Relevant modulation by ferrous ions of N-methyl-D-aspartate receptors in ischemic brain injuries

Activation of the N-methyl-D-aspartate (NMDA) receptor would induce rapid opening of an ion channel permeable to Ca2+ ions across cell membranes, followed by an increase in the concentration of free Ca2+ ions in the cytoplasm and subsequent signaling cascade from the cytoplasm to the nucleus for consolidation of a transient extracellular signal carried by L-glutamate in the central nervous system. Both neuronal plasticity and cell death have been shown to involve intracellular free Ca2+ ions incorporated through this receptor-operated cation channel in the brain. On the other hand, iron is also abundant in the brain, with an essential role in mechanisms underlying maintenance of cellular integrity and function. Ferrous ions are believed to participate in neuronal cell death through generation of reactive oxygen species in ischemic brain injuries, for instance, while ferrous but not ferric ions are shown to block the influx of Ca2+ ions across NMDA receptor channels in cultured neurons. In this review article, we will summarize the possible relationship between iron and NMDA receptor channels in mechanisms associated with neuronal cell death in brains with ischemia.