Cortical Spreading Depolarizations in a Mouse Model of Subarachnoid Hemorrhage

AbstractPrevious studies showed that complement activation is associated with poor functional outcome after aneurysmal subarachnoid hemorrhage (SAH). We investigated whether complement activation is underlying brain injury after aneurysmal SAH (n = 7) and if it is an appropriate treatment target. We investigated complement expression in brain tissue of aneurysmal SAH patients (n = 930) and studied the role of common genetic variants in C3 and C5 genes in outcome. We analyzed plasma levels (n = 229) to identify the functionality of a single nucleotide polymorphism (SNP) associated with outcome. The time course of C5a levels was measured in plasma (n = 31) and CSF (n = 10). In an SAH mouse model, we studied the extent of microglia activation and cell death in wild-type mice, mice lacking the C5a receptor, and in mice treated with C5-specific antibodies (n = 15 per group). Brain sections from aneurysmal SAH patients showed increased presence of complement components C1q and C3/C3b/iC3B compared to controls. The complement component 5 (C5) SNP correlated with C5a plasma levels and poor disease outcome. Serial measurements in CSF revealed that C5a was > 1400-fold increased 1 day after aneurysmal SAH and then gradually decreased. C5a in plasma was 2-fold increased at days 3–10 after aneurysmal SAH. In the SAH mouse model, we observed a ≈ 40% reduction in both microglia activation and cell death in mice lacking the C5a receptor, and in mice treated with C5-specific antibodies. These data show that C5 contributes to brain injury after experimental SAH, and support further study of C5-specific antibodies as novel treatment option to reduce brain injury and improve prognosis after aneurysmal SAH.

Download Full-text

Abstract WP308: Role of Microthrombi and Vasospasm in the Development of Delayed Neurological Deficits After Subarachnoid Hemorrhage in Mice

Stroke ◽

10.1161/str.51.suppl_1.wp308 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Devin W McBride ◽

Ari Dienel ◽

Remya A Veettil ◽

Kanako Matsumura ◽

Peeyush Kumar T. ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Mouse Model ◽

Experimental Studies ◽

Brain Slices ◽

Neurological Deficits ◽

Male Mice ◽

Male And Female ◽

Delayed Neurological Deterioration ◽

First Time

Rationale: Microthrombosis has been suggested as a major factor contributing to delayed neurological deterioration in patients after subarachnoid hemorrhage (SAH). However, experimental studies on the role of microthrombi in delayed deficits after SAH has not been investigated. Our hypothesis is that, following SAH, mice which develop delayed neurological deficits have a greater number of microthrombi than mice which do not develop delayed neurological deficits. Methods: SAH was induced in adult male and female C57BL/6 mice via endovascular perforation. Mice were randomly assigned into sham (n=6/sex) or SAH groups (n=22-24/sex). Neurobehavior was performed on days 1-3, 5, and 7 post-SAH using a composite neuroscore. Animals were sacrificed on the day of delayed deficits or 7 days post-SAH. Microthrombi count and vessel diameters (for vasospasm) were measured using H&E stained brain slices. All outcomes were performed and all data were analyzed by a blinded investigator. Results: Seventeen percent (4/24) of male mice and thirty-six percent (8/22) of female mice developed delayed deficits on days 3-5 post-SAH (Figures 1A and 1B). Those mice which developed delayed deficits had significantly more microthrombi in their brains than mice which did not develop delayed deficits; vasospasm did not correlate with delayed deficits. Additionally, female SAH mice develop delayed deficits at a higher frequency than males (Figure 1C). Conclusions: This work shows for the first time delayed deficits in a SAH mouse model. Further, microthrombi correlated with delayed deficits, whereas no correlation was between delayed deficits and vasospasm. The data within this study suggests that preventing microthrombi may improve functional recovery and reduce the risk of delayed deficits.

Download Full-text

Long-Lasting Cerebral Vasospasm, Microthrombosis, Apoptosis and Paravascular Alterations Associated with Neurological Deficits in a Mouse Model of Subarachnoid Hemorrhage

Molecular Neurobiology ◽

10.1007/s12035-017-0514-6 ◽

2017 ◽

Vol 55 (4) ◽

pp. 2763-2779 ◽

Cited By ~ 13

Author(s):

Mohamad El Amki ◽

Martine Dubois ◽

Antoine Lefevre-Scelles ◽

Nicolas Magne ◽

Mélanie Roussel ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Mouse Model ◽

Cerebral Vasospasm ◽

Neurological Deficits

Download Full-text

Alterations of caveolin-1 expression in a mouse model of delayed cerebral vasospasm following subarachnoid hemorrhage

Experimental and Therapeutic Medicine ◽

10.3892/etm.2016.3568 ◽

2016 ◽

Vol 12 (4) ◽

pp. 1993-2002 ◽

Cited By ~ 3

Author(s):

