Intra-parenchymal ferrous iron infusion causes neuronal atrophy, cell death and progressive tissue loss: Implications for intracerebral hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is a devastating stroke causing considerable tissue destruction from mechanical trauma and secondary degeneration. Free iron, released over days from degrading erythrocytes, causes free radicals that likely contribute to delayed injury. Indeed, an intracerebral injection of iron rapidly kills cells and causes cerebral edema. We expanded upon these observations by: determining a dose–response relationship of iron infusion, examining the structural appearance of surviving striatal neurons, and evaluating injury over months. First, we measured 24-h edema in rats given 3.8, 19.0 or 38.0μg infusions of FeCl2 (i.e., 30μL of a 1, 5 or 10mmol/L solution). Second, rats were given these infusions (vs. saline controls) followed by behavioral assessment and histology at 7days. Third, dendritic structure was measured in Golgi–Cox stained neurons at 7days after a 0.95-μg dose (30μL of a 0.25mmol/L solution). Last, rats survived 7 or 60days post-injection (19.0μg) for histological assessment. Larger doses of iron caused greater injury, but this was generally not reflected in behavior that indicated similar deficits among the 3.8–38.0μg groups. Similarly, edema occurred but was not linearly related to dose. Even after a low iron dose the surviving neurons in the peri-injury zone were considerably atrophied (vs. contralateral side and controls). Finally, continuing tissue loss occurred over weeks with prominent neuronal death and iron-positive cells (e.g., macrophages) at 60days. Iron alone may account for the chronic degeneration found after ICH in rodent models.