Myelin basic protein (MBP) is an auto-antigen able to induce intractable pain from innocuous mechanical stimulation (mechanical allodynia). The mechanisms provoking this algesic MBP activity remain obscure. Our present study demonstrates that membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) releases the algesic MBP peptides from the damaged myelin, which then reciprocally enhance the expression of MT1-MMP in nerve to sustain a state of allodynia. Specifically, MT1-MMP expression and activity in rat sciatic nerve gradually increased starting at day 3 after chronic constriction injury (CCI). Inhibition of the MT1-MMP activity by intraneural injection of the function-blocking human DX2400 monoclonal antibody at day 3 post-CCI reduced mechanical allodynia and neuropathological signs of Wallerian degeneration, including axon demyelination, degeneration, edema and formation of myelin ovoids. Consistent with its role in allodynia, the MT1-MMP proteolysis of MBP generated the MBP69-86-containing epitope sequences in vitro. In agreement, the DX2400 therapy reduced the release of the MBP69-86 epitope in CCI nerve. Finally, intraneural injection of the algesic MBP69-86 and control MBP2-18 peptides differentially induced MT1-MMP and MMP-2 expression in the nerve. With these data we offer a novel, self-sustaining mechanism of persistent allodynia via the positive feedback loop between MT1-MMP and the algesic MBP peptides. Accordingly, short-term inhibition of MT1-MMP activity presents a feasible pharmacological approach to intervene in this molecular circuit and the development of neuropathic pain.

Patients with end-stage liver disease show sarcopenia, and preoperative sarcopenia is independently associated with patient mortality after liver transplantation. However, few studies have examined the relationship between perioperative loss of core muscle and patient mortality in living donor liver transplantation (LDLT). This study was performed to investigate the association between a perioperative decrease in the psoas muscle index (PMI) and patient mortality after LDLT. Adult patients (age ≥ 18 years) undergoing LDLT between January 2009 and December 2016 were classified into low-loss (>25th quartile) versus high-loss (≤25th quartile) groups according to PMI change between the day before surgery and postoperative day (POD) 7. Patient survival was compared between the 2 groups, and factors affecting survival were analyzed. The median (interquartile range) level of PMI change from the day before surgery to POD 7 was -4.8% (-11.7%-1.2%). Although there was no preoperative difference in PMI between the low-loss and high-loss groups, patients with PMI change ≤-11.7% showed poorer survival than those with PMI change >-11.7% during the follow-up period. A PMI decrease ≤-11.7% between the day before surgery and POD 7 is an independent predictor of patient mortality after LDLT. In addition, intraoperative packed red blood cell transfusion, graft fat percentage, and reoperation and infection after surgery were significantly associated with patient mortality. In conclusion, a PMI decrease ≤-11.7% between the day before surgery and POD 7 is an independent predictor of patient mortality after LDLT. It is necessary to identify the factors responsible for the perioperative decrease in skeletal muscle mass and to ascertain if they are modifiable to improve patient survival after LDLT. Liver Transplantation 24 623-633 2018 AASLD.