White matter T2 hyperintensities and blood-brain barrier disruption in the hyperacute stage of subarachnoid hemorrhage in male mice: The role of lipocalin-2.

Yasunori Toyota,Guohua Xi,Richard F Keep,Jialiang Wei,Ya Hua

doi:10.1111/cns.13221

Yasunori Toyota, Guohua Xi + Show 3 more

Open Access

https://doi.org/10.1111/cns.13221

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Abstract

AimsThe current study examined whether white matter injury occurs in the hyperacute (4 hours) phase after subarachnoid hemorrhage (SAH) and the potential role of blood‐brain barrier (BBB) disruption and an acute phase protein, lipocalin 2 (LCN2), in that injury.MethodsSubarachnoid hemorrhage was induced by endovascular perforation in adult mice. First, wild‐type (WT) mice underwent MRI 4 hours after SAH to detect white matter T2 hyperintensities. Second, changes in LCN2 expression and BBB disruption associated with the MRI findings were examined. Third, SAH‐induced white matter injury at 4 hours was compared in WT and LCN2 knockout (LCN2 KO) mice.ResultsAt 4 hours, most animals had uni‐ or bilateral white matter T2 hyperintensities after SAH in WT mice that were associated with BBB disruption and LCN2 upregulation. However, some disruption and LCN2 upregulation was also found in mice with no T2‐hyperintensity lesion. In contrast, there were no white matter T2 hyperintensities in LCN2 KO mice after SAH. LCN2 deficiency also attenuated BBB disruption, myelin damage, and oligodendrocyte loss.ConclusionsSubarachnoid hemorrhage causes very early BBB disruption and LCN2 expression in white matter that is associated with and may precede T2 hyperintensities. LCN2 deletion attenuates MRI changes and pathological changes in white matter after SAH.

Highlights

Subarachnoid hemorrhage (SAH) is a cerebrovascular disease with high mortality and morbidity rates
In addi‐ tion, we have found that experimental SAH induced by endovascular perforation induces white matter damage that can be detected by magnetic resonance imaging (MRI) as T2‐hyperintensities 24 hours post ictus.[4]
The major findings of the present study are (a) experimental SAH induced by endovascular perforation in mice resulted in very early (4 hour) T2 hyperintensities and blood‐brain barrier (BBB) disruption in white matter; (b) SAH resulted in increased lipocalin 2 (LCN2) expression in white mat‐ ter, with LCN2 being increased more in mice with T2 hyperinten‐ sities than those without; (c) the sources of LCN2 after SAH were astrocytes, endothelial cells, and oligodendrocytes, while the LCN2 receptor (24p3R) was found on astrocytes, microglia/macrophages, and oligodendrocytes 4 hours after SAH; (d) LCN2 deficiency atten‐ uated SAH‐induced BBB disruption, oligodendrocyte loss, and MBP degradation in white matter

Summary

| INTRODUCTION

Subarachnoid hemorrhage (SAH) is a cerebrovascular disease with high mortality and morbidity rates. We have previously reported a role of LCN2 in white matter injury at 24 hours after SAH.[4,8] LCN2 is best described as an acute phase siderophore‐binding protein that has a role of chemokine inducer. LCN2 has been implicated in the apoptotic cell death, regulation of cell differentiation and endog‐ enous iron chelation Whether it is upregulated in the hyperacute phase after SAH and has a role in BBB and parenchymal injury during that phase is unknown. The present study investigated white matter parenchymal and BBB injury in the hyperacute (4 hours) phase after SAH. It examined the role of LCN2 by comparing SAH‐induced injury in wild‐type (WT) and LCN2 knockout mice undergoing endovascular perforation

| MATERIALS AND METHODS

| DISCUSSION

Findings

| CONCLUSION