Advances in Neuronal Cell Death 2007

In a stroke lesion, there is a core of necrotic cell death surrounded by a zone of tissue at risk, termed the penumbra. In the penumbra, there is usually less severe tissue damage. Programmed cell death (PCD) pathways have been documented to be present in the penumbra. While many studies have used the term apoptosis as equivalent to PCD, the absence of complete biochemical and morphological characteristics of apoptosis, coupled with the ineffectiveness of caspase inhibitors, indicates that there are other important cell death pathways activated during stroke. A few caspase-independent cell death pathways have been identified and there are likely more to be described.Stroke injury leads to the activation of a cell death program, dependent on poly(ADP-ribose) polymerase-1 (PARP1) activation1 and culminating in apoptosis inducing factor (AIF) mediated cell death.2 Poly(ADP-ribose) (PAR) polymer is the death signal in this pathway and Thanatos is the Greek personification of death and mortality, hence, the name parthanatos. In this form of cell death that occurs in many different organ systems during ischemia-reperfusion injury, PAR polymer translocates from the nucleus to the cytoplasm and mitochondria. This leads to release of AIF from the mitochondria, an effect that is inhibited by poly(ADP-ribose) glycohydrolase (PARG), an enzyme that degrades PAR polymer.3 After cerebral focal ischemia reperfusion injury, mice with reduced PARG levels had higher infarct volumes than controls. On the other hand, mice overexpressing PARG had significantly lower infarct volumes. Combined, the current data indicate that PAR is a powerful death signal. What is not yet understood are the mechanisms of PAR translocation out of the nucleus and PAR-mediated AIF release from the mitochondria. Parthanatos is caspase-independent and is biochemically and morphologically distinct from apoptosis.4 Regulation of PAR signaling may be a useful therapeutic intervention to reduce stroke-mediated damage.Additional …