Fig. 2

Various oligodendrocyte intrinsic mechanisms could lead to cell death of the oligodendrocyte during cuprizone intoxication. A Elevated levels of ROS can lead to permeabilization of mitochondria and subsequent release of cytochrome C and apoptosis-inducing factor-1. Cytosolic cyt c can activate caspase-9 and thus induce apoptosis in the oligodendrocyte, while apoptosis-inducing factor leads to cell death through PARP. B ROS reduces iron stored in ferritin from Fe³⁺ to Fe²⁺, which leads to iron release from ferritin. Free Fe²⁺ and ROS can induce lipid peroxidation, a hallmark of ferroptotic cell death. C Glutamate may reach toxic levels and act via NMDA receptors to permit excessive Ca² influx. NMDA receptor activity can be modulated by copper. Depending on the concentration of copper present, NMDA receptor channel function is enhanced or inhibited. Also, PrP^C can inhibit the NMDA receptor in the presence of copper. Elevated levels of glutamate and changes to copper concentration in the brain as a result of cuprizone administration therefore might increase Ca²⁺ accumulation in the cell to a toxic level and myelin degradation/oligodendrocyte death