Journal of Molecular Neuroscience

, Volume 34, Issue 1, pp 77–87 | Cite as

Neuroprotective Role of Antidiabetic Drug Metformin Against Apoptotic Cell Death in Primary Cortical Neurons

  • Mohamad-Yehia El-Mir
  • Dominique Detaille
  • Gloria R-Villanueva
  • Maria Delgado-Esteban
  • Bruno Guigas
  • Stephane Attia
  • Eric Fontaine
  • Angeles Almeida
  • Xavier Leverve
Article

Abstract

Oxidative damage has been reported to be involved in the pathogenesis of diabetic neuropathy and neurodegenerative diseases. Recent evidence suggests that the antidiabetic drug metformin prevents oxidative stress-related cellular death in non-neuronal cell lines. In this report, we point to the direct neuroprotective effect of metformin, using the etoposide-induced cell death model. The exposure of intact primary neurons to this cytotoxic insult induced permeability transition pore (PTP) opening, the dissipation of mitochondrial membrane potential (ΔΨm), cytochrome c release, and subsequent death. More importantly, metformin, together with the PTP classical inhibitor cyclosporin A (CsA), strongly mitigated the activation of this apoptotic cascade. Furthermore, the general antioxidant N-acetyl-l-cysteine also prevented etoposide-promoted neuronal death. In addition, metformin was shown to delay CsA-sensitive PTP opening in permeabilized neurons, as triggered by a calcium overload, probably through its mild inhibitory effect on the respiratory chain complex I. We conclude that (1) etoposide-induced neuronal death is partly attributable to PTP opening and the disruption of ΔΨm, in association with the emergence of oxidative stress, and (2) metformin inhibits this PTP opening-driven commitment to death. We thus propose that metformin, beyond its antihyperglycemic role, can also function as a new therapeutic tool for diabetes-associated neurodegenerative disorders.

Keywords

Cytochrome c release Etoposide Metformin Neuronal apoptosis Mitochondrial permeability transition pore 

Abbreviations

ΔΨm

mitochondrial membrane potential

AMPK

AMP-activated protein kinase

CsA

cyclosporin A

NAC

N-acetyl-l-cysteine

PI

propidium iodide

PTP

permeability transition pore

TMRM

tetramethyl-rhodamine methyl ester

Notes

Acknowledgments

The authors are very grateful to Drs. Juan P. Bolanos and Nicolas Wiernsperger for a stimulating discussion and to Mrs. MC Alguero Martín for her helpful technical assistance in flow cytometry. This work was partially supported by the JCyL (Grant SA062/03; Spain), INSERM, and Merck.

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Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Mohamad-Yehia El-Mir
    • 1
  • Dominique Detaille
    • 2
    • 3
  • Gloria R-Villanueva
    • 1
  • Maria Delgado-Esteban
    • 4
  • Bruno Guigas
    • 2
    • 3
  • Stephane Attia
    • 2
    • 3
  • Eric Fontaine
    • 2
    • 3
  • Angeles Almeida
    • 5
  • Xavier Leverve
    • 2
    • 3
  1. 1.Departamento de Fisiología y FarmacologíaUniversidad de SalamancaSalamancaSpain
  2. 2.INSERM U884 Bioénergétique Fondamentale et AppliquéeGrenoble CedexFrance
  3. 3.Université Joseph FourierGrenobleFrance
  4. 4.Departamento de Bioquímica y Biología MolecularUniversidad de SalamancaSalamancaSpain
  5. 5.Hospital Clinico Universitario de SalamancaSalamancaSpain

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