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Differential neurotoxicity of tricyclic antidepressants and novel derivatives in vitro in a dorsal root ganglion cell culture model☆

Published online by Cambridge University Press:  01 August 2007

I. Haller ,
P. Lirk ,
C. Keller ,
G. K. Wang ,
P. Gerner  and
L. Klimaschewski
I. Haller
Affiliation:
Medical University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Austria Medical University of Innsbruck, Division of Neuroanatomy, Austria
P. Lirk*
Affiliation:
Medical University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Austria
C. Keller
Affiliation:
Medical University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Austria
G. K. Wang
Affiliation:
Brigham and Women’s Hospital/Harvard Medical School, Department of Anesthesiology, Perioperative and Pain Medicine, Boston, USA
P. Gerner
Affiliation:
Brigham and Women’s Hospital/Harvard Medical School, Department of Anesthesiology, Perioperative and Pain Medicine, Boston, USA
L. Klimaschewski
Affiliation:
Medical University of Innsbruck, Division of Neuroanatomy, Austria
*
Correspondence to: Philipp Lirk, Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, Anichstr, 35, 6020 Innsbruck, Austria. E-mail: philipp.lirk@i-med.ac.at; Tel: +43 512 504 22400; Fax: +43 512 504 22450
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Summary

Background and objective

Tricyclic antidepressants are commonly employed orally to treat major depressive disorders and have been shown to be of substantial benefit in various chronic pain conditions. Among other properties they are potent Na+ channel blockers in vitro and show local anaesthetic properties in vivo. The present study aimed to determine their differential neurotoxicity, and that of novel derivatives as prerequisite for their potential use in regional anaesthesia.

Methods

To directly test neurotoxicity in adult peripheral neurons, the culture model of dissociated adult rat primary sensory neurons was employed. Neurons were incubated for 24 h with amitriptyline, N-methyl-amitriptyline, doxepin, N-methyl-doxepin, N-propyl-doxepin, desipramine, imipramine and trimipramine at 100 μmol, and at concentrations correlating to their respective potency in blocking sodium channels.

Results

All investigated substances showed considerable neurotoxic potency as represented in significantly decreased neuron numbers in cultures as compared to controls. Specifically, doxepin was more neurotoxic than amitriptyline, and both imipramine and trimipramine were more toxic than desipramine or amitriptyline. Novel derivatives of tricyclic antidepressants were, in general, more toxic than the parent compound.

Conclusions

Tricyclic antidepressants and novel derivatives thereof show differential neurotoxic potential in vitro. The rank order of toxicity relative to sodium channel blocking potency was desipramine < amitriptyline < N-methyl amitriptyline < doxepin < trimipramine < imipramine < N-methyl doxepin < N-propyl doxepin.

Keywords

ANTIDEPRESSIVE AGENTS TRICYCLICANAESTHESIA CONDUCTIONGANGLIA SPINALDRUG TOXICITYNEURONS
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 24 , Issue 8 , August 2007 , pp. 702 - 708
Copyright
Copyright © European Society of Anaesthesiology 2007

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Footnotes

☆

Received from the Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, Austria.

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