Prolonged Blood-Brain Barrier Injury Occurs After Experimental Intracerebral Hemorrhage and Is Not Acutely Associated with Additional Bleeding

Abstract

Intracerebral hemorrhage (ICH) causes blood-brain barrier (BBB) damage along with altered element levels in the brain. BBB permeability was quantified at 3, 7, and 14 days with Evans Blue dye after collagenase-induced ICH in rat. At peak permeability (day 3), a gadolinium (Gd)-based contrast agent was injected to further characterize BBB disruption, and X-ray fluorescence imaging (XFI) was used to map Gd, Fe, Cl, and other elements. XFI revealed that Ca, Cl, Gd, and Fe concentrations were significantly elevated, whereas K was significantly decreased. Therefore, using Gd-XFI, we co-determined BBB dysfunction with alterations in the metallome, including those that contribute to cell death and functional outcome. Warfarin was administered 3 days post-ICH to investigate whether additional or new bleeding occurs during peak BBB dysfunction, and hematoma volume was assessed on day 4. Warfarin administration prolonged bleeding time after a peripheral cut-induced bleed, but warfarin did not worsen hematoma volume. Accordingly, extensive BBB leakage occurred after ICH, but did not appear to affect total hematoma size.

Tracking elemental changes in an ischemic stroke model with X-ray fluorescence imaging

“…At present there are few studies employing XFI methods to study changes in ischemic or hemorrhagic stroke [9][10][11][15][16][17][18][19][20][21][22] . This paucity highlights the specialized nature of the team required to perform these types of studies.…”

“…Clustering 11,22 affords the means to identify metabolically distinct areas of tissue, allowing the differentiation of the infarct core from bulk brain tissue and an intermediate region surrounding the infarct core which we identify as the metabolic penumbra at early post-stroke time points or the PIZ at later time points. Clustering provides the means to track changes in element concentrations as well as the size in the regions over time.…”

The MC4 receptor agonist RO27‐3225 inhibits NLRP1‐dependent neuronal pyroptosis via the ASK1/JNK/p38 MAPK pathway in a mouse model of intracerebral haemorrhage

“…The initial haemorrhagic volume and the haematoma expansion are the two key factors of primary brain injury following ICH, even though early haematoma removal and prevention of haematoma expansion have not yielded conclusive benefits in clinical trials (Mendelow et al, ; Zhou et al, ). Neuroinflammation on the other hand plays a critical role in the pathogenesis of ICH‐induced secondary brain injury, leading to brain oedema formation, blood–brain barrier disruption, and neuronal cell death (Nadeau et al, ; Wilkinson et al, ). The molecular mechanisms of neuronal cell death, specifically associated with post‐ICH inflammation, are complex and poorly understood.…”

Valproate Sodium Protects Blood Brain Barrier Integrity in Intracerebral Hemorrhage Mice

“…The ICH models in mice were performed by bacterial collagenase injection into the right basal ganglia, as reported previously [ 8 ]. The operation procedures in sham mice were performed similarly but only PBS was injected.…”