27], LO [24], [41], and p38 MAPK [15] inhibitors.

Section snippets

Reagents

Unless otherwise stated, all chemicals were of reagent-grade quality, and were purchased from Sigma Chemical Co., St. Louis, MO, USA. For Western blot analysis, rabbit polyclonal (clone H-100) anti-12-lipoxygenase (LO) antibody, rabbit polyclonal (clone H-147) anti-p38 MAPK antibody, mouse monoclonal anti-ERK antibody (clone MK1), rabbit polyclonal (clone C17) anti-JNK1 antibody were obtained from Santa Cruz Biotechnology, Santa Cruz, CA, USA. Rabbit polyclonal anti-phospho-p38 MAPK antibody,

Body weights and blood glucose concentrations

In experiment 1, weight gain was reduced by 14% and 18% in untreated and fidarestat-treated diabetic mice compared with controls (Table 1). Fidarestat treatment slightly (6.1%), but significantly, increased weight gain in non-diabetic mice (p < 0.01 vs untreated controls). On the contrary, weight gain in diabetic mice was slightly (4.7%), but significantly, reduced by fidarestat treatment (p < 0.05 vs untreated diabetic group). Final blood glucose concentrations were elevated by 239% and 231% in

Discussion

The findings described herein identify the relationships among three major mechanisms implicated in the pathogenesis of DPN. They provide the first evidence of a key role of increased AR activity in diabetes-associated LO activation in peripheral nerve and spinal cord. They also point to LO contribution to p38 MAPK and ERK activation in the peripheral nerve and to p38 MAPK, ERK, and SAPK/JNK activation in DRG. Note, that neither diabetes-induced SAPK/JNK activation in the peripheral nerve, nor

Acknowledgments

The study was supported in part by the National Institutes of Health Grants DK074517, DK077141, DK081147, and the American Diabetes Association Research Grant 7-08-RA-102 (all to I.G.O.). The Cell Biology and Bioimaging Core utilized in this work is supported in part by COBRE (NIH P20 RR021945) and CNRU (NIH 1P30-DK072476) center grants from the National Institutes of Health. The authors thank Dr. Rama Natarajan for valuable help with antibodies selections.

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