Abstract
Disruption of the blood-brain barrier (BBB) and the subsequent formation of brain edema is the most severe consequence of intracerebral hemorrhage (ICH), leading to drastic neuroinflammatory responses and neuronal cell death. A better understanding of ICH pathophysiology to develop effective therapy relies on selecting appropriate animal models. The collagenase injection ICH model and the autologous arterial whole blood infusion ICH model have been developed to investigate the pathophysiology of ICH. However, it remains unclear whether the temporal progression and the underlying mechanism of BBB breakdown are similar between these two ICH models. In this study, we aimed to determine the progression and the mechanism of BBB disruption via the two commonly used murine ICH models: the collagenase-induced ICH model (c-ICH) and the double autologous whole blood ICH model (b-ICH). Intrastriatal injection of 0.05 U collagenase or 20 μL autologous blood was used for a comparable hematoma volume in these two ICH models. Then we analyzed BBB permeability using Evan’s blue and IgG extravasation, evaluated tight junction (TJ) damage by transmission electron microscope (TEM) and Western blotting, and assessed matrix metalloproteinase-9 (MMP-9) activity and aquaporin 4 (AQP4) mRNA expression by Gelatin gel zymography and RT-PCR, respectively. The results showed that the BBB leakage was associated with a decrease in TJ protein expression and an increase in MMP-9 activity and AQP4 expression on day 3 in the c-ICH model compared with that on day 5 in the b-ICH model. Additionally, using TEM, we found that the TJ was markedly damaged on day 3 in the c-ICH model compared with that on day 5 in the b-ICH model. In conclusion, the BBB was disrupted in the two ICH models; compared to the b-ICH model, the c-ICH model presented with a more pronounced disruption of BBB at earlier time points, suggesting that the c-ICH model might be a more suitable model for studying early BBB damage and protection after ICH.
Highlights
Intracerebral hemorrhage (ICH) is the second most common subtype of stroke, and it has a high mortality and disability rate (Wang, 2010; Lan et al, 2017)
We found that the blood brain barrier (BBB) leakage was associated with a decrease in tight junction (TJ) protein expression and an increase in matrix metalloproteinases 9 (MMP)-9 activity and aquaporin 4 (AQP4) mRNA expression on day 3 in the Collagenase ICH model (c-ICH) model but on day 5 in the blood ICH model (b-ICH) model
Combined with the characteristics of clinical ICH patients with locally elevated perihematomal permeabilitysurface area product (PS) derived from computed tomographic perfusion (CTP) imaging within 24 to 72 h after ICH (Xu et al, 2017), we conclude that the c-ICH model might be a more suitable model for studying early BBB damage and protection comparing to the b-ICH model
Summary
Intracerebral hemorrhage (ICH) is the second most common subtype of stroke, and it has a high mortality and disability rate (Wang, 2010; Lan et al, 2017). The pathophysiologic mechanism of ICH is complex, with excessive neuroinflammatory responses due to the activation of immune cells as well as the release of inflammatory cytokines (Hua et al, 2020; Ren et al, 2020; Boltze et al, 2021), which lead to the degradation of the bloodbrain barrier (BBB) and neuron death (Yang et al, 2017). There has been great interest in maintaining BBB integrity and inhibiting brain inflammation after ICH. The BBB is composed of brain microvascular endothelial cells (BMECs) and their tight junctions (TJs), basement membranes, pericytes, and astrocyte terminals. There is evidence that secondary injury induces BMEC cell death and impairment of peri-cellular TJs which result in BBB dysfunction after stroke (Wu et al, 2019)
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