title: Rufinamide Improves Functional and Behavioral Deficits via 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.
authors.forename: Shivsharan B
authors.initials: SB
authors.lastname: Kharatmal
authors.forename: Jitendra N
authors.initials: JN
authors.lastname: Singh
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar-160062 (Mohali), Punjab, India. sssharma@niper.ac.in.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Sharma
mesh_terms: D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005727:Ganglia, Spinal / Q000473:pathology; D001523:Mental Disorders / Q000188:drug therapy* / Q000209:etiology*; D009431:Neural Conduction / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014230:Triazoles; D013779:Tetrodotoxin; C079703:rufinamide