Neurobiology of disease · 2026
Temporal and cell-specific changes to cellular iron sequestration and lipid peroxidation in a murine model of neonatal hypoxic-ischemic brain injury.
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Vithayathil Joseph, Shankar Anjali, Foshe Sierra, Lin Baoyi, Milne Ginger L, Jensen Frances E, Talos Delia M, Dunaief Joshua L
Аннотация
BACKGROUND: Iron accumulation and lipid peroxidation are pathophysiologic mechanisms that contribute to neonatal hypoxic-ischemic (HI) brain injury. Characterization of spatiotemporal changes in these processes will help elucidate their role in ischemic neuronal injury as an initial step towards developing targeted interventions.
METHODS: HI was induced in post-natal day 9 mice using the modified-Vannucci model. Hippocampal tissue from ipsilateral HI exposed, contralateral hypoxia exposed and sham animals was collected at 6 h, 24 h, 72 h, 7d and 90d post-HI. Tissue was evaluated for cell death (TUNEL labeling), intracellular iron changes (flow cytometry, fluorescent mRNA/protein staining), and lipid peroxidation (mass spectrometry). Mass spectrometry measured isoprostanes (15-F2t-IsoP) and neuroprostanes (4-F4t-NP) as markers of arachidonic (ARA) and docosahexaenoic acid (DHA) peroxidation, respectively.
RESULTS: Compared to sham, the HI hippocampus showed increased intracellular labile iron levels that was maximal at 6 h post-HI with subsequent elevation in neuroprostanes and TUNEL labeling at 24 h post-HI. High throughput in situ mRNA labeling at 24 h post-HI showed changes in injured cells indicative of elevated labile iron and lipid peroxidation. At 72 h post-HI, labile iron levels, TUNEL labeling and lipid peroxidation declined corresponding with peak infiltration of ferritin positive microglia/macrophages and increased expression of glutathione peroxidase 4 (Gpx4) within surviving neurons.
CONCLUSIONS: These results characterize the relationship between intracellular labile iron, lipid peroxidation and cell death in neonatal HI. Injured cells display gene expression changes indicative of increased labile iron toxicity and lipid peroxidation. Microglial/macrophage iron sequestration and neuronal antioxidant responses may ameliorate further injury and represent targets for neuroprotective therapies.
METHODS: HI was induced in post-natal day 9 mice using the modified-Vannucci model. Hippocampal tissue from ipsilateral HI exposed, contralateral hypoxia exposed and sham animals was collected at 6 h, 24 h, 72 h, 7d and 90d post-HI. Tissue was evaluated for cell death (TUNEL labeling), intracellular iron changes (flow cytometry, fluorescent mRNA/protein staining), and lipid peroxidation (mass spectrometry). Mass spectrometry measured isoprostanes (15-F2t-IsoP) and neuroprostanes (4-F4t-NP) as markers of arachidonic (ARA) and docosahexaenoic acid (DHA) peroxidation, respectively.
RESULTS: Compared to sham, the HI hippocampus showed increased intracellular labile iron levels that was maximal at 6 h post-HI with subsequent elevation in neuroprostanes and TUNEL labeling at 24 h post-HI. High throughput in situ mRNA labeling at 24 h post-HI showed changes in injured cells indicative of elevated labile iron and lipid peroxidation. At 72 h post-HI, labile iron levels, TUNEL labeling and lipid peroxidation declined corresponding with peak infiltration of ferritin positive microglia/macrophages and increased expression of glutathione peroxidase 4 (Gpx4) within surviving neurons.
CONCLUSIONS: These results characterize the relationship between intracellular labile iron, lipid peroxidation and cell death in neonatal HI. Injured cells display gene expression changes indicative of increased labile iron toxicity and lipid peroxidation. Microglial/macrophage iron sequestration and neuronal antioxidant responses may ameliorate further injury and represent targets for neuroprotective therapies.