SRC-3 Deficiency Exacerbates Neurological Deficits in a Mouse Model of Intracerebral Hemorrhage: Role of Oxidative Stress

2021 ◽  
Author(s):  
Mingyang Deng ◽  
Jianyang Liu ◽  
Jialin He ◽  
Ziwei Lan ◽  
Zhiping Hu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mouse Model ◽  
Intracerebral Hemorrhage ◽  
Neurological Deficits

scholarly journals 17β-Estradiol Attenuates Intracerebral Hemorrhage-Induced Blood–Brain Barrier Injury and Oxidative Stress Through SRC3-Mediated PI3K/Akt Signaling Pathway in a Mouse Model

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110384
Author(s):  
Han Xiao ◽  
Jianyang Liu ◽  
Jialin He ◽  
Ziwei Lan ◽  
Mingyang Deng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Mouse Model ◽  
Intracerebral Hemorrhage ◽  
Signaling Pathway ◽  
Brain Edema ◽  
Akt Signaling ◽  
Neurological Deficits ◽  
Akt Signaling Pathway ◽  
And Oxidative Stress

Estrogen is neuroprotective in brain injury models, and steroid receptor cofactor 3 (SRC3) mediates estrogen signaling. We aimed to investigate whether and how SRC3 is involved in the neuroprotective effects of 17ß-estradiol (E2) in a mouse model of intracerebral hemorrhage (ICH). Ovariectomized female mice were treated with E2 after autologous blood injection-induced ICH. Brain damage was assessed by neurological deficit score, brain water content, and oxidative stress levels. Blood–brain barrier (BBB) integrity was evaluated by Evan's blue extravasation and claudin-5, ZO-1, and occludin levels. SRC3 expression and PI3K/Akt signaling pathway were examined in ICH mice treated with E2. The effect of SRC3 on E2-mediated neuroprotection was determined by examining neurological outcomes in SRC3-deficient mice undergone ICH and E2 treatment. We found that E2 alleviated ICH-induced brain edema and neurological deficits, protected BBB integrity, and suppressed oxidative stress. E2 enhanced SRC3 expression and PI3K-/Akt signaling pathway. SRC3 deficiency abolished the protective effects of E2 on ICH-induced neurological deficits, brain edema, and BBB integrity. Our results suggest that E2 suppresses ICH-induced brain injury and SRC3 plays a critical role in E2-mediated neuroprotection.

Abstract 125: Perturbation of Mitochondrial Calcium Uniporter Promotes Cardiac Oxidative Stress and Autophagy During Heart Failure

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Sudarsan Rajan ◽  
Santhanam Shanmughapriya ◽  
Dhanendra Tomar ◽  
Zhiwei Dong ◽  
Joseph Y Cheung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Mouse Model ◽  
Atp Depletion ◽  
Regulatory Role ◽  
Mitochondrial Calcium ◽  
Mitochondrial Bioenergetics ◽  
Complex Assembly ◽  
New Findings

