title: Inactivation of TNF-α ameliorates diabetic neuropathy in mice.
abstract: Tumor necrosis factor (TNF)-α is a potent proinflammatory cytokine involved in the pathogenesis of diabetic neuropathy. We inactivated TNF-α to determine if it is a valid therapeutic target for the treatment of diabetic neuropathy. We effected the inactivation in diabetic neuropathy using two approaches: by genetic inactivation of TNF-α (TNF-α(-/-) mice) or by neutralization of TNF-α protein using the monoclonal antibody infliximab. We induced diabetes using streptozotocin in wild-type and TNF-α(-/-) mice. We measured serum TNF-α concentration and the level of TNF-α mRNA in the dorsal root ganglion (DRG) and evaluated nerve function by a combination of motor (MNCV) and sensory (SNCV) nerve conduction velocities 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, TNF-α(+/+) 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 TNF-α(-/-) mice showed mild abnormalities of IENFD under basal conditions, diabetic TNF-α(-/-) mice showed no evidence of abnormal nerve function tests compared with nondiabetic mice. A single injection of infliximab in diabetic TNF-α(+/+) mice led to suppression of the increased serum TNF-α and amelioration of the electrophysiological and biochemical deficits for at least 4 wk. Moreover, the increased TNF-α mRNA expression in diabetic DRG was also attenuated by infliximab, suggesting infliximab's effects may involve the local suppression of TNF-α. Infliximab, an agent currently in clinical use, is effective in targeting TNF-α action and expression and amelioration of diabetic neuropathy in mice.
authors.affiliation: Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Yamakawa
authors.forename: Hideto
authors.initials: H
authors.lastname: Kojima
authors.forename: Tomoya
authors.initials: T
authors.lastname: Terashima
authors.forename: Miwako
authors.initials: M
authors.lastname: Katagi
authors.forename: Jiro
authors.initials: J
authors.lastname: Oi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Urabe
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sanada
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Kawai
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yasuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000235:genetics / Q000473:pathology; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000502:physiology*; D000069285:Infliximab; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D013311:Streptozocin; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin; D000069285:Infliximab