Antidepressants reveal differential effect against 1-methyl-4-phenylpyridinium toxicity in differentiated PC12 cells

Eur J Pharmacol. 2009 Feb 14;604(1-3):36-44. doi: 10.1016/j.ejphar.2008.12.025. Epub 2008 Dec 24.


Treatment of depression may ameliorate the cognitive disability and motor slowness in Parkinson's disease. It has been shown that antidepressants, including fluoxetine, may attenuate or exacerbate neuronal cell death. The present study assessed the effect of antidepressants (amitriptyline, tranylcypromine and fluoxetine) against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)) in relation to the mitochondria-mediated cell death process in differentiated PC12 cells. Amitriptyline and tranylcypromine attenuated the MPP(+)-induced cell death that may be associated with mitochondrial membrane permeability change and oxidative stress. Both compounds prevented the loss of the mitochondrial transmembrane potential, over-expression of Bax, reduction in Bcl-2 level, cytochrome c release, caspase-3 activation, formation of reactive oxygen species and depletion of GSH. The inhibitory effect of tranylcypromine was greater than that of amitriptyline on the basis of concentration. In contrast, fluoxetine revealed a toxic effect and exhibited an additive effect against the toxicity of MPP(+). Results show that amitriptyline and tranylcypromine may attenuate the MPP(+) toxicity by suppressing the mitochondrial membrane permeability change that leads to cytochrome c release and subsequent caspase-3 activation. The effects seem to be associated with the inhibitory action on the formation of reactive oxygen species and the depletion of GSH. In contrast, fluoxetine seems to exert an additive toxic effect against neuronal cell damage by increasing mitochondrial damage and oxidative stress.

MeSH terms

  • 1-Methyl-4-phenylpyridinium / toxicity*
  • Amitriptyline / pharmacology
  • Animals
  • Antidepressive Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Culture Techniques
  • Cell Differentiation / drug effects*
  • Cell Nucleus / drug effects
  • Cell Nucleus / pathology
  • Cell Survival / drug effects
  • DNA Fragmentation / drug effects
  • Fluoxetine / pharmacology
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Membranes / enzymology
  • Mitochondrial Membranes / metabolism
  • Oxidative Stress / drug effects
  • PC12 Cells
  • Permeability
  • Rats
  • Tranylcypromine / pharmacology


  • Antidepressive Agents
  • Fluoxetine
  • Amitriptyline
  • Tranylcypromine
  • 1-Methyl-4-phenylpyridinium