Rufinamide Improves Functional and Behavioral Deficits <i>via</i> Blockade of Tetrodotoxin-Resistant Sodium Channels in Diabetic Neuropathy

Abstract

Rufinamide is a structurally novel, antiepileptic drug approved for the treatment of Lennox-Gastaut syndrome. Its mechanism of action involves inhibition of voltage-gated Na+ channels (VGSCs) with possible membrane-stabilizing effects. VGSCs play a significant role in the pathogenesis of neuropathic pain. Therefore, we investigated the effects of rufinamide on tetrodotoxin-resistant sodium current (TTX-R I(Na)) in acutely dissociated rat dorsal root ganglion (DRG) neurons isolated from streptozotocin-induced diabetic rats by using whole-cell voltage-clamp configuration. In addition, the functional and behavioural nociceptive parameters were evaluated to assess its potential in diabetic neuropathy. Diabetic rats demonstrated the mechanical allodynia and thermal hyperalgesia with reduced nerve perfusion and conduction velocity as compared to control. Rufinamide treatments (3 and 10 mg/kg) significantly improved these functional and nociceptive deficits. Diabetic rat DRG neurons exhibited increased TTX-R I(Na) density as compared to control. The voltage-dependent activation and steady-state inactivation curves for TTX-R I(Na) in DRG neurons from diabetic rats were shifted negatively as compared to control. Rufinamide treatments significantly blocked the TTX-R Na+ channel activity as evident from significant reduction in I(Na) density and hyperpolarizing shift in activation and inactivation curves as compared to diabetic control. This suggests that rufinamide acts on TTX-R Na+ channels, reduces channel activity and attenuates nerve functional and behavioral parameters in diabetic rats. Altogether, these results indicate therapeutic potential of rufinamide in the treatment of diabetic neuropathy.

Current Status of the New Antiepileptic Drugs in Chronic Pain

“…Exact mechanism of action is still unknown, but in vitro studies suggest that it act through modulation of VGSC. It appears to prolong the inactive state of VGSC by slowing the recovery of these channels from inactivation (Wier et al, 2011; Kharatmal et al, 2015). VGSCs are key determinants regulating action potential generation and propagation; thus, changes in sodium channel function can have profound effects on neuronal excitability and pain signaling.…”

“…TTX-sensitive includes (Nav1.3, Nav1.7) and TTX-resistant includes (Nav1.8, Nav1.9; Elliott and Elliott, 1993; Rush et al, 1998). Rufinamide has a great affinity for TTX-resistant than TTX-sensitive channels (Kharatmal et al, 2015). Rufinamide attenuates allodynia response in animal models of inflammatory and diabetes induced neuropathic pain (Suter et al, 2013; Kharatmal et al, 2015).…”

“…Rufinamide has a great affinity for TTX-resistant than TTX-sensitive channels (Kharatmal et al, 2015). Rufinamide attenuates allodynia response in animal models of inflammatory and diabetes induced neuropathic pain (Suter et al, 2013; Kharatmal et al, 2015). It has completed phase IV clinical trial, but results are not posted (ClinicalTrials.gov Identifier: NCT01212458, 2014).…”

Pain transduction: a pharmacologic perspective

“…However, gain-of-function mutations in Nav 1.9 have been found to contribute to painful peripheral neuropathy [77, 78]. Additionally, researchers found Nav 1.9 to be involved with both acute and chronic inflammatory pain [79]. To demonstrate this, these researchers induced monoarthritis in mice via carrageenan injections.…”

“…Recently, Kharatmal et al [79] demonstrated that rufinamide decreases the activity of Nav 1.8 and 1.9 in a rat model of diabetic neuropathy. Blockage of these channels was observed to contribute to a decrease in both mechanical allodynia and thermal hyperalgesia in the study animals [79]. …”