We tested the inactivation of TNFα, a potent proinflammatory cytokine involved in the pathogenesis of diabetic neuropathy, as a target for the treatment of diabetic neuropathy. TNFα inactivation in diabetic neuropathy was evaluated by geneαtic inactivation of TNFα (TNFα-/- mice) or by neutralization of TNFα protein using monoclonal antibody infliximab. Diabetes was induced by streptozotocin in mice with or without TNFαα expression. We measured serum TNFα concentration and the level of TNFα mRNA in the dorsal root ganglion (DRG), and evaluated nerve function by a combination of motor and sensory nerve conduction velocities (MNCV and SNCV) and tail flick test, as well as cytological analysis of intraepidermal nerve fiber density (IENFD) and immunostaining of DRG for NF-κB p65 serine 276 phosphorylated and cleaved caspase-3. Compared with nondiabetic mice, TNFα+/+ diabetic mice displayed significant impairments of MNCV, SNCV, tail flick test and IENFD, as well as increased expression of NF-κB p65 and cleaved caspase-3 in their DRG. In contrast, although nondiabetic TNFα-/- mice showed mild abnormalities of IENFD under basal conditions, diabetic TNFα-/- mice showed no evidence of abnormal nerve function tests as compared with nondiabetic mice. A single injection of infliximab in diabetic TNFα+/+ mice led to suppression of the increased serum TNFα, and amelioration of the electrophysiological and biochemical deficits for at least 4 weeks. Moreover, the increased TNFα mRNA expression in diabetic DRG was also attenuated by infliximab, suggesting infliximab's effects may involve the local suppression of TNFα. Infliximab, an agent currently in clinical use, is effective in targeting TNFα action and expression and amelioration of diabetic neuropathy in mice.
- diabetic neuropathy
- dorsal root ganglion
- nerve conduction velocity
- Copyright © 2011, American Journal of Physiology - Endocrinology and Metabolism