Progesterone and stroke recovery: a match ultimately won by survivin?

Stroke represents one of the most important causes of injury and disability worldwide. It is commonly connected with an obstruction of blood flow in a major cerebral vessel, which, if not quickly resolved, will lead to an infarcted area of tissue that cannot be therapeutically salvaged. There are currently no effective therapeutic strategy for stroke. A growing body of evidence indicates that progesterone (PROG), given in the acute stage of stroke, limits tissue damage and improves functional outcome. The pathophysiology of ischemic brain injury involves a number of mechanisms leading to neuronal damage including apoptosis. Apoptotic cell death during the phase of reperfusion is an important contributor to lethal reperfusion-induced injury. The endothelium holds a pivotal role in cardiovascular health and disease. Endothelial progenitor cells (EPCs) are the major source of cells in endothelial repair after vascular injury. It has been suggested that caspase-independent mechanisms of programmed cell death may contribute significantly to ischemic injury through the critical signaling molecule apoptosis-inducing factor (AIF). Opposing the proapoptotic actions of AIF is survivin. This protein is the smallest member of the inhibitor of the apoptosis gene family that seems to play a crucial role in vascular cell responses to ischemia in either the heart or brain. Studies not only have suggested a role for survivin in the extent of vascularization of the infarct but also have supported the notion for treatment of brain injury by upregulation of survivin. Intriguingly, survivin has also been described to mediate the antiapoptic effects of ischemic preconditioning via phosphoinositide 3-kinase/protein kinase B (PI3K/ Akt) pathways and that the signaling interaction between PI3K/Akt and survivin seems to be essential for EPC proliferation. Recently it has been reported that PROG is neuroprotective against ischemic brain damage through its effects on the PI3K/AKT signaling pathway. Thus, we advance the hypothesis that the therapeutic benefit of PROG administration after stroke may be due to its effects in modulating survivin for re-endothelialization after vascular injury by the PI3K/AKT signaling pathway. The identification of signal interactions associated with survivin regulation and function at the cellular level may provide novel approaches to therapeutically optimize angiogenesis not only in stroke, but in all illnesses in which the outcome is dependent on vascular endothelial cell survival and death. Moreover, studies should be conducted to determine whether genetic polymorphisms and epigenetic factors could contribute to explain the variability of morbidity and mortality in stroke.