Neutralization of CD95 ligand promotes regeneration and functional recovery after spinal cord injury

Abstract

The clinical outcome of spinal cord injury (SCI) depends in part on the extent of secondary damage, to which apoptosis contributes. The CD95 and tumor necrosis factor (TNF) ligand/receptor systems play an essential role in various apoptotic mechanisms. To determine the involvement of these ligands in SCI-induced damage, we neutralized the activity of CD95 ligand (CD95L) and/or TNF in spinal cord-injured mice. Therapeutic neutralization of CD95L, but not of TNF, significantly decreased apoptotic cell death after SCI. Mice treated with CD95L-specific antibodies were capable of initiating active hind-limb movements several weeks after injury. The improvement in locomotor performance was mirrored by an increase in regenerating fibers and upregulation of growth-associated protein-43 (GAP-43). Thus, neutralization of CD95L promoted axonal regeneration and functional improvement in injured adult animals. This therapeutic strategy may constitute a potent future treatment for human spinal injury.

TNF Alpha and Fas Mediate Tissue Damage and Functional Outcome after Traumatic Brain Injury in Mice

“…Fas receptor, and Fas-FADD-caspase-8 DISC, are upregulated in post-traumatic rodent and human brain (Qiu et al, 2002), and Fas inhibition reduces cell death in experimental stroke and traumatic spinal cord injury models (Casha et al, 2005;Demjen et al, 2004;MartinVillalba et al, 2001MartinVillalba et al, , 1999. These studies suggest a detrimental role for Fas, yet Fas signaling can also promote cell survival and proliferation (Lambert et al, 2003).…”

Inhibition of CXCR1 and CXCR2 chemokine receptors attenuates acute inflammation, preserves gray matter and diminishes autonomic dysreflexia after spinal cord injury

“…Both Fas and p75 receptors are implicated in apoptosis and contain intracytoplasmic death domains that activate caspases after SCI. 5,15 Previously, neutralization of the Fas receptor ligand by antibody 6 or by soluble Fas receptor infusion 5 has been shown to reduce apoptosis, promote regeneration and improve neurological recovery after dorsal column transection or spinal cord clip-compression, respectively. Although the mechanism Reparixin diminished the expression of Fas and p75 receptors is unknown, the inhibited oligodendrocyte apoptosis and preservation of the white matter around the SCI lesion 7 could be attributed to reduced levels of Fas and p75.…”

“…In this paper, we also observed that Reparixin treatment reduced the area of the spinal cord lesion, but also report a neuroprotective benefit as neurons were more abundant near the SCI lesion of Reparixin-treated rats, compared with saline-treated rats (Figure 4). Sparing of the white and gray matter could be expected as Fas is expressed by multiple cell types, including oligodendrocytes, microglia and neurons, 6 whereas p75 is predominantly expressed by oligodendrocytes. 15 In addition to neutrophils and macrophages, CXCR2 expression has also been reported on neurons and associated with cell survival after brain injury.…”

“…1 Recently, treatment strategies designed to selectively reduce inflammation and cell death after SCI have demonstrated increased axonal sparing, neuroprotection and improved neurological outcomes after SCI. [2][3][4][5][6] Targets have included chemokine receptors, 3,4,7 cell adhesion integrins, 2,8 and cytokines and death receptors 5,6 that are upregulated after SCI.…”

“…13,14 We hypothesized that acute treatment of Reparixin would modulate the acute inflammatory response, promote whiteand gray-matter sparing and improve blood pressure regulation after SCI by diminishing the development of autonomic dysreflexia. The attenuated expression of death receptors Fas and p75, previously linked to SCI-induced apoptosis, 5,6,15 was explored as a potential mechanism for the beneficial Reparixin treatment effects.…”