Voltage-Gated Sodium Channels as Therapeutic Targets for Treatment of Painful Diabetic Neuropathy.

Abstract

Painful diabetic neuropathy (PDN) is one of most common complication of diabetes, usually affecting 50% of diabetic patients and remains important cause of morbidity, mortality and deterioration of quality of life. PDN is well characterised by chronic hyperglycemia, alterations in expression and kinetics of voltage-gated sodium channels (VGSCs) and neuro-inflammation which together may result into sensorimotor deficits in peripheral nervous system. Peripheral nociceptive neurons express variety of sodium channel isoforms particularly Nav1.3, Nav1.7, Nav1.8 and Nav1.9, each play a key role in physiology of nociception by undergoing respective dynamic changes in expression and voltage-dependent gating properties. Thus, they are critical determinants of sensory neuronal excitability and associated neuropathic pain signal. Recent preclinical and clinical trial research has shed light on VGSCs as most compelling target in the treatment of PDN, a development that may open up new therapeutic approaches involving subtype selective sodium channel blockers to boost clinical efficacy, cost effectiveness, better tolerability and targeted treatment. In this review, we have summarized structure and functions of VGSCs and their involvement in the pathophysiology of neuropathic pain along with the current status of pharmacological interventions targeted at VGSCs in the treatment of diabetic neuropathy.