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Chondroitinase And Insulin-like Growth Factor Promote Nerve Regeneration After Limb Transplantation
Nataliya Kostereva, PhD; Yong Wang, MD; Jignesh Unadkat, MD; Rami Zanoun, MD; Wensheng Zhang, PhD; Timothy Ng, MD; Xin Xiao Zheng, MD; Vijay Gorantla, MD, PhD;
University of Pittsburgh

Introduction: Improvement of nerve regeneration and functional recovery is an important goal after nerve injury repair or limb transplantation, both of which are clinical reality. We hypothesize that agents such as chondroitinase, Insulin-like Growth Factor 1 (IGF-1) and tacrolimus are neurotherapeutic via different mechanisms. We studied efficacy of these modalities on nerve regeneration after experimental limb transplantation as measured by histomorphometric outcomes.

Methods: Lewis (LEW) rats were recipients of orthotopic hindlimb transplants from fully MHC mismatched Brown Norway (BN) donors. The sciatic nerve (SN) was coapted in all recipients. Control rats (group 1, n=5) received FK506 alone (0.5mg/kg/day IP). Group 2 (n=3) received chondroitinase ABC (CH)(1U/30uL Tris-HCl) injection in the donor nerve stump prior to coaptation. Group 3 (n=5) received IGF-1 at 200ng/100uL PBS (IM/day) in the transplanted limb. These last two groups (2,3) also received FK506 (0.5mg/kg/day) for 35 days (end point) to prevent acute limb/nerve rejection. Harvested SNs were cut 1 cm proximal (P) and 1 cm distal (D) to coaptation site (M). Epon embedded 500 nm nerve sections (P, M, D) were stained with 1% toluidine blue. Blinded samples were examined with binary histomorphometry software for parameters using fascicular area (FA), fiber density (FD), myelin thickness (MT), G-ratio (GR) and % nerve tissue (NT). Samples were also stained for Schwann cell marker (S100).

Results: No statistically significant difference was seen in P and D sections across groups. For M sections that represent most severely affected sites, CH treatment increased %NT 2.6 fold as compared to controls and IGF-1 (P<0.01 for both). Chondroitinase increased MT 1.7 fold to controls (P<0.01) and 1.5 fold to IGF-1 treatment (P<0.05). Staining with anti-S100 antibody has shown no significant difference between treatments and control, but number of cells has increased in CH group according to nuclear staining.

Conclusion: Chondroitinase ABC and IGF-1 augment nerve regeneration after limb transplantation with chondroitinase having superior overall efficacy on nerve histomorphometry. As they act on distinct biochemical pathways, these may have additive or synergistic effects when used in combination thus optimizing nerve regeneration. Novel treatments to improve nerve regeneration and accelerate function are key to management and rehabilitation of neurotrauma or after limb transplantation.

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