title: Viral vector mediated continuous expression of interleukin-10 in DRG alleviates pain in type 1 diabetic animals.
abstract: Painful diabetic neuropathy is a common and difficult to treat complication of diabetes. A growing body of evidence implicates the role of inflammatory mediators in the damage to the peripheral axons and in the pathogenesis of neuropathic pain. Increased expression of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the peripheral nervous system suggests the possibility of change in pain perception in diabetes. In this study we investigated that continuous delivery of IL10 in the nerve fibers achieved by HSV vector mediated transduction of dorsal root ganglion (DRG) in animals with Type 1 diabetes, blocks the nociceptive and stress responses in the DRG neurons by reducing IL1β expression along with inhibition of phosphorylation of p38 MAPK (mitogen-activated protein kinase) and protein kinase C (PKC). The continuous expression of IL10 also alters Toll like receptor (TLR)-4 expression in the DRG with increased expression of heat shock protein (HSP)-70 in conjunction with the reduction of pain. Taken together, this study suggests that macrophage activation in the peripheral nervous system may be involved in the pathogenesis of pain in Type 1 diabetes and therapeutic benefits of HSV mediated local expression of IL10 in the DRG with the reduction of a number of proinflammatory cytokines, subsequently inhibits the development of painful neuropathy along with a decrease in stress associated markers in the DRG. This basic and preclinical study provides an important evidence for a novel treatment strategy that could lead to a clinical trial for what is currently a treatment resistant complication of diabetes.
authors.affiliation: Center of Excellence in Diabetes and Obesity, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, United States.
authors.forename: Vikram
authors.initials: V
authors.lastname: Thakur
authors.affiliation: Center of Excellence in Diabetes and Obesity, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, United States.
authors.forename: Mayra
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: Center of Excellence in Diabetes and Obesity, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, United States.
authors.forename: Kristen
authors.initials: K
authors.lastname: Pennington
authors.affiliation: Center of Excellence in Diabetes and Obesity, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, United States. Electronic address: munmun.chattopadhyay@ttuhsc.edu.
authors.forename: Munmun
authors.initials: M
authors.lastname: Chattopadhyay
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000378:metabolism* / Q000628:therapy; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018139:Simplexvirus / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases
keywords: DRG; Diabetic neuropathy; Gene therapy; Inflammation, TLR4; Interleukin-10; Pain