title: Mitigation of direct neurotoxic effects of lidocaine and amitriptyline by inhibition of p38 mitogen-activated protein kinase in vitro and in vivo.
abstract: BACKGROUND
  Local anesthetic-induced direct neurotoxicity (paresthesia, failure to regain normal sensory and motor function) is a potentially devastating complication of regional anesthesia. Local anesthetics activate the p38 mitogen-activated protein kinase (MAPK) system, which is involved in apoptotic cell death. The authors therefore investigated in vitro (cultured primary sensory neurons) and in vivo (sciatic nerve block model) the potential neuroprotective effect of the p38 MAPK inhibitor SB203580 administered together with a clinical (lidocaine) or investigational (amitriptyline) local anesthetic.
  
  
  METHODS
  Cell survival and mitochondrial depolarization as marker of apoptotic cell death was assessed in rat dorsal root ganglia incubated with lidocaine or amitriptyline either with or without the addition of SB203580. Similarly, in a sciatic nerve block model, the authors assessed wallerian degeneration by light microscopy to detect a potential mitigating effect of MAPK inhibition.
  
  
  RESULTS
  Lidocaine at 40 mm/approximately 1% and amitriptyline at 100 microm reduce neuron count, but coincubation with the p38 MAPK inhibitor SB203580 at 10 mum significantly reduces cytotoxicity and the number of neurons exhibiting mitochondrial depolarization. Also, wallerian degeneration and demyelination induced by lidocaine (600 mm/approximately 15%) and amitriptyline (10 mm/approximately 0.3%) seem to be mitigated by SB203580.
  
  
  CONCLUSIONS
  The cytotoxic effect of lidocaine and amitriptyline in cultured dorsal root ganglia cells and the nerve degeneration in the rat sciatic nerve model seem, at least in part, to be mediated by apoptosis but seem efficiently blocked by an inhibitor of p38 MAPK, making it conceivable that coinjection might be useful in preventing local anesthetic-induced neurotoxicity.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Lirk
authors.forename: Ingrid
authors.initials: I
authors.lastname: Haller
authors.forename: Robert R
authors.initials: RR
authors.lastname: Myers
authors.forename: Lars
authors.initials: L
authors.lastname: Klimaschewski
authors.forename: Yi-Chuan
authors.initials: YC
authors.lastname: Kau
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Hung
authors.forename: Peter
authors.initials: P
authors.lastname: Gerner
mesh_terms: D000639:Amitriptyline / Q000633:toxicity*; D000779:Anesthetics, Local / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D008012:Lidocaine / Q000633:toxicity*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000779:Anesthetics, Local; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D000639:Amitriptyline; D008012:Lidocaine; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580