Progressive neurological damage after brain or
spinal cord trauma causes loss of motor function and treatment is very limited. Clotting and
hemorrhage occur early after spinal cord (SCI) and
traumatic brain injury (TBI), inducing aggressive immune cell activation and progressive neuronal damage. Thrombotic and thrombolytic
proteases have direct effects on neurons and glia, both healing and also damaging bidirectional immune cell interactions.
Serine proteases in the thrombolytic cascade, tissue- and
urokinase-type
plasminogen activators (tPA and uPA), as well as the
clotting factor thrombin, have varied effects, increasing neuron and glial cell growth and migration (tPA), or conversely causing apoptosis (
thrombin) and activating inflammatory cell responses. tPA and uPA activate
plasmin and
matrix metalloproteinases (
MMPs) that break down connective tissue allowing immune cell invasion, promoting neurite outgrowth.
Serine proteases also activate
chemokines.
Chemokines are small
proteins that direct immune cell invasion but also mediate neuron and glial cell communication. We are investigating a new class of
therapeutics, virus-derived immune modulators; One that targets coagulation pathway
serine proteases and a second that inhibits
chemokines. We have demonstrated that local infusion of these biologics after SCI reduces
inflammation providing early improved motor function. Serp-1 is a Myxomavirus-derived
serine protease inhibitor, a
serpin, that inhibits both thrombotic and thrombolytic
proteases. M-T7 is a virus-derived
chemokine modulator. Here we review the roles of thrombotic and thrombolytic
serine proteases and
chemoattractant proteins,
chemokines, as potential therapeutic targets for SCI. We discuss virus-derived immune modulators as treatments to reduce progressive
inflammation and ongoing nerve damage after SCI.