Beneficial effect of TNF-α inhibition on diabetic peripheral neuropathy

Journal of Neuroinflammation

Guoxiong Xu³  Lubna Nadeem¹  Yinghui Chen⁴  Xiaohong Shi² 

[1] Research Centre for Women’s and Infants’ Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada;Department of Endocrinology, Jinshan Hospital, Fudan University, 1508 Longhang Road, Shanghai 201508, P.R China;Center Laboratory, Jinshan Hospital, Fudan University, 1508 Longhang Road, Shanghai 201508, P.R China;Department of Neurology, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, P.R China

关键词: Myelin basic protein;    Nerve conduction velocity;    rhTNFR:Fc;    TNF-α;    Cytokine;    Diabetes;   

Others  :  1159958
DOI  :  10.1186/1742-2094-10-69

 received in 2013-04-16, accepted in 2013-05-20,  发布年份 2013

【 摘 要 】

Background

Tumor necrosis factor-α (TNF-α) is an important inflammatory factor produced by activated macrophages and monocytes and plays an important role in the pathogenesis of diabetic peripheral neuropathy (DPN). To evaluate the effect of TNF-α signaling suppression and the potential of TNF-α in the treatment of DPN, a recombinant human TNF-α receptor-antibody fusion protein (rhTNFR:Fc) was used. We focused on the pathophysiology of the sciatic nerve and examined the expression of myelin basic protein (MBP) under DPN status with or without TNF-α inhibition.

Methods

The DPN rat model was generated by intraperitoneal injection of streptozotocin and by feeding with a high-fat, high-sugar diet. The nerve conduction velocity (NCV) in sciatic nerve of rat was monitored over a period of four weeks. The histopathological changes in nerve tissue were examined through traditional tissue histology and ultrastructure transmission electron microscopy (TEM). The expression of MBP was examined through western blot analysis.

Results

The DPN induced rats showed significant signs of nerve damage including lower NCV, demyelination of nerve fibers, disorganization of lamellar and axonal structures, and decreased expression of MBP in the nerve tissue. The inhibition of TNF-α in the DPN rats resulted in a significant recovery from those symptoms compared to the DPN rats.

Conclusions

Our study demonstrates that TNF-α plays a key role in the pathogenesis of DPN and its inhibition by rhTNFR:Fc can prove to be a useful therapeutic strategy for the treatment of and/or prevention from DPN symptoms.

