698 Animal Model of a Common HFE Mutation Modifies Recovery Following Intracerebral Hemorrhage

Abstract

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 through increased oxidative stress. Genetic variations in iron metabolism such as the H63D HFE mutation have been shown to modify disease progression in neurodegenerative diseases such as Parkinson’s, but have not been studied in ICH. METHODS: An autologous blood infusion model was utilized to create an ICH in the right caudate of H67D (human homolog of the H63D HFE mutation) and WT mice. Motor recovery was assessed using latency to fall from rotarod. 3-days post-ICH, the extent of neurodegeneration and mitochondrial damage in glial cells in the perihematomal area were measured using Fluorojade-B (FJB) and Cytochrome-C (CytC) immunofluorescent staining respectively. Levels of key regulatory proteins in the antioxidant and iron storage systems (Nrf2, GPX4, and FTH1) were evaluated using immunoblotting. RESULTS: H67D mice demonstrated significantly increased motor recovery at two- and three-days post-ICH compared to WT. H67D mice displayed significantly decreased degenerated neurons and CytC+ glial cells in the perihematomal region compared to WT. Furthermore, levels of Nrf2, GPX4, and FTH1 were significantly increased in the ICH-affected hemisphere of H67D mice. CONCLUSIONS: Our data suggest that the H67D HFE mutation modifies ICH recovery through significant improvements in motor recovery and decreases in damaged cells in the perihematomal region. The mechanism appears to be an upregulation of the endogenous antioxidant systems. These data 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.