About 600,000 Americans suffer ischemic stroke each year, 8% of whom die within 30 days. A further 15-30% are permanently disabled and 20% require institutional care. Direct and indirect costs of stroke is therefore immense. The treatment of ischemic stroke remains one of the most challenging areas of medicine today. At present, only one agent is approved (Alteplase, rt-PA), and for only a brief window of time (onset of symptoms less than three hours). Since many patients present far beyond this three hour window, not surprisingly most patients receive only palliative care. In order to open the window of therapeutic opportunity the pharmaceutical industry is currently focusing on the development of molecules able to protect neural tissue from ischemic damage (see for example our recent report implicating glycogen synthase kinase-3 inhibitors in the treatment of stroke). Considerably evidence is available supporting a role of apoptosis in cerebral ischemia. While damaged neurons often die from necrosis, apoptosis contributes significantly to cell death subsequent to cerebral ischemia, with apoptosis being predominant when the excitotoxic insult is relatively mild. Mediators of apoptosis are activated following cerebral ischemia, while inhibition of caspases also reduces infarct size in transient focal ischemia. The apoptosis cascade is complicated and understanding how it is activated during stroke is crucial to the optimal development of therapies. In particular apoptotic signaling pathways can be divided into two main routes. Mediators that bind the TNF family of cytokine receptors, including TNFR1, FAS and TRAIL receptors activated the extrinsic pathway. Receptor activation recruits and activates caspase 8 in the cytosol which in turn activates procaspase-3 to initiate a cascade of effector caspases, led by caspase-3. Stress-induced signals such as DNA damage initiate the mitochondrial release of cytochrome c and other apoptogenic factors to recruit and activate the initiator caspase-9. Activated caspase-9 can, in turn, activate caspase-3 thus converging with the death receptor pathway. Current evidence suggests that in neuronal ischemic death, apoptosis is activated both via death receptor family proteins and by mitochondrial signals. Although the two routes operate largely independently of each other under most conditions, cross-talk can be provided by BH3-interacting-domain death agonist (Bid), a pro-apoptotic Bcl-2 family member. University of Pittsburgh researchers have recently identified the implication of this Bid in neuronal ischemia. This group subjected bid-deficient mice to acute ischemia induced by left middle cerebral artery occlusion followed by reperfusion. The volume of ischemic infarct was significantly smaller in the bid-deficient brains than in the wild-type brains, suggesting that Bid participated in the ischemic neuronal death. Indeed, following the ischemic treatment there was a significant reduction of apoptosis in the ischemic areas, particularly in the inner infarct border zone (the penumbra), of the bid-deficient brains. This therapeutic benefit was attributed to the near total blockade of the internal apoptosis pathway early on in the course of ischemia/reperfusion injury. Bid therefore represents an attractive target for future therapeutic interventions.

Entry date October, 2002

Adapted from Yin et al, J Biol Chem 2002 Aug 27

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