Ye Xiong ◽

Xue-Min Wang ◽

Ming Zhong ◽

Ze-Qun Li ◽

Zhi Wang ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Mouse Model ◽

Cerebral Vasospasm ◽

Caveolin 1 ◽

Delayed Cerebral Vasospasm

Download Full-text

Abstract 195: Sulforaphane Protects Against Subarachnoid Hemorrhage and Alters the Expression of Inflammatory and Extracellular Matrix Remodeling Genes in a Mouse Model of Intracranial Aneurysm

Stroke ◽

10.1161/str.48.suppl_1.195 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Crissey L Pascale ◽

David M Sawyer ◽

Lauren A Pace ◽

Brannan E O’Neill ◽

Devon O’Donnell ◽

...

Keyword(s):

Extracellular Matrix ◽

Subarachnoid Hemorrhage ◽

Treatment Group ◽

Mouse Model ◽

Intracranial Aneurysm ◽

Lower Incidence ◽

Control Group ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Rt Pcr

Introduction: Oxidative stress has been shown to play an important role in the pathogenesis of intracranial aneurysm (IA). Sulforaphane is an isothiocyanate that exhibits antioxidant properties via the Nrf2 transcription factor. We tested whether sulforaphane would protect against IA formation and subarachnoid hemorrhage (SAH) in a mouse model. Methods: C57BL/6 mice were treated intraperitoneally with either 0.5mg/kg/day of sulforaphane (treatment group, n = 32) or a vehicle solution (control group, n = 26) prior to being subjected to a well-established IA induction protocol involving unilateral nephrectomy, mineralocorticoid administration, and intracranial injection of elastase. Sulforaphane/vehicle treatments were begun seven days prior to elastase injection, and continued daily for the duration of the experiment. Animals were followed for 14 days until sacrifice, with measurement of the number of aneurysms formed and ruptured in each animal. Intracranial vessel tissue was collected, pooled, and analyzed using real-time PCR (RT-PCR) with experiments performed in triplicate (n = 3). Results: There was a lower incidence of IA in the treatment group (1.06 +/- 0.24 per animal) than in the control group (1.54 +/- 0.33), but this trend did not reach significance. The incidence of SAH in the treatment group (0.53 +/- 0.09 per animal) was approximately 50% lower than in the control group (1.08 +/- 0.21, p = 0.012). RT-PCR showed significant (p < 0.05) differences in the expression of interferon gamma, matrix metalloproteinase 9, collagen Ia2, interleukin-6, myosin heavy chain, and SM22 between the treatment and control groups. Conclusions: Treatment with sulforaphane resulted in a significantly lower incidence of SAH in a mouse model of IA. The expression of genes involved in inflammation and extracellular matrix remodeling were altered by sulforaphane administration.

Download Full-text

Successful Serial Imaging of the Mouse Cerebral Arteries Using Conventional 3-T Magnetic Resonance Imaging

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.78 ◽

2015 ◽

Vol 35 (9) ◽

pp. 1523-1527 ◽

Cited By ~ 7

Author(s):

Hiroshi Makino ◽

Kazuya Hokamura ◽

Takahiro Natsume ◽

Tetsuro Kimura ◽

Yoshinobu Kamio ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Subarachnoid Hemorrhage ◽

Magnetic Resonance ◽

Mouse Model ◽

Intracranial Aneurysm ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Cerebral Arteries ◽

Resonance Imaging ◽

Serial Imaging ◽

Aneurysm Formation

Serial imaging studies can be useful in characterizing the pathologic and physiologic remodeling of cerebral arteries in various mouse models. We tested the feasibility of using a readily available, conventional 3-T magnetic resonance imaging (MRI) to serially image cerebrovascular remodeling in mice. We utilized a mouse model of intracranial aneurysm as a mouse model of the dynamic, pathologic remodeling of cerebral arteries. Aneurysms were induced by hypertension and a single elastase injection into the cerebrospinal fluid. For the mouse cerebrovascular imaging, we used a conventional 3-T MRI system and a 40-mm saddle coil. We used non-enhanced magnetic resonance angiography (MRA) to detect intracranial aneurysm formation and T2-weighted imaging to detect aneurysmal subarachnoid hemorrhage. A serial MRI was conducted every 2 to 3 days. MRI detection of aneurysm formation and subarachnoid hemorrhage was compared against the postmortem inspection of the brain that was perfused with dye. The imaging times for the MRA and T2-weighted imaging were 3.7 ± 0.5 minutes and 4.8 ± 0.0 minutes, respectively. All aneurysms and subarachnoid hemorrhages were correctly identified by two masked observers on MRI. This MRI-based serial imaging technique was useful in detecting intracranial aneurysm formation and subarachnoid hemorrhage in mice.

Download Full-text