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A Deadly Combination in Epileptic Seizures

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A Deadly Combination in Epileptic Seizures Bim, Bad, and Bax: a deadly combination in epileptic seizures Jerome Niquet, Claude G. Wasterlain J Clin Invest. 2004;113(7):960-962. https://doi.org/10.1172/JCI21478. Commentary Several Bcl-2 family members, including Bim, may contribute to programmed cell death by inducing mitochondrial cytochrome c release, which activates caspase-9 and then caspase-3, the “executioner” of the cell. In this issue of the JCI, Shinoda and collaborators show the key role of Bim in epileptic seizure–induced neuronal injury and identify the contribution of transcription factors responsible for seizure-induced Bim upregulation . Find the latest version: https://jci.me/21478/pdf commentaries Bim, Bad, and Bax: a deadly combination in epileptic seizures Jerome Niquet1,2 and Claude G. Wasterlain1,2,3 1Epilepsy Research Laboratory, Veteran’s Administration Greater Los Angeles Healthcare System, West Los Angeles, California, USA. 2Department of Neurology and 3Brain Research Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA. Several Bcl-2 family members, including Bim, may contribute to pro- of the JCI, the same group attempts to iden- grammed cell death by inducing mitochondrial cytochrome c release, which tify the key proteins controlling cytochrome activates caspase-9 and then caspase-3, the “executioner” of the cell. In this c and apoptotic death in the same KA- issue of the JCI, Shinoda and collaborators show the key role of Bim in induced model of SE and reports that Bim, epileptic seizure–induced neuronal injury and identify the contribution of which is usually sequestered in the endo- transcription factors responsible for seizure-induced Bim upregulation (see plasmic reticulum–dynein complex, was the related article beginning on page 1059). released from that complex and from asso- ciation with 14-3-3 (6). Immunoprecipita- Neuronal death following brain insults release. The balance between proapoptotic tion experiments suggest that Bim and often results from the execution of cellular factors (BH3-interacting domain death ago- Bcl-w form an oligomer (6), presumably programs that resemble those involved in nist [Bid], Bcl-2–associated death protein releasing Bax (7), which then translocates to developmentally programmed cell death. [Bad], Bcl-2–interacting mediator of cell the mitochondria (4). Shinoda et al. now Cell demise is often brought about by the death [Bim], Bcl-2–associated X protein report that hippocampal Bim expression activation of caspases, a family of cysteine [Bax], and Bcl-2 homologous antagonist was upregulated by seizures. In the in vitro proteases. When what is usually called the killer [Bak]) and antiapoptotic factors seizure model, neuronal survival increased “extrinsic” pathway of programmed cell (Bcl-2, Bcl-x, and Bcl-w) determines cyto- when Bim expression was suppressed by death is induced, the first step involves the chrome c release and the fate of the cell (1). Bim antisense oligonucleotides, suggesting activation of extracellular cell death recep- This balance depends not only on the that the Bim pathway had a key role in tors of the TNF superfamily, which recruit respective levels of expression of these fac- seizure-induced cell death (6). However, in a other proteins to form a complex that acti- tors but also on their post-translational different seizure model (in which SE is vates caspase-8, which in turn activates cas- modifications and interactions (1). induced in rats by intraventricular KA pase-3 (Figure 1) (1). This “executioner” cas- administration, which might have direct pase kills the cell through its widespread Seizures induce the “intrinsic” toxic effects), Korhonen et al. showed that proteolytic effects, activating DNA break- pathway of the cell death program the Bim pathway did not contribute to hip- down, inactivating DNA repair enzymes, Henshall and collaborators use a model of pocampal injury, as Bim expression was and attacking the cytoskeleton, among status epilepticus (SE; severe repetitive rapidly downregulated (8). other activities. In the “intrinsic” pathway of epileptic seizures) induced by injection of programmed cell death, the mitochondrion kainic acid (KA) into the rat amygdala. In Upstream control mechanisms: plays a critical role by releasing cytochrome rats with KA-induced SE, the authors role of the transcription factors c from its intermembrane space to the observed all the key elements of “intrinsic” Shinoda et al. (6) investigated the up- cytosol, where, in association with apoptot- pathway induction: cytochrome c release; stream mechanisms of Bim upregulation ic protease-activating factor-1 and dATP, it apoptosome formation; caspase-9 and cas- and cytochrome c release. Bim expression forms the apoptosome complex, activating pase-3 activation (Figure 1); neuroprotec- may be controlled by transcription factors caspase-9, which in turn activates caspase-3 tion by caspase-9 and caspase-3 inhibitors; of the forkhead in rhabdomyosarcoma (Figure 1) (1). Cytochrome c release is regu- and double-stranded