Apoptotic cell death is well established, but other types of programmed cell death have remained elusive. Reporting in Nature Chemical Biology, researchers from Harvard Medical School have come a step closer to unravelling a distinct form of non-apoptotic cell death.

The treatment of cells with 'death-receptor ligands' triggers the canonical apoptosis pathway and induces cell death even in the presence of a general caspase inhibitor. The resulting necrosis-like, non-apoptotic cell-death phenotype — which the researchers termed 'necroptosis' — has been observed in many cell types, which implies that it might represent a common pathway.

“The one thing that has been lacking so far has been a way to figure out what proteins are involved in these other pathways”, said Shai Shaham, Rockefeller University (The Scientist, 31 May 2005). But, by screening a library of chemical compounds, Junying Yuan and colleagues might have found a way — they identified necrostatin-1, which specifically inhibits all known examples of necroptosis.

“The next step...”, according to Alan Faden of Georgetown University Medical Center, “...is to use necrostatin-1 to identify the components of the signal transduction cascade responsible for necroptosis.” (The Scientist, 31 May 2005).

The inhibitor was also used to explore the in vivo role of necroptosis. Ischaemic brain injury, as seen in stroke, is associated with both apoptotic and non-apoptotic cell death. Injecting necrostatin-1 into the ventricles of mice with stroke-like injury significantly reduced the volume of dead brain tissue. “This protection suggests that necroptosis is involved in this form of pathologic cell death”, the authors say (The Scientist, 31 May 2005).