**Neuroprotective Approaches to Enhance Recovery in Cervical Spondylotic Myelopathy
Michael G. Fehlings, MD, PhD, FRCSC

Background.  Cervical spondylotic myelopathy (CSM) is a chronic progressive disorder in which the cervical spinal cord undergoes compression secondary to degenerative disc disease or ossification of the posterior longitudinal ligament.  CSM is the most common cause of spinal cord impairment world-wide and yet has received remarkably little attention from a translational research perspective.  Despite advances in decompressive surgery, there are no effective neuroprotective treatments for CSM, which reflects a lack of detailed understanding of the pathophysiology underlying neural degeneration in this condition.  Thus, novel neuroprotective strategies are needed.

Hypotheses.  Based on promising preliminary results and previous work in complementary models of traumatic SCI, the present proposal examines the following hypotheses:  1)  Fas-mediated apoptosis contributes significantly to cell death in a novel preclinical model of CSM and in human CSM; 2)  The inhibition of apoptosis with an anti-FasL antibody will attenuate cell death and enhance neurobehavioral recovery in models of CSM; 3)  The inhibition of apoptosis with the sodium/glutamate blocker riluzole will attenuate cell death and enhance neurobehavioral recovery in models of CSM; 4)  Neuroprotective approaches includind Fas-inhibition and riluzole treatment will augment the beneficial effects of spinal cord decompression in models of CSM.

Experimental Approach.  Studies will be undertaken in the Twy/twy mouse model of spontaneous C2-C3 cord compression, in a novel rodent model of induced progressive cervical cord compression, and using human postmortem spinal cord tissue obtained from deceased CSM patients.  A combination of molecular, neuroanatomical, and neurobehavioral techniques will be used to address key pathophysiological questions and to examine promising therapeutic approaches.

Aim 1.  Assessment of the significance of inflammation and Fas-mediated apoptosis in the pathophysiology of CSM.

Aim 2.  Examination of the neuroprotective effects of Fas-inhibition and/or administration of the sodium/glutamate
antagonist riluzole in rodent models of CSM.

Aim 3.  Examination of the potential complementary effects of spinal cord decompression and neuroprotective approaches (riluzole and/or antiFasL) in a rodent model of CSM.

Impact.  This application seeks to explore key pathophysiological mechanisms underlying neural degeneration in CSM and to assess promising translationally relevant therapeutic approaches for this common and disabling cause of neurological impairment.  Given that riluzole is FDA-approved for the treatment of amytrophic lateral sclerosis and is undergoing Phase I trails in traumatic spinal cord injury, the current study could provide key preclinical data to facilitate a trial in patients with CSM.  

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**Current and ongoing research