Role of hepcidin and its downstream proteins in early brain injury after experimental subarachnoid hemorrhage in rats.

Early brain injury (EBI) is a major cause of mortality from subarachnoid hemorrhage (SAH). We aimed to study the pathophysiology of EBI and explore the role of hepcidin, a protein involved in iron homeostatic regulation, and its downstream proteins. One hundred and thirty-two male Sprague-Dawley rats were assigned into groups (n = 24/group): sham, SAH, SAH + hepcidin, SAH + hepcidin-targeting small interfering ribonucleic acid (siRNA), and SAH + scramble siRNA. Three hepcidin-targeting siRNAs and one scramble siRNA for hepcidin were injected 24 h before hemorrhage induction, and hepcidin protein was injected 30 min before induction. The rats were neurologically evaluated at 24 h and euthanized at 72 h. Hepcidin, ferroportin-1, and ceruloplasmin protein expression were measured by immunohistochemistry and Western blotting. Brain water content, blood-brain barrier (BBB) leakage, non-heme tissue iron and Garcia scale were evaluated. Hepcidin expression increased in the cerebral cortex and hippocampus after experimental SAH (P < 0.05 compared to sham), while ferroportin-1 and ceruloplasmin decreased (P < 0.05). Hepcidin injection lowered the expression of ferroportin-1 and ceruloplasmin further but siRNA reduced the levels of hepcidin (P < 0.05 compared to SAH) resulting in recovery of ferroportin-1 and ceruloplasmin levels. Apoptosis was increased in SAH rats compared to sham (P < 0.05) and increased slightly more by hepcidin, but decreased by siRNA (P < 0.05 compared to SAH). SAH rats had lower neurological scores, high brain water content, BBB permeability, and non-heme tissue iron (P < 0.05). In conclusion, downregulation of ferroportin-1 and ceruloplasmin caused by hepcidin enhanced iron-dependent oxidative damage and may be the potential mechanism of SAH.

Optimal hemoglobin concentration in patients with aneurysmal subarachnoid hemorrhage after surgical treatment to prevent symptomatic cerebral vasospasm.

Medical complications occur frequently after aneurismal subarachnoid hemorrhage (aSAH), such as cerebral vasospasm (CVS), anemia, etc. The relationship between hemoglobin (Hgb) concentration and the occurrence of CVS after aSAH remains largely elusive. A total of 218 patients with postoperative aSAH were recruited. Symptomatic cerebral vasospasm (SCVS) was initially diagnosed on the basis of their clinical signs and symptoms, and confirmed by imaging tests. The patients were then divided into four groups on the basis of the postoperative mean Hgb concentration (<11, 11-12, 12-13, and >13 g/dl). The possible influential factors that were statistically significant in the initial univariate analysis were subjected to a multivariable logistic regression analysis. Univariate analysis showed that Hunt and Hess neurological grade on admission, intraoperative aneurysm rupture, CT Fisher grade, and postoperative mean Hgb were associated significantly with SCVS in aSAH patients after surgical treatment (P<0.05). Subsequent multivariable analysis showed that postoperative mean Hgb remained significant after adjustment for Hunt and Hess neurological grade on admission and CT fisher grade. The incidence of SCVS in the group with an Hgb concentration 11-12 g/dl was found to be the lowest among all groups [odds ratio (OR), 3.29, 95% confidence interval (CI), 1.43-7.58, P=0.005; OR, 3.63, 95% CI, 1.41-9.34, P=0.007; OR, 5.34, 95% CI, 1.85-15.43, P=0.002]. Postoperative Hgb concentration is an independent risk factor for SCVS in aSAH patients following surgery, and maintaining the concentration at 11-12 g/dl may reduce the incidence of SCVS.