title: Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy.
abstract: Calpain plays an important role in the pathophysiology of neurological and cardiovascular complications, but its functional association in diabetic neuropathy is not yet elucidated. Therefore, we investigated the role of calpain in modulation of tetrodotoxin-resistant sodium channels (TTX-R Na(+) channels) in dorsal root ganglion (DRG) neurons using a pharmacological approach. The effects of a calpain inhibitor, MDL 28170 (3 and 10 mg/kg, i.p.) on TTX-R Na(+) channels in DRG neurons of streptozotocin-induced diabetic rats were assessed by using whole-cell patch-clamp technique. In addition to this biochemical, functional and behavioral deficits were also measured. Diabetic rats demonstrated the mechanical allodynia and thermal hyperalgesia with reduced nerve perfusion and conduction velocity as compared to control. MDL 28170 treatments significantly recovered these functional and nociceptive deficits. Moreover, diabetic rats exhibited increased calpain activation, lipid peroxidation and proinflammatory cytokines as compared to control. Drug treatment significantly improved these biochemical deficits. Additionally, DRG neurons from diabetic rats illustrated a significant increase in TTX-R sodium current (INa) density as compared to control. MDL 28170 treatments in diabetic rats significantly blocked the altered channel kinetics with hyperpolarizing shift in voltage-dependence of steady-state activation and inactivation curves. All together, our study provides evidence that calpain activation is directly associated with alterations in TTX-R Na(+) channels and triggers functional, nociceptive and biochemical deficits in experimental diabetic neuropathy. The calpain inhibitor, MDL 28710 have shown beneficial effects in alleviating diabetic neuropathy via modulation of TTX-R Na(+) channel kinetics and reduction of oxidative stress and neuro-inflammation.
authors.affiliation: Electrophysiology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
authors.forename: Shivsharan B
authors.initials: SB
authors.lastname: Kharatmal
authors.affiliation: Electrophysiology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
authors.forename: Jitendra N
authors.initials: JN
authors.lastname: Singh
authors.affiliation: Electrophysiology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India. Electronic address: sssharma@niper.ac.in.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002154:Calpain / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004151:Dipeptides / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000503:physiopathology; D006023:Glycoproteins / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D059226:Nociceptive Pain / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004151:Dipeptides; D006023:Glycoproteins; D015222:Sodium Channels; C039304:calpain inhibitors; D002154:Calpain; C058076:calpain inhibitor III
keywords: Calpain; Diabetic neuropathy; Dorsal root ganglion; MDL 28170; Tetrodotoxin-resistant sodium channels