Vein wrapping for chronic nerve constriction injury in a rat model: Study showing increases in VEGF and HGF production and prevention of pain-associated behaviors and nerve damage

摘要

Background: Although efficacious clinical results have been reported after vein wrapping for the treatment of recurrent compressive neuropathy, the mechanism of nerve protection remains uncertain. Methods: Eight-week-old male Wistar rats (n = 90) were randomly divided into three groups: sham procedure, chronic constriction injury, and chronic constriction injury plus vein wrapping. Mechanical withdrawal thresholds and walking patterns were measured with use of von Frey filaments and the CatWalk system, respectively. We investigated L4-L5 dorsal root ganglia immunohistochemically at fourteen days postsurgery and sciatic nerves histologically at fourteen days and again five months postsurgery. Concentrations of several sciatic neurotrophic factors in the ligated sciatic nerves were quantified with use of ELISA (enzyme-linked immunosorbent assay). Results: In behavioral tests, the rats in which the chronic constriction injury had been followed by vein wrapping displayed significantly greater pain responses than the sham group, and the group with untreated chronic constriction injury showed greater pain responses than the vein-wrapping group (both p < 0.05). Immunoreactive markers of inflammation and nerve damage, calcitonin gene-related peptide (CGRP) and activating transcription factor-3 (ATF3), were upregulated in dorsal root ganglion neurons in the constriction-injury and vein-wrapping groups compared with those in the sham group, with greater upregulation in the constriction-injury group than in the vein-wrapping group (both p < 0.01). Histologic observation showed marked nerve degeneration and scar tissue formation around the sciatic nerve in the constriction-injury group, but these effects were prevented to some extent in the vein-wrapping group. Vascular endothelial growth factor (VEGF) levels at one and three days postsurgery and hepatocyte growth factor (HGF) levels at three, seven, fourteen, and twenty-eight days postsurgery were significantly higher in the vein-wrapping group than in the other groups (p < 0.05). Conclusions: Vein wrapping decreased pain-associated behavior and nerve damage caused by chronic constriction injury. VEGF and HGF produced in response to vein grafts may play a mechanistic role. Clinical Relevance: These findings may lead to development of new therapies employing growth factors, with or without other materials, that simulate vein wrapping.