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.
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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
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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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El-Mir and Detaille have contributed equally to this work.
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El-Mir, MY., Detaille, D., R-Villanueva, G. et al. Neuroprotective Role of Antidiabetic Drug Metformin Against Apoptotic Cell Death in Primary Cortical Neurons. J Mol Neurosci 34, 77–87 (2008). https://doi.org/10.1007/s12031-007-9002-1
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DOI: https://doi.org/10.1007/s12031-007-9002-1