Role of Lipocalin-2 in Brain Injury After Subarachnoid Hemorrhage in Female Mice

TL;DR

This study shows that lipocalin-2 contributes to brain injury after subarachnoid hemorrhage in female mice and that its deletion reduces damage and improves recovery.

Contribution

The study demonstrates that Lcn2 is a critical mediator of early brain injury in female mice after SAH, suggesting it as a potential therapeutic target.

Findings

Lcn2 expression was upregulated in multiple brain regions after SAH, especially in astrocytes.

Lcn2 knockout mice showed reduced oxidative stress, ferritin induction, and brain injury markers.

Neurological recovery improved in Lcn2 knockout mice compared to wild-type mice after SAH.

Abstract

Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disorder with high mortality and long-term disability. It is more prevalent in women than men, but most preclinical research has been performed in male animals. Upregulation of lipocalin-2 (Lcn2), an acute-phase protein involved in iron homeostasis and neuroinflammation, has been implicated in hemorrhagic brain injury in male animals. The purpose of this study was to examine whether genetic deletion of Lcn2 also reduces early brain injury after SAH in female mice. Adult female wild-type (WT) and Lcn2 knockout (KO) mice were subjected to endovascular perforation to induce SAH. Lcn2 expression was assessed by immunohistochemistry and Western blotting, while brain injury was evaluated using MRI T2 lesion measurement, blood–brain barrier (BBB) permeability assays, Fluoro-Jade C staining, and Garcia’s neurological scoring. We found that Lcn2 expression was upregulated in multiple brain regions after SAH, particularly in astrocytes. Compared with WT mice, Lcn2 KO mice exhibited significantly reduced oxidative stress, attenuated ferritin induction, smaller T2 lesions, decreased BBB leakage, reduced neuronal degeneration, and improved neurological recovery over 7 days. These findings identify Lcn2 as a critical mediator of early brain injury after SAH in female mice. These results further support targeting Lcn2 as a therapeutic strategy to reduce brain damage and improve outcomes in SAH patients.

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