Involvement of mitochondrial signaling pathways in the mechanism of Fas‐mediated apoptosis after spinal cord injury

Abstract

Activation of the Fas receptor has been recently linked to apoptotic cell death after spinal cord injury (SCI). Although it is generally considered that Fas activation mediates apoptosis predominantly through the extrinsic pathway, we hypothesized that intrinsic mitochondrial signaling could be involved in the underlying mechanism of Fas-induced apoptosis after SCI. In the present study, we utilized the Fejota clip compression model of SCI at T5-6 in C57BL/6 Fas-deficient (lpr) and wild-type mice. Complementary studies were conducted using an in vitro model of trauma or a Fas-activating antibody to induce apoptosis in primary neuronal-glial mixed spinal cord cultures. After in vivo SCI, lpr mice, in comparison with wild-type mice, exhibited reduced numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells at the lesion, reduced expression of truncation of Bid (tBid), apoptosis-inducing factor, activated caspase-9 and activated caspase-3, and increased expression of the antiapoptotic proteins Bcl-2 and Bcl-xL. After in vitro neurotrauma or the induction of Fas signaling by the Jo2 activating antibody, lpr spinal cord cultures showed an increased proportion of cells retaining mitochondrial membrane integrity and a reduction of tBid expression, caspase-9 and caspase-3 activation, and TUNEL-positive cells as compared to wild-type spinal cord cultures. The neutralization of Fas ligand (FasL) protected against traumatically induced or Fas-mediated caspase-3 activation and the loss of mitochondrial membrane potential and tBid expression in wild-type spinal cord cultures. However, in lpr spinal cord cultures, FasL neutralization had no protective effects. In summary, these data provide direct evidence for the induction of intrinsic mitochondrial signaling pathways following Fas activation after SCI.

Neutralization of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Reduces Spinal Cord Injury Damage in Mice

“…In this line, increased FasL and TNF-a expression have also been reported after SCI, although their neutralization is not always correlated to functional outcome (Demjen et al, 2004;Genovese et al, 2008;Yu et al, 2009). In this paper, we show the prominent function of TRAIL and the related molecules in the cell death phenomena related to SCI, as well as how the molecular phenomena underlying can be partially prevented by neutralization of TRAIL, resulting in significant improvement of histopathological and functional outcome.…”

Kainate-Mediated Excitotoxicity Induces Neuronal Death in the Rat Spinal Cord In Vitro via a PARP-1 Dependent Cell Death Pathway (Parthanatos)

“…However, pyknosis may be observed as a result of various cell death pathways (Burgoyne 1999). This realization prompted us to explore alternative processes for delayed death since we have recently observed that cells die even several hours after washout of kainate (Mazzone et al 2010) even if, in the field of spinal cord injury research, a common view is that the early cell death is predominantly by necrosis followed by apoptosis (Liu et al 1997;Baptiste and Fehlings 2006) that can be caspase-dependent (Liu et al 2002;Yu et al 2009) and caspase-independent (Eliasson et al 1997;Mandir et al 2000;Verdaguer et al 2002;Won et al 2002;Yuan et al 2003;Cho and Toledo-Pereyra 2008;Kanno et al 2009). Recently, an alternative cell death pathway, termed parthanatos, involving hyperactivity of poly(ADPribose) polymerase-1 (PARP-1) has been considered important to spinal cord injury (Scott et al 1999;Genovese et al 2005;Wu et al 2009) because it would strongly impair the mitochondrial energy stores.…”

Effects of Dexamethasone on Autophagy and Apoptosis in Acute Spinal Cord Injury

“…Some scholars believe that animal and clinical trials have proven that large doses of steroids have significant curative effects, supporting the administration of early high-dose glucocorticoid therapy following spinal cord injury [19][20][21][22]. Recently, Liu et al as well as other researchers have reported that small doses of glucocorticoids induce autophagy and protect cartilage cells, but long-term large doses can promote chondrocyte apoptosis [23].…”