title: N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death.
abstract: Transient global ischemia in rats induces delayed death of hippocampal CA1 neurons. Early events include caspase activation, cleavage of anti-death Bcl-2 family proteins and large mitochondrial channel activity. However, whether these events have a causal role in ischemia-induced neuronal death is unclear. We found that the Bcl-2 and Bcl-x(L) inhibitor ABT-737, which enhances death of tumor cells, protected rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-x(L) is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment, ΔN-Bcl-x(L). We found that ABT-737 administered before or after ischemia inhibited ΔN-Bcl-x(L)-induced mitochondrial channel activity and neuronal death. To establish a causal role for ΔN-Bcl-x(L), we generated knock-in mice expressing a caspase-resistant form of Bcl-x(L). The knock-in mice exhibited markedly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings suggest that truncated Bcl-x(L) could be a potentially important therapeutic target in ischemic brain injury.
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Dimitry
authors.initials: D
authors.lastname: Ofengeim
authors.forename: Ying-Bei
authors.initials: YB
authors.lastname: Chen
authors.forename: Takahiro
authors.initials: T
authors.lastname: Miyawaki
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Silvio
authors.initials: S
authors.lastname: Sacchetti
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Flannery
authors.forename: Kambiz N
authors.initials: KN
authors.lastname: Alavian
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pontarelli
authors.forename: Brian A
authors.initials: BA
authors.lastname: Roelofs
authors.forename: John A
authors.initials: JA
authors.lastname: Hickman
authors.forename: J Marie
authors.initials: JM
authors.lastname: Hardwick
authors.forename: R Suzanne
authors.initials: RS
authors.lastname: Zukin
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Jonas
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use; D009924:Organ Culture Techniques; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: C501332:ABT-737; C494813:Bcl2l1 protein, rat; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051020:bcl-X Protein