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

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.
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https://www.hal.inserm.fr/inserm-00388540
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Submitted on : Tuesday, May 26, 2009 - 10:36:33 PM
Last modification on : Tuesday, November 30, 2021 - 3:44:02 PM

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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, Humana Press, 2008, 34 (1), pp.77-87. ⟨10.1007/s12031-007-9002-1⟩. ⟨inserm-00388540⟩

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