Neuroprotective Approaches to Enhance Recovery in Cervical Spondylotic Myelopathy
Yu WR, Lee J, Liu T, Satkunendrarajah K, Kiehl TR, Fehlings MG

Although cervical spondylotic myelopathy (CSM) is a common cause of chronic spinal
cord dysfunction in humans, little is known about the molecular mechanisms underlying
the progressive neural degeneration characterized by this condition. To characterize and
validate potential neuroprotective strategies, we developed novel mouse (twy/twy) and
rat models of chronic progressive cervical spinal cord compression to show a significant
decline in locomotor function, forelimb function, trunk stability/coordination, an increase
in mechanical allodynia, and impaired axonal conduction. Based on animal models of
CSM, we hypothesized that Fas-mediated apoptosis and inflammation may play an
important role in the pathobiology of human CSM and that neutralization of the Fas
ligand (FasL) using a function-blocking-antibody would reduce cell death, attenuate
inflammation, promote axonal repair and enhance functional neurological outcomes in
rodent models of CSM. We examined molecular changes in post-mortem human spinal
cord tissue from eight cases of patients with CSM and four control cases using
immunohistochemistry. Complementary studies were conducted using 4 month-old
twy/twy mice treated with a FasL specific antibody (50ug i.p twice weekly for 4 weeks;
n=12 per group). We found Fas-mediated apoptosis of neurons and oligodendrocytes and
an increase in inflammatory cells in the compressed spinal cords of patients with CSM.
Furthermore, neutralization of the Fas ligand with a function-blocking antibody in
twy/twy mice reduced macrophage/microglia infiltration, glial scar formation and
caspase-9 activation, and upregulated Bcl-2 expression, resulting in functional
neurological recovery. Our data demonstrate, for the first time in humans, the potential
contribution of Fas-mediated cell death and inflammation to the pathobiology of CSM.
The targeting of a death receptor pathway is a viable neuroprotective strategy to attenuate
neural degeneration and optimize neurological recovery in CSM. Our findings will open
the door to the possibility of complementary treatments to surgical decompression.

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