Modulation of apoptosis by hypothermia. After a serious insult the cell can trigger apoptosis, a highly regulated cell death mechanism. Intrinsic Pathway. Hypothermia increases ATP stores and slows ion channels then maintaining the integrity of the membranes. Hypothermia applied together or immediately after injury decreases the production of ROS. These events limit the rupture of the outer mitochondrial membrane and the release of proapoptotic molecules like cytochrome c into the cytosol. The hypothermia-induced increase in nitric oxide also avoids cytochrome c release and it is even reported that early NO production can exert a negative feedback regulation of iNOS [34]. Moreover, iNOS transcription activated by NFB was diminished after hypothermia [35]. Since catalase is absent in mitochondria, maintaining GSH redox cycle is critical to avoid H₂O₂ accumulation. There is abundant evidence that hypothermia keeps GSH pool. Extrinsic Pathway. It was found that hypothermia decreases the affinity of the death ligands-death receptors, with the consequent inhibition of the initiator caspases like caspase-8 or the NFB-family molecules.