Effects of thrombin and protease nexin-1 on peripheral nerve regeneration

Thrombin and serine protease inhibitors such as protease nexin-1 (PN-1) have been implicated in neurite outgrowth activity. We compared rat sciatic nerve regeneration in 10-mm silicone tubes, bridging an 8-mm nerve gap, that were prefilled with thrombin (1.5 IU) and PN-1 (50 micrograms/mL or 1 mg/mL) to those filled with saline solution (control). Neural regeneration and fibrinoid matrix progression (deposition of extracellular matrix) were analyzed at 1, 4, 17, and 21 days after silicone tube implantation. At 1 and 4 days after implantation, thrombin reduced fibrinoid matrix length propagation from both the proximal and distal transected nerve stumps, but PN-1 and saline did not interfere with matrix progression (p < .05). Seventeen days after implantation, the number of silicone tubes containing myelinated neuronal regenerates at the mid-tube region was 1 of 6 for thrombin, 6 of 9 for PN-1, and 6 of 10 for saline solution. Twenty-one days after implantation, 11 of 11 tubes with saline solution, 9 of 11 with PN-1 at 1 mg/mL, and 7 of 9 with PN-1 at 50 micrograms/mL had myelinated neural regenerates in the mid-silicone tube region, while only 2 of 9 thrombin-containing silicone tubes contained myelinated axons. There was no statistically significant difference in myelinated neurite regenerates at 17 and 21 days after implantation among silicone tubes prefilled with saline solution and PN-1 (50 micrograms/mL or 1 mg/mL). Thrombin interfered with matrix progression and significantly reduced the number of myelinated neurite regenerates (p = .01). The PN-1 and saline solutions did not inhibit matrix progression or affect the number of myelinated axonal regenerates (p = .92).