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The possibility to prevent nucleus pulposus-induced functional and structural nerve root injury by selective tumor necrosis factor-α inhibition was assessed in an experimental model in the pig spine.The objective of the study was to evaluate the role of tumor necrosis factor-α in the mediation of nucleus pulposus-induced nerve injury by using selective inhibition.The cytokine tumor necrosis factor-α has been suggested to play a key role in the nerve root injury induced by local application of nucleus pulposus. However, previous studies have not been able to distinguish the effects between tumor necrosis factor-α and other disc-related cytokines because of the use of nonspecific cytokine inhibition.Autologous nucleus pulposus was harvested from a lumbar disc and applied to the porcine sacrococcygeal cauda equina. The pigs were simultaneously treated with two selective tumor necrosis factor-α inhibitors (etanercept n = 8 and infliximab n = 5), a heparin analogue (enoxaparin n = 5) or saline for control (n = 5). After 7 days the nerve conduction velocity over the application zone was determined and samples of the exposed nerve roots were collected for light microscopic evaluation.The two tumor necrosis factor-α inhibitors prevented the reduction of nerve conduction velocity and also seemed to limit the nerve fiber injury, the intracapillary thrombus formation, and the intraneural edema formation. However, treatment with enoxaparin did not seem to be different from control regarding reduction of nerve conduction velocity or histologic changes.The data clearly indicate that tumor necrosis factor-α is involved in the basic pathophysiologic events leading to nerve root structural and functional changes after local application of nucleus pulposus. The study therefore provides a basic scientific platform with potential clinical implications regarding the use of anti-tumor necrosis factor-α medication as treatment in patients with disc herniation and sciatica.