Distribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve.
Tumor necrosis factor-alpha (TNF) is a pro-inflammatory cytokine that is implicated in the initiation of neuropathic pain. Locally administered TNF antagonist etanercept offers a promising new treatment approach to target neuropathic pain. Here we evaluate the distribution and binding specificity for TNF isoforms of locally administered etanercept into injured and uninjured rat sciatic nerve. Distribution and co-localization of etanercept and TNF in the injured and uninjured nerve was evaluated at 1, 24, 48 and 96 h after etanercept local application using immunohistochemistry. In addition, binding specificity of etanercept for TNF isoforms was analyzed using immunoblot assay system in nerve lysates. A new observation was that locally administered etanercept reached the endoneurium of the injured but not the uninjured nerve 1 h after its application and mainly co-localized with TNF-positive structures, morphologically similar to Schwann cells and macrophages. We further noticed that immunoblot analyses for etanercept demonstrated its preferential binding to transmembrane and trimer TNF isoforms. Finally, locally administered etanercept inhibited pain-related behaviors in a rat sciatic nerve crush model. We conclude that locally administered etanercept reaches the endoneurial space in the injured nerve and preferentially binds to transmembrane and bioactive trimer TNF isoforms to modulate neuropathic pain. Locally administered etanercept has potential as a targeted immunomodulating agent to treat local pathogenesis in neuropathic pain after peripheral nerve injury.
Kato
K
K
Department of Anesthesiology, University of California, San Diego and the VA Medical Center, 9500 Gilman Drive, La Jolla, CA 92093-0629, USA. kinshikato@gmail.com
Kikuchi
S
S
Shubayev
V I
VI
Myers
R R
RR
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D000068800:Etanercept; D005260:Female; D005500:Follow-Up Studies; D007074:Immunoglobulin G / Q000378:metabolism* / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D007155:Immunologic Factors / Q000378:metabolism* / Q000494:pharmacology; D009409:Nerve Crush; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D020033:Protein Isoforms; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D012584:Sciatic Nerve / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000378:metabolism*; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D007074:Immunoglobulin G; D007155:Immunologic Factors; D020033:Protein Isoforms; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept