title: Limited protection of TAT-Bcl-X(L) against pneumolysin-induced neuronal cell death.
abstract: Severe brain damage in patients with pneumococcal meningitis is in part caused by the cytosolic pneumococcal protein pneumolysin. The devastating effect of this neurotoxin might be alleviated by interfering with the cell death pathways that it sets in motion. An important player in these pathways is Bcl-X(L), an antiapoptotic protein of the Bcl-2 family, which is neuroprotective in various in vitro and in vivo models of cell death. We investigated whether its membrane-permeable form, the TAT-Bcl-X(L) fusion protein, is capable of protecting human SH-SY5Y neuroblastoma cells against pneumolysin-induced cell death. Under mild pneumolysin-induced neuronal injury, TAT-Bcl-X(L) increased cell viability significantly by approximately 40% (82.7 +/- 16.1% versus 70.0+/-8.2%; p = 0.04). When the cells were exposed to a more rigorous pneumolysin treatment, TAT-Bcl-X(L) had no protective effects. This suggests the involvement of additional neuronal death pathways in pneumolysin-induced cell death, which are not controlled by Bcl-X(L). Therefore, Bcl-X(L), a promising therapeutic candidate for ischemia and neurodegenerative diseases, is only of partial efficacy in preventing the direct neurotoxicity of pneumolysin.
authors.affiliation: Department of Neurology, University of Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ebert
authors.forename: Gunnar P H
authors.initials: GP
authors.lastname: Dietz
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mitchell
authors.forename: Uwe
authors.initials: U
authors.lastname: Michel
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Roland
authors.initials: R
authors.lastname: Nau
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001426:Bacterial Proteins / Q000008:administration & dosage*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015696:Gene Products, tat / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013301:Streptolysins / Q000008:administration & dosage*; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; D001426:Bacterial Proteins; C494812:Bcl2l1 protein, mouse; D015696:Gene Products, tat; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D013301:Streptolysins; D051020:bcl-X Protein; C032290:plY protein, Streptococcus pneumoniae