title: Decrease in neuroimmune activation by HSV-mediated gene transfer of TNFα soluble receptor alleviates pain in rats with diabetic neuropathy.
abstract: The mechanisms of diabetic painful neuropathy are complicated and comprise of peripheral and central pathophysiological phenomena. A number of proinflammatory cytokines are involved in this process. Tumor necrosis factor α (TNF-α) is considered to be one of the major contributors of neuropathic pain. In order to explore the potential role of inflammation in the peripheral nervous system of Type 1 diabetic animals with painful neuropathy, we investigated whether TNF-α is a key inflammatory mediator to the diabetic neuropathic pain and whether continuous delivery of TNFα soluble receptor from damaged axons achieved by HSV vector mediated transduction of DRG would block or alter the pain perception in animals with diabetic neuropathy. Diabetic animals exhibited changes in threshold of mechanical and thermal pain perception compared to control rats and also demonstrated increases in TNFα in the DRG, spinal cord dorsal horn, sciatic nerve and in the foot skin, 6 weeks after the onset of diabetes. Therapeutic approaches by HSV mediated expression of p55 TNF soluble receptor significantly attenuated the diabetes-induced hyperalgesia and decreased the expression of TNFα with reduction in the phosphorylation of p38MAPK in the spinal cord dorsal horn and DRG. The overall outcome of this study suggests that neuroinflammatory activation in the peripheral nervous system may be involved in the pathogenesis of painful neuropathy in Type 1 diabetes which can be alleviated by local expression of HSV vector expressing p55 TNF soluble receptor.
authors.affiliation: Department of Neurology, University of Michigan, USA; University of Texas, Health Science Center at Houston, Houston, TX, USA.
authors.forename: Kathryn L Maier
authors.initials: KL
authors.lastname: Ortmann
authors.affiliation: Department of Neurology, University of Michigan, USA; VA Ann Arbor Healthcare System, Ann Arbor, MI, USA. Electronic address: munmun.chattopadhyay@ttuhsc.edu.
authors.forename: Munmun
authors.initials: M
authors.lastname: Chattopadhyay
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003929:Diabetic Neuropathies / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D005528:Foot; D005727:Ganglia, Spinal / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000209:etiology / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D007249:Inflammation; D008297:Male; D009437:Neuralgia / Q000209:etiology / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D017288:Pain Threshold; D020671:Posterior Horn Cells / Q000378:metabolism; D011312:Pressure / Q000009:adverse effects; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000627:therapeutic use*; D012584:Sciatic Nerve / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics; D016037:Single-Blind Method; D012867:Skin / Q000378:metabolism; D014161:Transduction, Genetic; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics / Q000627:therapeutic use*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; C069521:recombinant human tumor necrosis factor-binding protein-1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: DRG; Diabetic neuropathy; Gene therapy; Inflammation; Pain behavior; TNF-α