Brain Iron Metabolism and Brain Injury Following Subarachnoid Hemorrhage: iCeFISH-Pilot (CSF Iron in SAH)

Abstract

Objectives To explore the relationship between levels of non-protein bound iron in cerebrospinal fluid and the development of early brain injury in patients with aneurysmal SAH. Design Prospective observational cohort pilot study. Setting Neurointensive care unit of an academic, tertiary medical center Patients Patients admitted with aneurysmal subarachnoid hemorrhage Hunt and Hess grades 2 to 4 requiring ventriculostomy insertion as part of their clinical management. Interventions None. Measurements and main results Samples of cerebrospinal fluid (CSF) were obtained on days 1, 3, and 5. A fluorometric assay that relies on an oxidation sensitive probe was used to measure unbound iron, and levels of iron-handling proteins were measured by means of enzyme-linked immunosorbent assays. We prospectively collected and recorded demographic, clinical, and radiological data. A total of 12 patients were included in this analysis. Median Hunt and Hess score on admission was 3.5 (IQR: 1) and median modified Fisher scale score was 4 (IQR: 1). Seven of 12 patients (58%) developed delayed cerebral ischemia (DCI). Day 5 non-transferrin bound iron (NTBI) (7.88±1 vs. 3.58± 0.8, p= 0.02) and mean NTBI (7.39± 0.4 vs. 3.34±0.4 p= 0.03) were significantly higher in patients who developed DCI. Mean and day 3 levels of redox-active iron correlated with development of angiographic vasospasm in logistic regression analysis (p= 0.02); while mean redox-active iron and lower levels of ceruloplasmin on days 3, 5 and peak were correlated with development of deep cerebral infarcts. Conclusions our preliminary data indicate a causal relationship between unbound iron and brain injury following SAH and suggest a possible protective role for ceruloplasmin in this setting, particularly in the prevention of cerebral ischemia. Further studies are needed to validate these findings and to probe their clinical significance.

Programmed Cell Deaths and Potential Crosstalk With Blood–Brain Barrier Dysfunction After Hemorrhagic Stroke

“…Fibrin cleaved from fibrinogen has been reported to play a potential role in neuroinflammation and microglial activation (Lim-Hing and Rincon, 2017). Iron, degraded from hemoglobin, is one of most important factors among various components for hemorrhagic stroke-induced BBB hyperpermeability (Hua et al, 2007;Gomes et al, 2014), which is supported by ICH/SAH studies revealing alleviated brain edema with administration of the iron chelator, deferoxamine (Lee et al, 2010;Okauchi et al, 2010;Yu et al, 2014), or a heme oxygenase (HO) inhibitor (Wagner et al, 2000;Han et al, 2018). HO plays a critical role in the degradation of heme and the release of free ferrous iron (Kamat et al, 2019).…”

“…However, according to the mechanisms of BBB dysfunction and ferroptosis discussed above, the role of ferroptosis on BBB damage warrants more attention. We have mentioned above with sufficient evidence that iron, when degraded from hemoglobin, has a critically important role in BBB hyperpermeability after hemorrhagic stroke, and decreasing iron content through various methods significantly reversed the brain edema (Wagner et al, 2000;Hua et al, 2007;Gomes et al, 2014;Yu et al, 2014). The key point of this problem lies in the poor understanding regarding the exact mechanism of iron overload-induced BBB hyperpermeability.…”

Brain iron overload following intracranial haemorrhage

“…148 This increase is accompanied by a significant upregulation in HO-1 levels in microglia and neuronal death via oxidative DNA injury 149. A pilot study in human patients suggested a causal relationship between free iron in the CSF following SAH and brain injury 150. Indeed, suppression of hepcidin (and thus inhibition of FP1 internalisation) attenuated brain damage following experimental SAH, suggesting the importance of intracellular iron accumulation 29.…”

The role of TLR4 and HO‐1 in neuroinflammation after subarachnoid hemorrhage

“…Free heme released into the subarachnoid space during SAH is metabolized by HO-1, releasing iron (Fe 2+ ), biliverdin, and carbon monoxide (CO) (Kikuchi, Yoshida, & Noguchi, 2005).Free iron is thought to cause cell membrane damage via free radicals and the Fenton reaction (Loftspring, 2010). Previous studies have shown a causal relationship between free iron and brain injury following SAH (Gomes et al, 2014).…”