DNA breaks (2, 3). In (FKHR) family, including FKHR and lated by the Bcl-2 family of proteins, which rats with KA-induced SE, Bad was dissociat- FKHR-like-1 (FKHRL-1) (9). In the KA- are pro- or antiapoptotic, depending on ed from chaperone protein 14-3-3, which induced model of SE, the authors showed their ability to promote or suppress its allowed it to dimerize with Bcl-xl. Bax, dis- a downregulation of the phosphorylated placed from Bcl-xl binding, translocated to (inactive) forms of FKHR and FKHRL-1, Nonstandard abbreviations used: apoptopsis-induc- the mitochondria, causing release of suggesting that their unphosphorylated ing factor (AIF); Bcl-2–associated death promoter (Bad); cytochrome c and activation of caspase-9 (active) forms were upregulated and Bcl-2–associated X protein (Bax); Bcl-2–interacting and caspase-3. Administration of the cal- translocated to the nucleus, where they mediator of cell death (Bim); BH3 interacting domain death agonist (Bid); forkhead in rhabdomyosarcoma cineurin inhibitor FK506 was neuroprotec- upregulated Bim expression. In vitro, (FKHR); FKHR-like-1 (FKHRL-1); kainic acid (KA); tive, possibly by blocking Bad dephospho- epileptic seizure–like activity increased status epilepticus (SE). rylation and preventing its dissociation binding of FKHR to the Bim promoter. Conflict of interest: The authors have declared that no from 14-3-3 (4). However, in an in vitro Blocking the dephosphorylation of FKHR conflict of interest exists. model of SE, FK506 did not prevent cell and/or FKHRL-1 with sodium orthovana- Citation for this article: J. Clin. Invest. 113:960–962 (2004). death or caspase-3 activation (5), suggesting date improved the survival of hippocam- doi:10.1172/JCI200421478. that Bad’s role was secondary. In this issue pal neurons. In the cortex of the same ani- 960 The Journal of Clinical Investigation http://www.jci.org Volume 113 Number 7 April 2004 commentaries not a specific inhibitor, might be due to inhibition of a phosphatase that is not part of the Bim pathway. The assumption that cell death mechanisms involved in the in vitro and in vivo seizure models are similar might be optimistic: FK506 is neuroprotec- tive in the in vivo model (4) and not in the in vitro model (5). Cross-talk between pathways In summary, the studies from Shinoda et al. (6) suggest a central role for mitochondria in the process of epileptic seizure–induced cell death. Specific death effector proteins (Bim in KA-induced SE, but also Bid and/or Bad; Bad in ischemia, but perhaps with Bid and/or Bim) may initiate this pathway (1, 11). Once the cell suicide program has been initiated, however, pathway specificity is replaced by redundancy, and “promiscu- ous” caspases activate each other through multiple feedback loops. For example, the initiator caspases 8 and 9 activate the exe- cutioner caspases 3 and 7. Active caspase-3, in turn, cleaves caspases 2, 6, 8, 10, and per- Figure 1 haps 9, providing a tremendous amplifica- Putative neuronal death pathways induced by epileptic seizures. In the “extrinsic” pathway of tion loop (1). Caspase-8 cleaves Bid, which programmed cell death, activation of extracellular cell death receptors of the TNF superfamily releases cytochrome c, bridging the “extrin- (Fas and tumor necrosis factor receptor 1 [TNFR1]) induces activation of catalytic enzymes cas- sic” and “intrinsic” pathways (11). This pase-8 and caspase-3, causing widespread proteolytic damage and cell death. Mitochondria might explain why specific caspase in- have a central role in the other forms of programmed cell death. In the “intrinsic” pathway, hibitors rarely achieve complete protection cytochrome c release is triggered by translocation of the proapoptotic factor Bax to the mito- from neuronal injury and might prompt us chondria. Seizures induce dephosphorylation of transcription factors FKHR and FKHRL-1, lead- to question the wisdom of the quest for ing to the upregulation of the proapoptotic factor Bim, which forms an oligomer with Bcl-w, trig- gering Bax activation. Seizures may also induce dissociation of Bad from chaperone protein inhibitor specificity. 14-3-3. Released Bad binds to Bcl-xl, provoking dissociation of Bax–Bcl-xl and Bax release. Bax Another conclusion from those studies penetrates the mitochondrial outer membrane and triggers cytochrome c release from the inter- (1–6, 11) is that many key elements of the membrane space to the cytosol, where it activates caspase-9, which then activates caspase-3. “extrinsic” and “intrinsic” pathways of pro- Alternatively, cytochrome c release may be induced after Bid truncation by active caspase-8, grammed cell death are constitutively linking the “extrinsic” and “intrinsic” pathways. In “programmed necrosis,” seizures deplete ener- expressed, and therefore their de novo syn- gy reserves, leading to mitochondrial calcium overloading, opening of the mitochondrial transi- thesis is not required in order for these pro- tion pore, and/or mitochondrial swelling and rupture of the outer membrane. Subsequent teins to play an active role in neuronal cytochrome c release activates the caspase cascade and leads to cell demise.
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