Animal Model of a Common HFE Mutation Sustains Recovery Following Intracerebral Hemorrhage

Introduction: Intracerebral hemorrhage (ICH) is a devastating disease with a one-year mortality rate of 45%. In the setting of an ICH, the breakdown of blood releases iron into the brain parenchyma. This excess iron contributes to stroke-induced neurodegeneration as it creates a cytotoxic environment. Our group has previously shown that an animal model carrying a common genetic variant in a gene related to iron metabolism (H67D HFE) modifies recovery following intracerebral hemorrhage at 3-days post-ICH. The objective of the current study is to determine the extent to which these effects persist past the 3-day post-ICH timepoint.

Methods: An autologous blood infusion model was utilized to create an ICH in the right caudate of H67D (n = 13) and WT mice (n = 13). A subset of mice was euthanized at 7-days post-ICH while the remaining were euthanized at 30-days post-ICH. Motor recovery was assessed using latency to fall from rotarod. Furthermore, levels of a key antioxidant regulatory protein (GPX4) and an iron storage protein (FTH1) in the brains of these animals were evaluated using immunoblotting.

Results: H67D mice sustained significantly increased functional recovery through 30-days post-ICH compared to WT mice. Additionally, levels of GPX4 and FTH1 were significantly increased in the ICH-affected hemisphere of H67D mice at 7-days post-ICH. At 30-Days post-ICH, levels of FTH1 remained significantly elevated in the ICH-affected hemisphere of H67D mice, however, GPX4 levels were not significantly different.

Conclusion : Our data suggests that the effects of the H67D HFE mutation on ICH recovery persist to the 30-day post-ICH timepoint. The mechanism appears to be an upregulation of the endogenous antioxidant systems that may subside by 30-days. These data further suggest that a study determining the impact of HFE mutations on clinical outcomes in ICH is warranted. Given the prevalence of the H63D HFE mutation in humans, the impact of this mutation on ICH could be highly significant.