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

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 24h with amitriptyline, N-methyl-amitriptyline, doxepin, N-methyl-doxepin, N-propyl-doxepin, desipramine, imipramine and trimipramine at 100 mu mol, 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.