Mitochondrial division inhibitor 1 protects cortical neurons from excitotoxicity: a mechanistic pathway.

ABSTRACT

Mitochondrial division inhibitor 1 (Mdivi-1) is a selective cell-permeable inhibitor of dynamin-related protein-1 (Drp1) and mitochondrial division. To investigate the effect of Mdivi-1 on cells treated with glutamate, cerebral cortex neurons isolated from neonatal rats were treated with 10 mM glutamate for 24 hours. Normal cultured cells and dimethyl sulfoxide-cultured cells were considered as controls. Apoptotic cells were detected by flow cytometry. Changes in mitochondrial morphology were examined by electron microscopy. Drp1, Bax, and caspase-3 expression was evaluated by western blot assays and immunocytochemistry. Mitochondrial membrane potential was detected using the JC-1 probe. Twenty-four hours after 10 mM glutamate treatment, Drp1, Bax and caspase-3 expression was upregulated, Drp1 and Bax were translocated to mitochondria, mitochondrial membrane potential was decreased and the rate of apoptosis was increased. These effects were inhibited by treatment with 50 µM Mdivi-1 for 2 hours. This finding indicates that Mdivi-1 is a candidate neuroprotective drug that can potentially mitigate against neuronal injury caused by glutamate-induced excitotoxicity.