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Improvement of spinal non-viral IL-10 gene delivery by D-mannose as a transgene adjuvant to control chronic neuropathic pain
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نویسنده
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dengler e.c. ,alberti l.a. ,bowman b.n. ,kerwin a.a. ,wilkerson j.l. ,moezzi d.r. ,limanovich e. ,wallace j.a. ,milligan e.d.
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منبع
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journal of neuroinflammation - 2014 - دوره : 11 - شماره : 0
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چکیده
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Background: peri-spinal subarachnoid (intrathecal; i.t.) injection of non-viral naked plasmid dna encoding the anti-inflammatory cytokine,il-10 (pdna-il-10) suppresses chronic neuropathic pain in animal models. however,two sequential i.t. pdna injections are required within a discrete 5 to 72-hour period for prolonged efficacy. previous reports identified phagocytic immune cells present in the peri-spinal milieu surrounding the i.t injection site that may play a role in transgene uptake resulting in subsequent il-10 transgene expression. methods: in the present study,we aimed to examine whether factors known to induce pro-phagocytic anti-inflammatory properties of immune cells improve i.t. il-10 transgene uptake using reduced naked pdna-il-10 doses previously determined ineffective. both the synthetic glucocorticoid,dexamethasone,and the hexose sugar,d-mannose,were factors examined that could optimize i.t. pdna-il-10 uptake leading to enduring suppression of neuropathic pain as assessed by light touch sensitivity of the rat hindpaw (allodynia). results: compared to dexamethasone,i.t. mannose pretreatment significantly and dose-dependently prolonged pdna-il-10 pain suppressive effects,reduced spinal il-1β and enhanced spinal and dorsal root ganglia il-10 immunoreactivity. macrophages exposed to d-mannose revealed reduced proinflammatory tnf-α,il-1β,and nitric oxide,and increased il-10 protein release,while il-4 revealed no improvement in transgene uptake. separately,d-mannose dramatically increased pdna-derived il-10 protein release in culture supernatants. lastly,a single i.t. co-injection of mannose with a 25-fold lower pdna-il-10 dose produced prolonged pain suppression in neuropathic rats. conclusions: peri-spinal treatment with d-mannose may optimize naked pdna-il-10 transgene uptake for suppression of allodynia,and is a novel approach to tune spinal immune cells toward pro-phagocytic phenotype for improved non-viral gene therapy. © 2014 dengler et al.; licensee biomed central ltd.
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کلیدواژه
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Allodynia; Cytokine; Dexamethasone; Immunofluorescence microscopy; Interleukin-1β; Intrathecal injection; M2 polarized; Rat; Sciatic nerve
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آدرس
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department of neurosciences,unm school of medicine,university of new mexico health sciences center,1 university of new mexico,albuquerque,nm 87131-0001, United States, department of neurosciences,unm school of medicine,university of new mexico health sciences center,1 university of new mexico,albuquerque,nm 87131-0001, United States, department of neurosciences,unm school of medicine,university of new mexico health sciences center,1 university of new mexico,albuquerque,nm 87131-0001, United States, department of neurosciences,unm school of medicine,university of new mexico health sciences center,1 university of new mexico,albuquerque,nm 87131-0001, United States, department of neurosciences,unm school of medicine,university of new mexico health sciences center,1 university of new mexico,albuquerque,nm 87131-0001, United States, department of neurosciences,unm school of medicine,university of new mexico health sciences center,1 university of new mexico,albuquerque,nm 87131-0001, United States, department of anesthesiology and critical care medicine,school of medicine,university of new mexico health sciences center,1 university of new mexico,msc10 6000,albuquerque,nm 87106, United States, department of neurosciences,unm school of medicine,university of new mexico health sciences center,1 university of new mexico,albuquerque,nm 87131-0001, United States, department of neurosciences,unm school of medicine,university of new mexico health sciences center,1 university of new mexico,albuquerque,nm 87131-0001,united states,department of neurosciences,health sciences center,school of medicine,university of new mexico,albuquerque,nm 87131-5223, United States
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Authors
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