Targeting anti-inflammatory treatment can ameliorate injury-induced neuropathic pain.

Tumor necrosis factor-α plays important roles in immune system development, immune response regulation, and T-cell-mediated tissue injury. The present study assessed the net value of anti-tumor necrosis factor-α treatment in terms of functional recovery and inhibition of hypersensitivity after peripheral nerve crush injury. We created a right sciatic nerve crush injury model using a Sugita aneurysm clip. Animals were separated into 3 groups: the first group received only a skin incision; the second group received nerve crush injury and intraperitoneal vehicle injection; and the third group received nerve crush injury and intraperitoneal etanercept (6 mg/kg). Etanercept treatment improved recovery of motor nerve conduction velocity, muscle weight loss, and sciatic functional index. Plantar thermal and von Frey mechanical withdrawal thresholds recovered faster in the etanercept group than in the control group. On day 7 after crush injury, the numbers of ED-1-positive cells in crushed nerves of the control and etanercept groups were increased compared to that in the sham-treated group. After 21 days, ED-1-positive cells had nearly disappeared from the etanercept group. Etanercept reduced expression of interleukin-6 and monocyte chemotactic and activating factor-1 at the crushed sciatic nerve. These findings demonstrate the utility of etanercept, in terms of both enhancing functional recovery and suppressing hypersensitivity after nerve crush. Etanercept does not impede the onset or progression of Wallerian degeneration, but optimizes the involvement of macrophages and the secretion of inflammatory mediators

Effects of etanercept on behavioral tests.

<p><b>A)</b> von Frey test <b>B)</b> Plantar test The von Frey mechanical withdrawal threshold and plantar thermal withdrawal threshold after crush operation. Control and etanercept groups exhibited mechanical hyperalgesia and thermal hyperalgesia on day 21, with effects attenuated by etanercept therapy (**<i>p</i><0.01; *<i>p</i><0.05; ‡<i>p</i><0.01; †<i>p</i><0.05, compared to sham group).</p

Effects of etanercept on TNF-α and IL-6 expression.

<p>Protein levels of TNF-α (<b>A</b>) and IL-6 (<b>B</b>) were determined in homogenized sciatic nerves. TNF-α levels were significantly increased 2 days after crush injury, but IL-6 upregulation lasted more than 21 days. Etanercept inhibited upregulation of IL-6 levels (**<i>p</i><0.01; *<i>p</i><0.05; ‡<i>p</i><0.01; †<i>p</i><0.05, compared to the sham group).</p

Effects of etanercept on sciatic functional index.

<p>Variations in sciatic functional index between groups after nerve crush injury. Sciatic functional index differed significantly between the 3 groups (**<i>p</i><0.01; *<i>p</i><0.05).</p

Effect of etanercept on wet muscle weight measurement.

<p>Control group showed a significantly lower percentage of wet muscle weight than the etanercept group on day 21 (**<i>p</i><0.01).</p

Immunohistochemical staining for macrophage marker ED-1 in crushed sciatic nerve sections.

<p><b>A)</b> Sham-treated 7 days after surgery; <b>B)</b> control 7 days after surgery; <b>C)</b> etanercept-treated 7 days after surgery; <b>D)</b> sham-treated 21 days after surgery; <b>E)</b> control 21 days after surgery; and <b>F)</b> etanercept-treated 21 days after surgery. By 21 days, ED-1-positive cells had nearly disappeared from the etanercept group.</p