Decrease in neuroimmune activation by HSV-mediated gene transfer of TNF alpha soluble receptor alleviates pain in rats with diabetic neuropathy

作者：Ortmann Kathryn L Maier; Chattopadhyay Munmun^*

来源：Brain, Behavior, and Immunity, 2014, 41: 144-151.

DOI：10.1016/j.bbi.2014.05.009

• Diabetic neuropathy
• Pain behavior
• TNF-alpha
• DRG
• Gene therapy
• Inflammation

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 alpha (TNF-alpha) 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-alpha is a key inflammatory mediator to the diabetic neuropathic pain and whether continuous delivery of TNF alpha 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 TNF alpha 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 alpha soluble receptor significantly attenuated the diabetes-induced hyperalgesia and decreased the expression of TNF alpha 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.

• 出版日期2014-10