Regulatory effects associated with changes in intracellular potassium level in susceptibility to mitochondrial depolarization and excitotoxicity.

Excitotoxicity has been believed to be one of the causes of neurodegenerative diseases such as Alzheimer's disease and Huntington's disease. So far, much research has been done to suppress the neuronal excessive excitations, however, we still have not achieved full control, which may be due to the lack of some factors. As a matter of course, there is an urgent need to clarify all mechanisms that inhibit the onset and progression of neurodegenerative diseases. We found that potassium ion level regulation may be important in the sense that it suppresses mitochondrial depolarization rather than hyperpolarization of cell membrane potential. Minoxidil, an opener of ATP-activated potassium (KATP) channels decreased injury with middle cerebral artery occlusion in vivo experiment using TTC staining. In the primary cortical neurons, N-methyl-D-aspartate (NMDA)-induced mitochondrial depolarization was suppressed by minoxidil treatment. Minoxidil inhibited the increase in levels of cleaved caspase 3 and the release of cytochrome c into the cytosol, further reducing potassium ion levels. It was observed decreased potassium levels in neurons by the treatment of minoxidil. Those effects of minoxidil were blocked by glibenclamide. Therefore, it was suggested that minoxidil, via opening of KATP channels, reduced intracellular potassium ion level that contribute to mitochondrial depolarization, and suppressed subsequent NMDA-induced mitochondrial depolarization. Our findings suggest that the control of ion levels in neurons could dominate the onset and progression of neurodegenerative diseases.