Hence, the interaction between TWEAK and Fn14 activates a proinflammatory cell signaling pathway, which GW786034 has been linked to cell death during cerebral ischemia. Accordingly, a genetic deficiency of TWEAK or Fn14, or treatment with anti TWEAK neutralizing antibodies or a solu ble Fn14 Fc decoy receptor reduces the volume of the ischemic lesion following the induction of experi mental ischemic stroke. It has been reported that TWEAK induces apoptotic cell death in neuronal cultures. However, it is known that TWEAK is a poor cytotoxic agent that induces cell death in conjunction with other sensitizers via multiple mechanisms, including caspase dependent apoptosis and cathepsin mediated necrosis.

In contrast Inhibitors,Modulators,Libraries with these observations, experimental work with glial cell tumors indicate that the interaction between TWEAK and Fn14 has a pro survival effect mediated by the induction of B cell lym phoma 2 proteins. The cytokine TNF a is a member of the TNF superfam ily of ligands synthesized as a monomeric type 2 trans membrane protein that is inserted into the membrane as a homotrimer and cleaved by the matrix metalloprotease TNF converting enzyme to a 51 kDa soluble circulating trimer. Importantly, although it has been demonstrated that, following the onset of ischemic stroke, the expression of TNF a in the peripheral Inhibitors,Modulators,Libraries circulation and central nervous system increases, the effect of TNF a in the ischemic brain is as of yet unclear. Accordingly, some have demonstrated that increased TNF a has a dele terious effect in the acute phases of cerebral ischemia and that TWEAK induced cell death is mediated by the interaction between TNF a and TNF receptor 1.

In contrast, others have shown that an increase in circulating Inhibitors,Modulators,Libraries TNF a by treatment with either TNF a or lipopolysaccharide before the onset of the ische mia has a beneficial effect in the ischemic Inhibitors,Modulators,Libraries brain and med iates the development of ischemic tolerance. The extracellular signal Inhibitors,Modulators,Libraries regulated kinases 1 and 2 are members of the family of mitogen acti vated protein kinases that have been associated with neurodegeneration and ischemic cell death. How ever, a growing body of recent evidence indicates that ERK 1 2 activation has a pro survival effect in the ischemic brain, mediated by its ability to attenuate apoptotic cell death. Accordingly, ERK 1 2 mediate the phosphorylation and inactivation of the Bcl 2 asso ciated death promoter protein. Additionally, ERK 1 2 induce the expression of pro survival Bcl 2 proteins, notably Bcl 2 and Bcl xL. Our work indicates that the interaction between TWEAK and Fn14 leads to the development protein inhibitor of ischemic tolerance.