Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons.
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.
Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain.
Mohamad-Yehia
MY
El-Mir
Dominique
D
Detaille
Gloria
G
R-Villanueva
Maria
M
Delgado-Esteban
Bruno
B
Guigas
Stephane
S
Attia
Eric
E
Fontaine
Angeles
A
Almeida
Xavier
X
Leverve
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D005047:Etoposide; D016572:Cyclosporine; D045304:Cytochromes c; D008687:Metformin