White Matter Injury After Subarachnoid Hemorrhage

Abstract

Background and Purpose We recently observed early white matter injury after experimental subarachnoid hemorrhage (SAH) but the underlying mechanisms are uncertain. This study investigated the potential role of matrix metalloproteinase (MMP)-9 in blood-brain barrier (BBB) disruption and consequent white matter injury. Methods SAH was induced by endovascular perforation in adult male mice. The following three experiments were devised: (1) mice underwent MRI at 24 h after SAH and were euthanized to determine BBB disruption and MMP-9 activation in white matter; (2) to investigate the role of MMP-9 in BBB disruption, lesion volumes on MRI were compared between wild-type (WT) and MMP-9-knockout (MMP-9−/−) mice at 24 h after SAH; (3) WT and MMP-9−/− mice underwent MRI at 1 and 8 days after SAH to detect time-dependent changes in brain injury. Brains were used to investigate myelin integrity in white matter. Results In WT mice with SAH, white matter showed BBB disruption (albumin leakage) and T2-hyperintensity on MRI. MMP-9 activity was elevated at 24 h after SAH. MMP-9−/− mice had less white matter T2-hyperintensity after SAH than WT mice. At 8 days after SAH, WT mice had decreased myelin integrity and MMP-9−/− mice developed less white matter injury. Conclusions SAH causes BBB disruption and consequent injury in white matter. MMP-9 plays an important role in those pathologies and could be a therapeutic target for SAH-induced white matter injury.

Multimodality MRI assessment of grey and white matter injury and blood-brain barrier disruption after intracerebral haemorrhage in mice

“…Disruption of the BBB is associated with brain oedema40 and white matter injury4142, which contribute to secondary injury in ICH14154344. MacLellan et al 15.…”

Mechanisms of Global Cerebral Edema Formation in Aneurysmal Subarachnoid Hemorrhage

“…59–61 Several different experimental models suggest that MMP-9 activity mediates blood-brain barrier breakdown and subsequent vasogenic edema following aSAH. Genetic deletion of MMP-9 both protects the integrity of the blood-brain barrier 62 and reduces edema formation 63 in mouse models of aSAH. Pharmacologic inhibition of MMP-9 using either minocycline 58,64 or a specific MMP-9 inhibitor 65 both restores blood-brain barrier integrity and reduces brain edema in rat models of aSAH.…”

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice

“…Prior work observed diffuse neuronal death up to 7 days after SAH induction using the anterior prechiasmatic injection approach used for the current study [9,29,23,22]. Additional studies using the endovascular perforation model have reported acute white matter injury-independent of ischemic stroke-using MRI [30][31][32], ultrastructural assessment with electron microscopy [32], and assessment of molecular markers for white matter injury, including beta-APP [30]. Notably, investigators have described posterior dominant involvement of white matter tracts following an endovascular puncture model of SAH [33] which is consistent with our findings of persistent posterior-dominant deficits in RSFC (Figures 1 and 3).…”