【 授权许可】

   
2013 Shi et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 2.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Wooten K: Clinical features and electrodiagnosis of diabetic peripheral neuropathy in the dysvascular patient. Phys Med Rehabil Clin N Am 2009, 20:657-676.
• [2]Tesfaye S, Selvarajah D: Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev 2012, 28(Suppl 1):8-14.
• [3]Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D: Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005, 28:956-962.
• [4]Krendel DA, Costigan DA, Hopkins LC: Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 1995, 52:1053-1061.
• [5]Wang Y, Schmeichel AM, Iida H, Schmelzer JD, Low PA: Enhanced inflammatory response via activation of NF-kappaB in acute experimental diabetic neuropathy subjected to ischemia-reperfusion injury. J Neurol Sci 2006, 247:47-52.
• [6]Schram MT, Chaturvedi N, Schalkwijk CG, Fuller JH, Stehouwer CD: Markers of inflammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes–the EURODIAB Prospective Complications Study. Diabetologia 2005, 48:370-378.
• [7]Satoh J, Yagihashi S, Toyota T: The possible role of tumor necrosis factor-alpha in diabetic polyneuropathy. Exp Diabesity Res 2003, 4:65-71.
• [8]Zoppini G, Faccini G, Muggeo M, Zenari L, Falezza G, Targher G: Elevated plasma levels of soluble receptors of TNF-alpha and their association with smoking and microvascular complications in young adults with type 1 diabetes. J Clin Endocrinol Metabol 2001, 86:3805-3808.
• [9]Gonzalez-Clemente JM, Mauricio D, Richart C, Broch M, Caixas A, Megia A, Gimenez-Palop O, Simon I, Martinez-Riquelme A, Gimenez-Perez G, Vendrell J: Diabetic neuropathy is associated with activation of the TNF-alpha system in subjects with type 1 diabetes mellitus. Clin Endocrinol (Oxf) 2005, 63:525-529.
• [10]Moriwaki Y, Yamamoto T, Shibutani Y, Aoki E, Tsutsumi Z, Takahashi S, Okamura H, Koga M, Fukuchi M, Hada T: Elevated levels of interleukin-18 and tumor necrosis factor-[alpha ] in serum of patients with type 2 diabetes mellitus: Relationship with diabetic nephropathy. Metab Clin Exp 2003, 52:605-608.
• [11]Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM, Reaven GM: A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism 2000, 49:1390-1394.
• [12]Harati Y: Diabetic neuropathies: unanswered questions. Neurol Clin 2007, 25:303-317.
• [13]Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH: Vascular risk factors and diabetic neuropathy. N Engl J Med 2005, 352:341-350.
• [14]Tavakkoly-Bazzaz J, Amoli MM, Pravica V, Chandrasecaran R, Boulton AJ, Larijani B, Hutchinson IV: VEGF gene polymorphism association with diabetic neuropathy. Mol Biol Rep 2010, 37:3625-3630.
• [15]Miranda-Massari JR, Gonzalez MJ, Jimenez FJ, Allende-Vigo MZ, Duconge J: Metabolic correction in the management of diabetic peripheral neuropathy: improving clinical results beyond symptom control. Curr Clin Pharmacol 2011, 6:260-273.
• [16]Gaede P, Lund-Andersen H, Parving HH, Pedersen O: Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008, 358:580-591.
• [17]Said G, Lacroix C, Lozeron P, Ropert A, Plante V, Adams D: Inflammatory vasculopathy in multifocal diabetic neuropathy. Brain 2003, 126:376-385.
• [18]Gundogdu BM: Diabetic peripheral neuropathy: an update on pathogenesis and management. Curr Neurol Neurosci Rep 2006, 6:1-4.
• [19]Lappas M, Permezel M, Rice GE: Advanced glycation endproducts mediate pro-inflammatory actions in human gestational tissues via nuclear factor-kappaB and extracellular signal-regulated kinase 1/2. J Endocrinol 2007, 193:269-277.
• [20]Boulton AJ, Malik RA, Arezzo JC, Sosenko JM: Diabetic somatic neuropathies. Diabetes Care 2004, 27:1458-1486.
• [21]Sinnreich M, Taylor BV, Dyck PJ: Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 2005, 11:63-79.
• [22]Fromont A, De Seze J, Fleury MC, Maillefert JF, Moreau T: Inflammatory demyelinating events following treatment with anti-tumor necrosis factor. Cytokine 2009, 45:55-57.
• [23]Malik RA, Newrick PG, Sharma AK, Jennings A, Ah-See AK, Mayhew TM, Jakubowski J, Boulton AJ, Ward JD: Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy. Diabetologia 1989, 32:92-102.
• [24]Estrella JS, Nelson RN, Sturges BK, Vernau KM, Williams DC, LeCouteur RA, Shelton GD, Mizisin AP: Endoneurial microvascular pathology in feline diabetic neuropathy. Microvasc Res 2008, 75:403-410.
• [25]Dogrul A, Gul H, Yesilyurt O, Ulas UH, Yildiz O: Systemic and spinal administration of etanercept, a tumor necrosis factor alpha inhibitor, blocks tactile allodynia in diabetic mice. Acta Diabetol 2011, 48:135-142.
• [26]Zhang C, Cai S, Chen P, Chen JB, Wu J, Wu SJ, Zhou R: Inhibition of tumor necrosis factor-alpha reduces alveolar septal cell apoptosis in passive smoking rats. Chin Med J (Engl) 2008, 121:597-601.