Fas/CD95/APO‐1 Can Function as a Death Receptor for Neuronal Cells in Vitro and in Vivo and is Upregulated Following Cerebral Hypoxic‐Ischemic Injury to the Developing Rat Brain

Abstract

Fas/CD95/Apo-1 is a cell surface receptor that transduces apoptotic death signals following activation and has been implicated in triggering apoptosis in infected or damaged cells in disease states. Apoptosis is a major mechanism of neuronal loss following hypoxic-ischemic injury to the developing brain, although the role of Fas in this process has not been studied in detail. In the present study, we have investigated the expression and function of Fas in neuronal cells in vitro and in vivo. Fas was found to be expressed in the 14 day old rat brain, with strongest expression in the cortex, hippocampus and cerebellum. Cross-linking of Fas induced neuronal apoptosis both in neuronal PC12 cells in culture and following intracerebral injection in vivo, indicating that neuronal Fas was functional as a death receptor. This death was shown to be caspase dependent in primary neuronal cultures and was blocked by the selective caspase 8 inhibitor IETD. Finally, cerebral hypoxia-ischemia resulted in a strong lateralised upregulation of Fas in the hippocampus, that peaked six to twelve hours after the insult and was greater on the side of injury. These results suggest that Fas may be involved in neuronal apoptosis following hypoxic-ischemic injury to the developing brain.

Tissue inhibitor of metalloproteinases-3 facilitates Fas-mediated neuronal cell death following mild ischemia

“…As illustrated in the merged images, cortical neurons uniformly express both Fas and FasL in culture. These data are consistent with previous reports demonstrating that Fas 2,6,25,27 and FasL 2,25,27 are constitutively expressed by cultured rodent cortical neurons, and that expression of these death receptors and their ligands alone is not sufficient to induce neuronal death.…”

“…Although Fas signaling is historically recognized for its role in immune modulation, Fas and FasL are also expressed in the adult mammalian nervous system and are thought to contribute to cell death in CNS trauma, 2 neurodegenerative disease, 3 multiple sclerosis 4 and ischemia. [5][6][7][8][9] Following focal cerebral ischemia in rodents, Fas gene expression is upregulated as a downstream response to JunN-terminal kinase-3 (JNK-3) (stress-activated protein kinase) activation. 10 Since inhibition of Fas signaling is neuroprotective in both in vivo and in vitro rodent models of cerebral ischemia, 5,11 Fas activation is considered a key trigger of delayed neuronal death following stroke.…”

Effects of Opiate Drugs on Fas-Associated Protein with Death Domain (FADD) and Effector Caspases in the Rat Brain: Regulation by the ERK1/2 MAP Kinase Pathway

“…In type I cells (not dependent on mitochondrial signal amplification) (Barnhart et al, 2003), caspase-8 directly activates downstream effector caspases (eg caspases-3/6/7), allowing cleavage of numerous substrates leading to cell death (Cohen, 1997;MacEwan, 2002). Fasinduced death in the nervous system (Felderhoff-Mueser et al, 2000) was shown to share the same basic mechanisms with peripheral cells (Sastry and Rao, 2000).…”

Estrogen and Brain Protection

“…An increasing body of work has shown that Fas and Fas Ligand play an important role in the pathology of ischemic stroke (L. Rosenbaum et al, 2000). Both Fas and Fas ligand were upregulated by cerebral ischemia in brains of developing, as well as adult mice (Felderhoff-Mueser et al, 2000, 2003. Intriguingly, estrogen significantly reduced the level of Fas and the adaptor protein in mice undergoing post-ischemic stress (Jia et al, 2009).…”