In vitro, lidocaine-induced axonal injury is prevented by peripheral inhibition of the p38 mitogen-activated protein kinase, but not by inhibiting caspase activity.
BACKGROUND
All local anesthetics (LAs) are, to some extent, neurotoxic. Toxicity studies have been performed in dissociated neuron cultures, immersing both axon and soma in LA. This approach, however, does not accurately reflect the in vivo situation for peripheral nerve blockade, where LA is applied to the axon alone.


METHODS
We investigated lidocaine neurotoxicity in compartmental sensory neuron cultures, which are composed of one central compartment containing neuronal cell bodies and a peripheral compartment containing their axons, allowing for selective incubation. We applied lidocaine +/- neuroprotective drugs to neuronal somata or axons, and assessed neuron survival and axonal outgrowth.


RESULTS
Lidocaine applied to the peripheral compartment led to a decreased number of axons (to 59% +/- 9%), without affecting survival of cell bodies. During axonal incubation with lidocaine, the p38 mitogen-activated protein kinase inhibitor SB203580 (10 microM) attenuated axonal injury when applied to the axon (insignificant reduction of maximal axonal distance to 93% +/- 9%), but not when applied to the cell body (deterioration of maximal axonal length to 48% +/- 6%). Axonal co-incubation of lidocaine with the caspase inhibitor z-vad-fmk (20 microM) was not protective.


CONCLUSIONS
Whereas inhibition of either p38 mitogen-activated protein kinase or caspase activity promote neuronal survival after LA treatment of dissociated neuronal cultures, axonal degeneration induced by lidocain (40 mM) is prevented by p38 MAP kinase but not by caspase inhibition. We conclude that processes leading to LA-induced neurotoxicity in dissociated neuronal culture may be different from those observed after purely axonal application.
Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Innsbruck, Austria. philipp.lirk@i-med.ac.at
Philipp
P
Lirk
Ingrid
I
Haller
Hans Peter
HP
Colvin
Silke
S
Frauscher
Lukas
L
Kirchmair
Peter
P
Gerner
Lars
L
Klimaschewski
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000201:enzymology*; D020169:Caspases; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008012:Lidocaine / Q000633:toxicity*; D009475:Neurons, Afferent / Q000187:drug effects / Q000201:enzymology; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D008012:Lidocaine; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases