Profiling of Blood-Brain Barrier Disruption in Mouse Intracerebral Hemorrhage Models: Collagenase Injection vs. Autologous Arterial Whole Blood Infusion

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.

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Berberine Protects against Neurological Impairments and Blood-Brain Barrier Injury in Mouse Model of Intracerebral Hemorrhage

NeuroImmunoModulation ◽

10.1159/000520747 ◽

2021 ◽

pp. 1-10

Author(s):

Xiuwen Wu ◽

Xiaopeng Liu ◽

Liang Yang ◽

Yuanyu Wang

Keyword(s):

Intracerebral Hemorrhage ◽

Blood Brain Barrier ◽

Inflammatory Responses ◽

Brain Barrier ◽

Neurological Deficits ◽

Peroxisome Proliferator ◽

Intracerebral Injection ◽

Neuroprotective Effects ◽

Blood Brain ◽

Autologous Whole Blood

Background: Elevation of AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) signaling can suppress intracerebral hemorrhage (ICH)-induced neurological impairments. As an isoquinoline alkaloid, Berberine exerts neuroprotective effects in neurological disease models with activated AMPK/PGC1α signaling. Aim: We aim to study the effect of Berberine on ICH-induced brain injury and explore the potential molecular mechanism. Methods: ICH model was established in mice through intracerebral injection of autologous whole blood, followed by treatment with Berberine. Neurological impairments were assessed by the modified neurological severity score and behavioral assays. Brain edema and blood-brain barrier (BBB) integrity were assessed by water content in the brain, amount of extravasated Evans blue, and BBB tight junction components. Neuroinflammatory responses were assessed by inflammatory cytokine levels. AMPK/PGC1α signaling was examined by AMPK mRNA expression and phosphorylated AMPK and PGC1α protein levels. Results: Berberine (200 mg/kg) attenuated ICH-induced neurological deficits, motor and cognitive impairment, and BBB disruption. Berberine also suppressed ICH-induced inflammatory responses indicated by reduced production of inflammatory cytokines. Finally, Berberine drastically elevated AMPK/PGC1α signaling in the hemisphere of ICH mice. Conclusion: Our findings suggest that Berberine plays an important neuroprotective role against ICH-induced neurological impairments and BBB injury, probably by inhibition of inflammation and activation of AMPK/PGC1α signaling.

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Attenuation of hematoma size and neurological injury with curcumin following intracerebral hemorrhage in mice

Journal of Neurosurgery ◽

10.3171/2011.2.jns10784 ◽

2011 ◽

Vol 115 (1) ◽

pp. 116-123 ◽

Cited By ~ 44

Author(s):

Melanie D. King ◽

D. Jay McCracken ◽

F. Marlene Wade ◽

Steffen E. Meiler ◽

Cargill H. Alleyne ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Blood Brain Barrier ◽

Vasogenic Edema ◽

Autologous Blood ◽

Brain Barrier ◽

Neurological Injury ◽

Clinical Prognosis ◽

Proinflammatory Mediators ◽

Blood Brain ◽

Neurovascular Injury

Object Intracerebral hemorrhage (ICH) is associated with significant morbidity and mortality. Acute hematoma enlargement is an important predictor of neurological injury and poor clinical prognosis; but neurosurgical clot evacuation may not be feasible in all patients and treatment options remain largely supportive. Thus, novel therapeutic approaches to promote hematoma resolution are needed. In the present study, the authors investigated whether the curry spice curcumin limited neurovascular injury following ICH in mice. Methods Intracerebral hemorrhage was induced in adult male CD-1 mice by intracerebral administration of collagenase or autologous blood. Clinically relevant doses of curcumin (75–300 mg/kg) were administered up to 6 hours after ICH, and hematoma volume, inflammatory gene expression, blood-brain barrier permeability, and brain edema were assessed over the first 72 hours. Neurological assessments were performed to correlate neurovascular protection with functional outcomes. Results Curcumin increased hematoma resolution at 72 hours post-ICH. This effect was associated with a significant reduction in the expression of the proinflammatory mediators, tumor necrosis factor–α, interleukin-6, and interleukin-1β. Curcumin also reduced disruption of the blood-brain barrier and attenuated the formation of vasogenic edema following ICH. Consistent with the reduction in neuroinflammation and neurovascular injury, curcumin significantly improved neurological outcome scores after ICH. Conclusions Curcumin promoted hematoma resolution and limited neurological injury following ICH. These data may indicate clinical utility for curcumin as an adjunct therapy to reduce brain injury and improve patient outcome.

