Ferritin and Neurotoxicity: A Contributor to Deleterious Outcomes for Subarachnoid Hemorrhage

Ferritin is a protein that is critical for storing iron. Ferritin has recently been shown to play a role in iron homeostasis, immunomodulation, inflammation, and antioxidation. Previously, it was believed that ferritin was exclusively an intracellular peptide. However, there is significant evidence that ferritin is also in the serum, cerebral spinal fluid, and synovial fluid.

Within the brain, ferritin can bind to oligodendrocytes adjacent to the blood-brain barrier to allow a docking point for ferritin to be engulfed by microglia in the brain parenchyma. When iron supplies in the brain are low, the lysosomal-autophagy pathway is activated to degrade ferritin and mobilize iron. Iron is critical in the brain for the formation of myelin and used during cellular respiration. If this sequestration and degradation of iron are impaired, the oxidative effects of iron may leave the brain vulnerable to neurotoxic effects. Subarachnoid hemorrhage (SAH) causes hemolysis of erythrocytes leading to the release of iron. Subsequently, a rise in ferritin is observed which promotes the neurologic insult following SAH. The degree to which ferritin is elevated post-SAH may correlate with the downstream neurotoxicity.

The literature seems to point to a critical balance in ferritin levels. Ferritin is protective against further oxidative effects of iron, but ferritin also contributes to neurotoxic outcomes. In this review, we will discuss the role of ferritin in the brain. Specifically, we will address cerebral ferritin iron uptake and ferritin clearance. This homeostatic process influences the development and progression of SAH.