Significant Role of apoptosis-inducing factor (AIF) for brain damage following focal cerebral ischemia

Abstract

Every year, stroke is responsible for the death of 5.5 million people and thus accounts for 10% of all deaths in industrialized countries worldwide (Mackay and Mensah 2004). Despite such a high incidence and mortality, therapeutic options for stroke patients are still very limited (Lo et al. 2003). Currently, the only clinical treatment option for stroke is reperfusion therapy by local or systemic administration of recombinant tissue plasminogen activator (rtPA). A major drawback of rtPA, however, is that it may be fatal if given in hemorrhagic stroke, which has clinical symptoms very similar to ischemic stroke. Accordingly, rtPA therapy can only be initiated after cerebral hemorrhage has been ruled out by brain CT or NMR imaging. By the time diagnostic procedures have been completed, the therapeutic window for rtPA, i.e. 3 h after the onset of ischemia, has commonly closed. As a result less than 5% of all stroke patients are eligible for rtPA lysis according to current protocols (Adams et al. 2007). The remaining 95% may only hope for spontaneous reperfusion, which in most cases, however, occurs too late to prevent penumbral cell death and the subsequent loss of neurological function (Molina et al. 2001). Hence, a treatment strategy is required, which prolongs neuronal survival in the ischemic penumbra, i.e. under compromised cerebral blood flow conditions, until reperfusion occurs. A strategy that keeps neurons alive until reperfusion occurs may, however, not be the only goal for the development of novel stroke therapies. The main reason for this statement is that even after reperfusion, cell death signaling pathways triggered by the initial ischemic event remain activated and result in additional neuronal cell death under completely normal blood flow conditions. This was first demonstrated in experimental approaches where very brief ischemic episodes were induced, i.e. 30 min of middle cerebral artery occlusion in mice or rats (MCAo), which may resemble transient ischemic attacks (TIA) in patients. Under this condition neuronal cell death may occur with a delay of up to 24 h following reperfusion (Du et al. 1996; Endres et al. 1998). Subsequently, post-reperfusion cell death was also demonstrated following more severe ischemic episodes, which are associated with acute infarction and, hence, resemble acute stroke in humans. In the ischemic penumbra of mice subjected to 60 min MCAo, neurons die with a delay of only 3-6 h (Fig. 6.1a), i.e. also post-reperfusion, cell death seems to have a clinically relevant therapeutic window. Accordingly, an optimal therapeutic approach towards the treatment of stroke should include not only the protection of neuronal cells during the period of compromised blood flow, but also the prevention of cell death after reperfusion.