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CD200Fc Improves Neurological Function by Protecting the Blood–brain Barrier after Intracerebral Hemorrhage

Cell Transplantation ◽

10.1177/0963689719857655 ◽

2019 ◽

Vol 28 (9-10) ◽

pp. 1321-1328 ◽

Cited By ~ 1

Author(s):

Chen-sheng Le ◽

Xiao-di Hao ◽

Jia-wen Li ◽

Jia-wei Zhong ◽

Hao-ran Lin ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Blood Brain Barrier ◽

Functional Outcomes ◽

Neurological Diseases ◽

Autologous Blood ◽

Neurological Function ◽

Brain Barrier ◽

Blood Brain ◽

The Central Nervous System

CD200 is widely distributed in the central nervous system and plays an essential role in the immune response in neurological diseases. However, little is currently known about the effects of CD200 signaling on the blood–brain barrier (BBB) function after intracerebral hemorrhage (ICH). In this study, the role of CD200 during ICH in an autologous blood induced mouse ICH model was investigated. Following ICH, critical protein expression, BBB permeability, and neurological function were measured with or without CD200Fc administration. Our results showed that both the expression of CD200 and CD200R1 decreased after ICH and administration of CD200Fc attenuated BBB leakage and improved neurological functions. In conclusion, our work demonstrated that CD200Fc might be a potential treatment option for ICH by protecting the BBB and improving functional outcomes.

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Fibroblast growth factors preserve blood–brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice

Neurobiology of Disease ◽

10.1016/j.nbd.2012.01.008 ◽

2012 ◽

Vol 46 (1) ◽

pp. 204-214 ◽

Cited By ~ 46

Author(s):

Bin Huang ◽

Paul R. Krafft ◽

Qingyi Ma ◽

William B. Rolland ◽

Basak Caner ◽

...

Keyword(s):

Growth Factors ◽

Intracerebral Hemorrhage ◽

Blood Brain Barrier ◽

Fibroblast Growth Factors ◽

Brain Barrier ◽

Fibroblast Growth ◽

Barrier Integrity ◽

Blood Brain ◽

Preserve Blood ◽

Blood Brain Barrier Integrity

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Serum Markers of Blood-Brain Barrier Remodeling and Fibrosis as Predictors of Etiology and Clinicoradiologic Outcome in Intracerebral Hemorrhage

Frontiers in Neurology ◽

10.3389/fneur.2018.00746 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 10

Author(s):

Matthew D. Howe ◽

Liang Zhu ◽

Lauren H. Sansing ◽

Nicole R. Gonzales ◽

Louise D. McCullough ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Blood Brain Barrier ◽

Serum Markers ◽

Brain Barrier ◽

Blood Brain

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A cannabinoid receptor 2 agonist reduces blood–brain barrier damage via induction of MKP-1 after intracerebral hemorrhage in rats

Brain Research ◽

10.1016/j.brainres.2018.06.006 ◽

2018 ◽

Vol 1697 ◽

pp. 113-123 ◽

Cited By ~ 7

Author(s):

Lin Li ◽

Debo Yun ◽

Yuan Zhang ◽

Yihao Tao ◽

Qiang Tan ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Blood Brain Barrier ◽

Cannabinoid Receptor ◽

Brain Barrier ◽

Cannabinoid Receptor 2 ◽

Blood Brain ◽

Blood Brain Barrier Damage

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Intracerebral Hemorrhage and Diabetes Mellitus: Blood-Brain Barrier Disruption, Pathophysiology, and Cognitive Impairments

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210223145112 ◽

2021 ◽

Vol 20 ◽

Author(s):

Ghaith A. Bahadar ◽

Zahoor A Shah

Keyword(s):

Diabetes Mellitus ◽

Intracerebral Hemorrhage ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Comorbid Condition ◽

Barrier Disruption ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Brain Barrier Disruption ◽

The Impact

: There is a surge in diabetes incidence with an estimated 463 million individuals been diagnosed worldwide. Diabetes Mellitus (DM) is a major stroke-related comorbid condition that increases the susceptibility of disabling post-stroke outcomes. Although less common, intracerebral hemorrhage (ICH) is the most dramatic subtype of stroke that is associated with higher mortality, particularly in DM population. Previous studies have focused mainly on the impact of DM on ischemic stroke. Few studies have focused on impact of DM on ICH and discussed the blood-brain barrier disruption, brain edema, and hematoma formation. However, more recently, investigating the role of oxidative damage and reactive oxygen species (ROS) production in preclinical studies involving DM-ICH animal models has gained attention. But, little is known about the correlation between neuroinflammatory processes, glial cells activation, and peripheral immune cell invasion with DM-ICH injury. DM and ICH patients experience impaired abilities in multiple cognitive domains by relatively comparable mechanisms, which could get exacerbated in the setting of comorbidities. In this review, we discuss both the pathology of DM as a comorbid condition for ICH and the potential molecular therapeutic targets for the clinical management of the ICH and its recovery.

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