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Inactivation of TNF-alpha ameliorates diabetic neuropathy in mice

Tumor necrosis factor (TNF)-alpha is a potent proinflammatory cytokine involved in the pathogenesis of diabetic neuropathy. We inactivated TNF-alpha 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-alpha (TNF-alpha(-/-) mice) or by neutralization of TNF-alpha protein using the monoclonal antibody infliximab. We induced diabetes using streptozotocin in wild-type and TNF-alpha(-/-) mice. We measured serum TNF-alpha concentration and the level of TNF-alpha 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-kappaB p65 serine-276 phosphorylated and cleaved caspase-3. Compared with nondiabetic mice, TNF-alpha(+/+) diabetic mice displayed significant impairments of MNCV, SNCV, tail flick test, and IENFD as well as increased expression of NF-kappaB p65 and cleaved caspase-3 in their DRG. In contrast, although nondiabetic TNF-alpha(-/-) mice showed mild abnormalities of IENFD under basal conditions, diabetic TNF-alpha(-/-) mice showed no evidence of abnormal nerve function tests compared with nondiabetic mice. A single injection of infliximab in diabetic TNF-alpha(+/+) mice led to suppression of the increased serum TNF-alpha and amelioration of the electrophysiological and biochemical deficits for at least 4 wk. Moreover, the increased TNF-alpha mRNA expression in diabetic DRG was also attenuated by infliximab, suggesting infliximab’s effects may involve the local suppression of TNF-alpha. Infliximab, an agent currently in clinical use, is effective in targeting TNF-alpha action and expression and amelioration of diabetic neuropathy in mice

Keywords : abnormalities,analysis,Animals,antagonists & inhibitors,Anti-Inflammatory Agents,Antibodies,Antibodies,Monoclonal,Caspase 3,chemically induced,complications,Diabetes Mellitus,Experimental,Diabetic Neuropathies,drug effects,Drug Evaluation,Preclinical,drug therapy,Ganglia,Spinal,Gene Expression Regulation,Gene Silencing,genetics,Infliximab,metabolism,Mice,Mice,Inbred C57BL,Mice,Knockout,Molecular Targeted Therapy,pathology,pharmacology,physiology,Streptozocin,therapeutic use,Transcription Factor RelA,Tumor Necrosis Factor-alpha,, Tnf{Alpha},Ameliorates,Diabetic,Neuropathy, small fibre neuropathy uk

Date of Publication : 2011 Nov

Authors : Yamakawa I;Kojima H;Terashima T;Katagi M;Oi J;Urabe H;Sanada M;Kawai H;Chan L;Yasuda H;Maegawa H;Kimura H;

Organisation : Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan

Journal of Publication : Am J Physiol Endocrinol Metab

Pubmed Link : https://www.ncbi.nlm.nih.gov/pubmed/21810933

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