The potential for salmon fibrin and thrombin to mitigate pain subsequent to cervical nerve root injury

Abstract

Nerve root compression is a common cause of radiculopathy and induces persistent pain. Mammalian fibrin is used clinically as a coagulant but presents a variety of risks. Fish fibrin is a potential biomaterial for neural injury treatment because it promotes neurite outgrowth, is non-toxic, and clots readily at lower temperatures. This study administered salmon fibrin and thrombin following nerve root compression and measured behavioral sensitivity and glial activation in a rat pain model. Fibrin and thrombin each significantly reduced mechanical allodynia compared to injury alone (p<0.02). Painful compression with fibrin exhibited allodynia that was not different from sham for any day using stimulation by a 2 g filament; allodynia was only significantly different (p<0.043) from sham using the 4 g filament on days 1 and 3. By day 5, responses for fibrin treatment decreased to sham levels. Allodynia following compression with thrombin treatment were unchanged from sham at any time point. Macrophage infiltration at the nerve root and spinal microglial activation were only mildly modified by salmon treatments. Spinal astrocytic expression decreased significantly with fibrin (p<0.0001) but was unchanged from injury responses for thrombin treatment. Results suggest that salmon fibrin and thrombin may be suitable biomaterials to mitigate pain.

Salmon-derived thrombin inhibits development of chronic pain through an endothelial barrier protective mechanism dependent on APC

“…In addition to salmon thrombin’s anti-nociceptive, neuroprotective and anti-inflammatory capabilities distinct from human thrombin (38,39,60), this work is the first to show that it also uniquely blocks vessel permeability both in the spinal cord after neural injury and in HUVEC microvessels after TNF-α stimulation (Figs. 2B and 2C).…”

“…Fixed C7 spinal cord sections were fluorescently immunolabeled for rat IgG AlexaFluor 568 (1:200; Life Technologies). Images of the bilateral dorsal horns (n=3-6 sections/rat) were analyzed using a customized densitometry MATLAB code to quantify IgG labeling, which was then compared to labeling in tissue from naïve rats (39,40,43). Normalized percent IgG was compared between groups on days 1 and 7 using a two-way ANOVA (group × day) with Tukey’s HSD test.…”

“…Salmon thrombin (15min+STh, n=5) or human (15min+HTh, n=4) thrombin solutions were delivered directly on top of the C7 nerve root immediately after removal of the compression (38,39,43). A control group received 20μl of NB media alone to account for the effects of the vehicle (vehicle, n=5).…”

“…Salmon thrombin induces lower levels of platelet aggregation and astrocytic transcription of pro-inflammatory cytokines compared to human thrombin at the same concentration (37,38). We have shown that salmon thrombin uniquely inhibits the development of neuropathic pain after a nerve root compression injury and activates PAR1 to a lower degree than human thrombin (38,39). We hypothesize that salmon thrombin may prevent neural pain by exhibiting a higher affinity for protein C than mammalian thrombin promoting its ability to provide vascular protection.…”

“…Specifically, thrombin derived from salmon exhibits nearly indistinguishable clotting capabilities, but initiates different cell signaling cascades compared to human thrombin (36-39). Salmon thrombin induces lower levels of platelet aggregation and astrocytic transcription of pro-inflammatory cytokines compared to human thrombin at the same concentration (37,38).…”