Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. - Archive ouverte HAL Access content directly
Journal Articles Journal of Molecular Neuroscience Year : 2008

Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons.

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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 (DeltaPsim), 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 DeltaPsim, 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.

Dates and versions

inserm-00388540 , version 1 (26-05-2009)

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Mohamad-Yehia El-Mir, Dominique Detaille, Gloria R-Villanueva, Maria Delgado-Esteban, Bruno Guigas, et al.. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons.. Journal of Molecular Neuroscience, 2008, 34 (1), pp.77-87. ⟨10.1007/s12031-007-9002-1⟩. ⟨inserm-00388540⟩

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