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Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy

Bierhaus et al. (2012)

Nature Medicine 18:926–933.

Hyperalgesia, an increased sensitivity to pain, is a debilitating comorbidity afflicting a subset of diabetic patients particularly in advanced stages of disease [1]. While pain is a normal physiological protective response, hypersensitivity to pain is a major complication that severely lowers the quality of life in this subset of diabetic patients. Current treatments including antidepressants and antiepileptic agents provide partial symptomatic relief but do not address the underlying cause of the hyperalgesia, which has remained elusive. Although hyperglycaemia has long been considered a causative contributing factor, normalization of glucose levels only brings about modest benefits to patients. Recent evidence from animal models of diabetes, however, has implicated a highly-reactive glucose metabolite, methylglyoxal (MG), in diabetes-related neuropathic pain [2]. In this study by Bierhaus et al., the authors aimed to examine the role of MG in diabetic neuropathy-related hyperalgesia [3].

Using plasma samples from diabetic patients, the authors showed that MG levels are elevated in diabetic patients compared to healthy controls. Within diabetic patients, MG levels were higher in patients with pain compared to those without pain. To examine whether elevated levels of MG affect neuronal function, the authors assessed cyclooxygenase-2 (COX-2) induction as an indirect measure of altered neuronal function in cultured mouse dorsal root ganglion neurons treated with plasma from diabetic patients with pain, without pain, or from healthy controls. Plasma from diabetic patients resulted in a significant induction of COX-2 compared to healthy controls. Furthermore, COX-2 induction was even higher following treatment with plasma from diabetic patients with pain compared to those without pain. Finally, elevating MG levels by supplementation of plasma from diabetic patients without pain with exogenous MG to levels seen in patients with pain resulted in increased induction of COX-2, supporting a potential role for plasma MG in mediating diabetes-related hyperalgesia.

In order to examine the potential role of MG in diabetes-related hyperalgesia, the authors employed pharmacological and genetic approaches to modulate plasma MG levels.

Pharmacological inhibition of glyoxalase 1 (GLO1), the major MG-metabolising enzyme, resulted in elevated plasma MG levels and was accompanied by profound thermal hyperalgesia. Similarly, pronounced thermal hyperalgesia was observed in GLO1 knockdown mice (Glo1+/−) after injection of exogenous MG. Conversely, reduction of plasma MG levels using somatic gene transfer-mediated overexpression of GLO1 or following treatment with MG-scavenging synthetic peptides resulted in reduced thermal hyperalgesia. These findings suggest that elevation of plasma MG levels leads to profound hyperalgesia and that the lowering of MG levels leads to reduced thermal hyperalgesia.

In an effort to identify the downstream protein target of the highly reactive MG underlying the diabetes-associated hyperalgesia, the authors examined the expression and post-translational modifications of neuronal voltage-gated sodium channels (VGSC). Neuronal VGSC shape and propagate action potentials, and changes in their activity may account for the increase in electrical excitability thought to underlie the hyperalgesia. As there were no significant differences in the expression of the VGSCs Nav1.7, Nav1.8, or Nav1.9, the authors focused on post-translational modifications of the unique tetrodotoxin-resistant VGSC Nav1.8 given its exclusive expression in pain-signalling neurons as well as the presence of potential MG-reactive arginine residues in its DIII-DIV linker region (its inactivation gate). The authors show significant modifications of Nav1.8 in wild type mice treated with MG, in diabetic mice, and in Glo1+/− mice. Markedly more modifications of Nav1.8 were also observed in sciatic nerve tissue from patients with diabetes compared to patients without diabetes. Using mass spectroscopy, the authors confirmed the binding of MG to arginine residues within the linker region of the Nav1.8. These modifications of the Nav1.8 linker region by MG were shown in electrophysiological studies to result in altered Nav1.8 function, including reduced channel inactivation associated with increased whole-cell excitability. Finally using a small interfering RNA (siRNA)-mediated gene silencing approach and Nav1.8 knockout mice, the authors show that Nav1.8 expression is required for MG-mediated hyperalgesia. These studies show that MG-mediated modifications of the arginine residues of VGSC Nav1.8 found in pain-signalling neurons may indeed underlie diabetic hyperalgesia (Fig. 11).

image

Figure 1. Under normal physiological conditions, the levels of methylglyoxal and glyoxalase 1 are in homeostasis, resulting in the metabolism of methylglyoxal by glyoxalase 1 into d-lactate (a). In hyperalgesic diabetic patients, the levels of the highly-reactive methylglyoxal are elevated, leading to post-translational modification of the Nav1.8 sodium channel within its inactivation gate and altered channel function, resulting in hypersensitivity to painful stimuli (b).

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The study by Bierhaus et al. provides strong evidence implicating MG in the hyperalgesia experienced by a subset of diabetic patients. The authors show that levels of MG (as well as GLO1) and in particular its modification of the inactivation gate of Nav1.8, are key to this activity, findings that suggest that therapies targeted at normalizing plasma MG levels may be of therapeutic benefit. However, what accounts for the variation in the levels of MG between patients remains unclear. Whether genetic variation in genes of metabolic pathways leading to MG synthesis or breakdown (such as GLO1) is a contributing factor warrants further investigation. Indeed, delineation of such potential predisposing genetic susceptibility factor(s) would allow for identification of diabetic patients at-risk for hyperalgesia and tailored MG-directed therapy in the future.

References

  1. Top of page
  2. Abstract
  3. References
  • 1
    Calcutt NA, Backonja MM. Pathogenesis of pain in peripheral diabetic neuropathy. Curr Diab Rep 2007: 7 (6): 429434.
  • 2
    Jack MM, Ryals JM, Wright DE. Characterisation of glyoxalase I in a streptozocin-induced mouse model of diabetes with painful and insensate neuropathy. Diabetologia 2011: 54 (8): 21742182.
  • 3
    Bierhaus A, Fleming T, Stoyanov S et al. Methylglyoxal modification of Na(v)1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 2012: 18: 926933.