Human neuropathological and animal model evidence supporting a role for Fas-mediated apoptosis and inflammation in cervical spondylotic myelopathy

Abstract

Although cervical spondylotic myelopathy 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. Based on animal models of cervical spondylotic myelopathy and traumatic spinal cord injury, we hypothesized that Fas-mediated apoptosis and inflammation may play an important role in the pathobiology of human cervical spondylotic myelopathy. We further hypothesized that neutralization of the Fas ligand using a function-blocking antibody would reduce cell death, attenuate inflammation, promote axonal repair and enhance functional neurological outcomes in animal models of cervical spondylotic myelopathy. We examined molecular changes in post-mortem human spinal cord tissue from eight patients with cervical spondylotic myelopathy and four control cases. Complementary studies were conducted using a mouse model of cervical spondylotic myelopathy (twy/twy mice that develop spontaneous cord compression at C2-C3). We observed Fas-mediated apoptosis of neurons and oligodendrocytes and an increase in inflammatory cells in the compressed spinal cords of patients with cervical spondylotic myelopathy. Furthermore, neutralization of Fas ligand with a function-blocking antibody in twy/twy mice reduced neural inflammation at the lesion mediated by macrophages and activated microglia, glial scar formation and caspase-9 activation. It was also associated with increased expression of Bcl-2 and promoted dramatic 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 cervical spondylotic myelopathy. Complementary data in a murine model of cervical spondylotic myelopathy further suggest that targeting the Fas death receptor pathway is a viable neuroprotective strategy to attenuate neural degeneration and optimize neurological recovery in cervical spondylotic myelopathy. Our findings highlight the possibility of medical treatments for cervical spondylotic myelopathy that are complementary to surgical decompression.

Neurodegeneration in the Spinal Ventral Horn Prior to Motor Impairment in Cervical Spondylotic Myelopathy

“…6,33 In this study, we show extensive neurodegeneration several segments above the level of compression in the spinal ventral and dorsal horns in-vivo. Interestingly, the ventral horns showed diffusivity changes (i.e.…”

“…3 Next to focal myelopathy, [4][5][6] a cascade of neurodegenerative processes is evident in the grey and white matter above the site of compression in the cervical cord [7][8][9][10] and even in the sensorimotor cortex 11,12 that can be assessed non-invasively, amongst others, by magnetic resonance spectroscopy and diffusion tensor imaging (DTI) and other advanced MRI techniques sensitive to atrophy and microstructural changes. 13 Microstructural changes can be identified by diffusivity indices (e.g.…”

“…Reduced FA and increased MD have both been associated with loss of axonal count and myelin content. [14][15][16] Neuroprotective treatments 6,17 to improve functional independence and quality of life have entered clinical trials. 18 However, there is a need to detect and monitor subclinical trajectories prior to marked clinical impairment in tissue at risk (i.e.…”

Treatment considerations of cervical spondylotic myelopathy

“…2,11,15,16 The third component consists of histopathologic and vascular changes resulting in ischemia, infarction, apoptosis, and other toxic cell alterations. [17][18][19][20] The natural history of CSM seems dependent on the severity of the condition. It is generally accepted that patients with severe symptoms will not improve or will undergo a steady progression.…”

Cytokine Concentrations in the Cerebrospinal Fluid of Great Danes with Cervical Spondylomyelopathy

“…Gaps in the knowledge of the disease pathobiology have historically limited therapeutic advances in this human condition and current studies are actively investigating the disease pathogenesis with the objective of developing new neuroprotective approaches to improve outcome 3, 4, 5, 6, 7, 8, 9. Rodent models of cervical spondylotic myelopathy show that neuronal and oligodendrocyte apoptosis, chronic neuroinflammation, and microvascular compromise result in progressive neural degeneration and potentially irreversible spinal cord (SC) damage and could be related to treatment failure, poor long‐term outcome, or both 3, 4, 5, 6, 7, 8, 9. Similar changes have been observed in the SC of CSM‐affected dogs 2.…”