Intrinsic Pathway

Following experimental stroke, ischemic injury causes mitochondrial damage that can result in the generation of a permeability transition pore (MPT) (104). The MPT is thought to constitute a large channel in the inner mitochondrial membrane, which is normally closed and can be opened by calcium overload or other factors related to ischemia, such as oxidative stress. Those factors cause translocation of cyclophilin-D from the matrix to the MPT that activates the pore, allowing flux of solutes from the matrix to the intermembrane space (105). Persistent MPT opening allows mitochondrial swelling and disruption of the outer mitochondrial membrane. Release of proapoptotic factors, such as cytochrome c, AIF, endonuclease G, second mitochondria-derived caspase activator (Smac/DIABLO), and high temperature-dependent A2 (HtrA2/Omi, a human serine proteinase), into the cytosol is the ultimate result of MPT opening. Cytochrome c release has been extensively studied as a key factor in mediating ischemia-induced apoptosis (106). Cytochrome c interactswith apoptosis protease-activating factor-1 and dATP / ATP to form the apoptosome, which leads to the activation of procaspase-9, which, in turn, cleaves and activates procaspase-3. This sequence produces further downstream events, including the activation of caspase-activated DNase, that lead to internucleosomal DNA fragmentation.

Figure 4 Apoptosis pathways following cerebral ischemia. Intrinsic pathway : During brain ischemia and reperfusion, high levels of ROS, calcium ion (Ca2+), and proapoptogenic factors, such as Bax, lead to the release of cytochrome c (C). Once released into the cytosol, cytochrome c binds to Apaf-1 and procaspase-9 to form an apoptosome, which, in turn, activates caspase-3, leading to activation of CAD and subsequent cell death. Another pathway is the caspase-independentpathway, in which AIF is directly released from the mitochondria and translocates to the nucleus, where it induces apoptosis directly. Bcl-2, a mitochondrial outer membrane protein, is an antiapoptotic protein that can suppress mitochondrial release of cytochrome c and AIF. Extrinsic pathway: Several extracellular ligands have now been shown to cause apoptosis through binding their respective receptors. The Fas/FasL system is shown, as this pathway has been the best characterized to date. FasL binds to its respective cell membrane receptor, Fas, which then complexes to an adaptor molecule, FADD, resulting in the recruitment and activation of caspase-8. Caspase-8 then activates caspase-3, leading to cell death. The extrinsic pathway can also interface with the intrinsic pathway because caspase-8 can cleave one of the Bcl-2 family proteins, Bid to tBid. tBid then translocates to mitochondria, where it can trigger cytochrome c (C) and apoptosis-inducing factor release. Abbreviations: Apaf-1, apoptotic protease activating factor-1; CAD, caspase-activated DNAse; AIF, apoptosis initiating factor; FasL, Fas ligand; FADD, Fas associate death domain.

Figure 4 Apoptosis pathways following cerebral ischemia. Intrinsic pathway : During brain ischemia and reperfusion, high levels of ROS, calcium ion (Ca2+), and proapoptogenic factors, such as Bax, lead to the release of cytochrome c (C). Once released into the cytosol, cytochrome c binds to Apaf-1 and procaspase-9 to form an apoptosome, which, in turn, activates caspase-3, leading to activation of CAD and subsequent cell death. Another pathway is the caspase-independentpathway, in which AIF is directly released from the mitochondria and translocates to the nucleus, where it induces apoptosis directly. Bcl-2, a mitochondrial outer membrane protein, is an antiapoptotic protein that can suppress mitochondrial release of cytochrome c and AIF. Extrinsic pathway: Several extracellular ligands have now been shown to cause apoptosis through binding their respective receptors. The Fas/FasL system is shown, as this pathway has been the best characterized to date. FasL binds to its respective cell membrane receptor, Fas, which then complexes to an adaptor molecule, FADD, resulting in the recruitment and activation of caspase-8. Caspase-8 then activates caspase-3, leading to cell death. The extrinsic pathway can also interface with the intrinsic pathway because caspase-8 can cleave one of the Bcl-2 family proteins, Bid to tBid. tBid then translocates to mitochondria, where it can trigger cytochrome c (C) and apoptosis-inducing factor release. Abbreviations: Apaf-1, apoptotic protease activating factor-1; CAD, caspase-activated DNAse; AIF, apoptosis initiating factor; FasL, Fas ligand; FADD, Fas associate death domain.

AIF, another protein released from the mitochondria, can also produce breakdown of DNA in a caspase-independent fashion (107). Endogenous antiapoptotic proteins of the Bcl-2 family (Bcl-2, Bcl-XL, and others) antagonize mitochondrial release of such apoptogenic factors (108). Interrupting this pathway by blocking cytochrome c release or inhibiting caspase activation appears to reduce injury due to experimental stroke (109,110 ).

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