Although the central nervous system (CNS) of mammals has had poor prospects for regeneration, recent studies suggest this might improve from blocking "secondary cell loss" or apoptosis. In this regard, intravenous activated
protein C (aPC) improved neurologic outcomes in a rat
compression spinal cord injury (SCI) model.
Protein C activation occurs when the
serine protease thrombin binds to the cell surface
proteoglycan thrombomodulin (TM) forming a complex that halts coagulation. In culture, rTM blocks
thrombin's activation of
protease-activated receptors (PARs), that mediate
thrombin killing of neurons and glial reactivity. Both PAR1 and
prothrombin are rapidly upregulated after
contusion SCI in rats, prior to peak apoptosis. We now report
neuroprotective effects of intraperitoneal soluble recombinant human rTM on open-field locomotor rating scale (BBB) and spinal cord lesion volume when given 1 h after SCI. BBB scores from four separate experiments showed a 7.6 +/- 1.4 absolute score increase (p < 0.05) at 3 days, that lasted throughout the time course. Histological sections at 14 days were even more dramatic where a twofold reduction in lesion volume was quantified in rTM-treated rats.
Thionin staining revealed significant preservation of motor neuronal profiles both at, and two segments below, the lesion epicenter. Activated
caspase-3 immunocytochemistry indicated apoptosis was quite prominent in motor neurons in vehicle (saline) controls, but was dramatically reduced by rTM. Microglia, increased and activated after injury, were reduced with rTM treatment. Taken together, these and previous results support a prominent role for coagulation-
inflammation signaling cascades in the subacute changes following SCI. They identify a neuroprotective role for rTM by its inhibition of
thrombin generation and blockade of PAR activation.