The Role of Sodium Channels in Painful Diabetic and Idiopathic Neuropathy

Lauria, Giuseppe; Ziegler, Dan; Malik, Rayaz A.; Merkies, Ingemar S. J.; Waxman, Stephen G.; Faber, Catharina G.

doi:10.1007/s11892-014-0538-5

Cited by 37 publications

(22 citation statements)

References 91 publications

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“…Underlying causes of PN can be identified by taking a careful medical history alongside simple laboratory tests. However, of all patients with PN, 24–27% will have idiopathic neuropathy where no underlying cause can be identified 47 . In patients with diabetes, it is important to exclude other causes of PN (Table 3).…”

Section: Practical Stepped Approach To the Diagnosis Of Peripheral Nementioning

confidence: 99%

Diagnosing peripheral neuropathy in South‐East Asia: A focus on diabetic neuropathy

Malik

Andag-Silva

Dejthevaporn

et al. 2020

J of Diabetes Invest

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Burning and stabbing pain in the feet and lower limbs can have a significant impact on the activities of daily living, including walking, climbing stairs and sleeping. Peripheral neuropathy in particular is often misdiagnosed or underdiagnosed because of a lack of awareness amongst both patients and physicians. Furthermore, crude screening tools, such as the 10‐g monofilament, only detect advanced neuropathy and a normal test will lead to false reassurance of those with small fiber mediated painful neuropathy. The underestimation of peripheral neuropathy is highly prevalent in the South‐East Asia region due to a lack of consensus guidance on routine screening and diagnostic pathways. Although neuropathy as a result of diabetes is the most common cause in the region, other causes due to infections (human immunodeficiency virus, hepatitis B or C virus), chronic inflammatory demyelinating polyneuropathy, drug‐induced neuropathy (cancer chemotherapy, antiretrovirals and antituberculous drugs) and vitamin deficiencies (vitamin B1, B6, B12, D) should be actively excluded.

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Section: Practical Stepped Approach To the Diagnosis Of Peripheral Nementioning

confidence: 99%

Diagnosing peripheral neuropathy in South‐East Asia: A focus on diabetic neuropathy

Malik

Andag-Silva

Dejthevaporn

et al. 2020

J of Diabetes Invest

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“…PROPANE is a large, ongoing study of patients with DPN and idiopathic small fibre neuropathy aimed at determining whether mutations or polymorphisms of genes encoding sodium channels Na v 1.7, Na v 1.8, and Na v 1.9 may stratify patients with and without pain and, hence, promote future therapeutic breakthroughs …”

Section: Genetics and Diabetic Polyneuropathymentioning

confidence: 99%

Might genetics play a role in understanding and treating diabetic polyneuropathy?

Spallone

2017

Diabetes Metabolism Res

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Despite the high prevalence and impact on quality of life, costs, and survival, there are still unresolved issues regarding diabetic polyneuropathy (DPN): the lack of definite knowledge of its pathogenesis; the limited preventive action of glycaemic control in type 2 diabetes; and the unavailability of evidence-based effective disease-modifying treatment. How can genetics provide the tools to address these gaps? Ziegler et al for the GDS Group explore the novel hypothesis that genetic variability in transketolase (TKT) might contribute to susceptibility to DPN in patients with newly diagnosed type 1 and type 2 diabetes (well characterised for DPN). Transketolase diverts excess glycolytic metabolites from the hexosamine, protein kinase C, and advanced glycation endproduct pathways to the pentose phosphate pathway, with a protective effect against hyperglycaemia-induced damage. Moreover, thiamine and its derivative benfotiamine are among the few disease-modifying agents still under consideration as DPN treatment. The authors find significant associations of single-nucleotide polymorphisms of the TKT gene with the Total Symptom Score and thermal thresholds, in particular in male participants with type 2 diabetes. Moreover, they measure plasma methylglyoxal (a glycating agent, whose availability is hindered by TKT) without however finding a relation with TKT single-nucleotide polymorphisms. The link found between TKT genetic variability and nerve function measures is considered here in the context of DPN genetic studies and of experimental and clinical findings regarding thiamine and benfotiamine. The conclusion is that available data supports the decision to maintain focus on both the search for DPN genetic biomarkers and the therapeutic attempts to target thiamine, TKT, and methylglyoxal.

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“…One of the initial questions that must be addressed is what mechanisms trigger Na v 1.8-positive DRG neuron hyperexcitability in diabetes. Promising hypotheses include altered gene expression and posttranslational modification of key ion channels (24,25). For example, methylglyoxal, abundant during hyperglycemia (19,20), induces posttranslational modifications in Na v 1.8 sodium channels (26) that result in nociceptor hyperexcitability and mechanical allodynia in rodents.…”

Section: Introductionmentioning

confidence: 99%

Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy

Jayaraj¹,

Bhattacharyya²,

Belmadani³

et al. 2018

Journal of Clinical Investigation

110

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Painful diabetic neuropathy (PDN) is an intractable complication of diabetes that affects 25% of patients. PDN is characterized by neuropathic pain and small-fiber degeneration, accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability and loss of their axons within the skin. The molecular mechanisms underlying DRG nociceptor hyperexcitability and small-fiber degeneration in PDN are unknown. We hypothesize that chemokine CXCL12/CXCR4 signaling is central to this mechanism, as we have shown that CXCL12/CXCR4 signaling is necessary for the development of mechanical allodynia, a pain hypersensitivity behavior common in PDN. Focusing on DRG neurons expressing the sodium channel Nav1.8, we applied transgenic, electrophysiological, imaging, and chemogenetic techniques to test this hypothesis. In the high-fat diet mouse model of PDN, we were able to prevent and reverse mechanical allodynia and small-fiber degeneration by limiting CXCR4 signaling or neuronal excitability. This study reveals that excitatory CXCR4/CXCL12 signaling in Nav1.8-positive DRG neurons plays a critical role in the pathogenesis of mechanical allodynia and small-fiber degeneration in a mouse model of PDN. Hence, we propose that targeting CXCR4-mediated DRG nociceptor hyperexcitability is a promising therapeutic approach for disease-modifying treatments for this currently intractable and widespread affliction.

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The Role of Sodium Channels in Painful Diabetic and Idiopathic Neuropathy

Cited by 37 publications

References 91 publications

Diagnosing peripheral neuropathy in South‐East Asia: A focus on diabetic neuropathy

Diagnosing peripheral neuropathy in South‐East Asia: A focus on diabetic neuropathy

Might genetics play a role in understanding and treating diabetic polyneuropathy?

Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy

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