title: Lidocaine induces apoptosis via the mitochondrial pathway independently of death receptor signaling.
abstract: BACKGROUND
  Local anesthetics, especially lidocaine, can lead to persistent cauda equina syndrome after spinal anesthesia. Recently, lidocaine has been reported to trigger apoptosis, although the underlying mechanisms remain unknown. To elucidate the pathway of lidocaine-induced apoptosis, the authors used genetically modified cells with overexpression or deficiencies of key regulators of apoptosis.
  
  
  METHODS
  Human Jurkat T-lymphoma cells overexpressing the antiapoptotic protein B-cell lymphoma 2 as well as cells deficient of caspase 9, caspase 8, or Fas-associated protein with death domain were exposed to lidocaine and compared with parental cells. The authors evaluated cell viability, mitochondrial alterations, cytochrome c release, caspase activation, and early apoptosis. Apoptosis was in addition investigated in neuroblastoma cells.
  
  
  RESULTS
  In Jurkat cells, lidocaine reduced viability, associated with a loss of the mitochondrial membrane potential. At low concentrations (3-6 mm) of lidocaine, caspase 3 was activated and release of cytochrome c was detected, whereas at higher concentrations (10 mm), no caspase activation was found. Apoptosis by lidocaine was strongly reduced by B-cell lymphoma-2 protein overexpression or caspase-9 deficiency, whereas cells lacking the death receptor pathway components caspase 8 and Fas-associated protein with death domain were not protected and displayed similar apoptotic alterations as the parental cells. Lidocaine also induced apoptotic caspase activation in neuroblastoma cells.
  
  
  CONCLUSIONS
  Apoptosis is triggered by concentrations of lidocaine occurring intrathecally after spinal anesthesia, whereas higher concentrations induce necrosis. The data indicate that death receptors are not involved in lidocaine-induced apoptosis. In contrast, the observation that B-cell lymphoma-2 protein overexpression or the lack of caspase 9 abolished apoptosis clearly implicates the intrinsic mitochondrial death pathway in lidocaine-induced apoptosis.
authors.affiliation: Department of Anesthesiology, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Werdehausen
authors.forename: Sebastian
authors.initials: S
authors.lastname: Braun
authors.forename: Frank
authors.initials: F
authors.lastname: Essmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.forename: Peter
authors.initials: P
authors.lastname: Lipfert
authors.forename: Markus F
authors.initials: MF
authors.lastname: Stevens
mesh_terms: D056769:Alstrom Syndrome; D000779:Anesthetics, Local / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism / Q000502:physiology; D053181:Caspase 8 / Q000235:genetics; D053453:Caspase 9 / Q000172:deficiency / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019169:Jurkat Cells / Q000502:physiology; D008012:Lidocaine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects*; D051336:Mitochondrial Membranes / Q000502:physiology; D053218:Receptors, Death Domain / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000779:Anesthetics, Local; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053218:Receptors, Death Domain; D019938:Cyclin D1; D045304:Cytochromes c; D008012:Lidocaine; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9