Narrative review of rationale for IV deferoxamine plus intranasal insulin to ameliorate brain damage following resuscitation from cardiac arrest

Patients with out of hospital cardiac arrest suffer brain ischemia, and many die from brain injury despite cardiac resuscitation. Upon brain reperfusion molecular mechanisms of neuronal injury are amplified by iron toxicity, activated proteases, and inhibited protein synthesis. This narrative review covers the growth of our understanding of reperfusion injury together with suggestion of a therapeutic approach to limit or reverse neuronal injury during early reperfusion. Ischemic ATP depletion causes dysregulation of mitochondrial electron transport and Ca 2+ overloading of neuronal cytoplasm from both extracellular fluid and depletion of the endoplasmic reticulum Ca 2+ stores. Increased cytoplasmic Ca 2+ causes activation of the protease calpain-1 and phospholipase, which releases arachidonate from membranes. Upon reperfusion both mitochondria and metabolism of free arachidonate produce excessive superoxide, which reduces ferritin-stored Fe 3+ to soluble Fe 2+ (labile iron), thereby initiating ferroptosis lipid peroxidation. Depletion of endoplasmic reticulum Ca 2+ and ATP recovery cause an endoplasmic reticulum kinase to greatly inhibit protein synthesis. Thus, immediately upon reperfusion a biochemical crisis of iron-dependent lipid peroxidation, protease activation, and inhibited protein synthesis is present in vulnerable neurons. High-dose IV insulin given at reperfusion induces in vulnerable neurons activation of the survival kinase Akt, which can inhibit ferroptosis, reduce cytosolic Ca 2+ , downregulate proteases, drive recovery of protein synthesis, inhibit apoptosis, and improve neuron survival and neurological outcome. Brain Akt is also activated by intranasal insulin, which quickly reaches the brain with very little absorbed into the bloodstream in human studies. Research pharmacology suggests ∼200 U intranasal insulin can safely provide a human brain concentration similar to that from high-dose IV insulin. However, the toxic 4-hydroxynonenal product of iron-dependent lipid peroxidation can form inactivating adducts on Akt. Iron chelation by deferoxamine inhibits lipid peroxidation during brain reperfusion, and Phase-1 dosing and safety studies have been completed in stroke patients. Together these results form a rationale for prompt assessment of combined therapy with IV deferoxamine and intranasal insulin to improve neurological outcome after resuscitation.