Mitochondrial calcium ([Ca 2+ ] m ) is essential for cardiomyocyte viability, and aberration of [Ca 2+ ] m is known to elicit multiple cardiac stress conditions associated with ATP depletion, reactive oxygen species, and mitochondrial permeability transition pore opening, all of which can lead to metabolic stress and the loss of dysfunctional mitochondria by aberrant autophagy. Elucidating the regulatory role of m itochondrial c alcium u niporter (MCU)-mediated [Ca 2+ ] m in modulating cardiac mitochondrial bioenergetics and autophagy has high significance and clinical impact for many pathophysiological processes. [Ca 2+ ] m is exquisitely controlled by the inner mitochondrial membrane uniporter, transporters, regulators and exchangers including MCU, MCUR1, EMRE, MICU1, MICU2 and LETM1. Our recently published findings revealed that Mitochondrial Ca 2+ Uniporter Regulator 1 (MCUR1) serves as a scaffold factor for uniporter complex assembly. We found that deletion of MCUR1 impaired [Ca 2+ ] m uptake, mitochondrial Ca 2+ current ( I MCU ) and mitochondrial bioenergetics and is associated with increased autophagy. Our new findings indicate that the impairment of [Ca 2+ ] m uptake exacerbated autophagy following ischemia-reperfusion (I/R) injury. In support of our mouse model, human failing hearts show that MCUR1 protein levels are markedly decreased and autophagy markers are increased, demonstrating a crucial link between [Ca 2+ ] m uptake and autophagy during heart failure. Additionally, our results reveal that either oxidation or disruption of human MCU Cys-97 (in mouse Cys-96; gain-of-function MCU C96A mutant) produces a conformational change within the N terminal β-grasp fold of MCU which promotes higher-order MCU complex assembly and increased I MCU activity and mitochondrial ROS levels. The results of our studies using a novel cardiac-specific MCUR1-KO model and a constitutively active global MCU C96A KI mouse model (CRISPR-Cas9 genome edited) elucidate the regulatory role of [Ca 2+ ] m in cardiac bioenergetics and autophagy during oxidative stress and myocardial infarction. Thus, targeting assembly and the activity of MCU complex will offer a new potential therapeutic target in the treatment of cardiomyopathy and heart failure.

Infliximab improves endothelial dysfunction in a mouse model of antiphospholipid syndrome: Role of reduced oxidative stress

2015 ◽  
Vol 71 ◽  
pp. 93-101 ◽  
Author(s):  
Ygal Benhamou ◽  
Sébastien Miranda ◽  
Guillaume Armengol ◽  
Najah Harouki ◽  
Laurent Drouot ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Mouse Model ◽  
Antiphospholipid Syndrome

Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury

2004 ◽  
Vol 286 (6) ◽  
pp. H2442-H2451 ◽  
Author(s):  
Ikuyo Kusaka ◽  
Gen Kusaka ◽  
Changman Zhou ◽  
Mami Ishikawa ◽  
Anil Nanda ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Brain Injury ◽  
Cerebral Ischemia ◽  
Cerebral Infarction ◽  
Focal Cerebral Ischemia ◽  
Lipid Hydroperoxide ◽  
Neurological Deficits ◽  
Sprague Dawley

The objective of the present study was to examine the role of the angiotensin II type 1 receptor (AT1-R) in the diabetes-aggravated oxidative stress and brain injury observed in a rat model of combined diabetes and focal cerebral ischemia. Diabetes was induced by an injection of streptozotoxin (STZ; 55 mg/kg iv) at 8 wk of age. Two weeks after the induction of diabetes, some animals received continuous subcutaneous infusion of the AT1-R antagonist candesartan (0.5 mg·kg−1·day−1) for 14 days. Focal cerebral ischemia, induced by middle cerebral artery occlusion/reperfusion (MCAO), was conducted at 4 wk after STZ injection. Male Sprague-Dawley rats ( n = 189) were divided into five groups: normal control, diabetes, MCAO, diabetes + MCAO, and diabetes + MCAO + candesartan. The major observations were that 1) MCAO produced typical cerebral infarction and neurological deficits at 24 h that were accompanied by elevation of NAD(P)H oxidase gp91phox and p22phox mRNAs, and lipid hydroperoxide production in the ipsilateral hemisphere; 2) diabetes enhanced NAD(P)H oxidase gp91phox and p22phox mRNA expression, potentiated lipid peroxidation, aggravated neurological deficits, and enlarged cerebral infarction; and 3) candesartan reduced the expression of gp91phox and p22phox, decreased lipid peroxidation, lessened cerebral infarction, and improved the neurological outcome. We conclude that diabetes exaggerates the oxidative stress, NAD(P)H oxidase induction, and brain injury induced by focal cerebral ischemia. The diabetes-aggravated brain injury involves AT1-Rs. We have shown for the first time that candesartan reduces brain injury in a combined model of diabetes and cerebral ischemia.

scholarly journals IL (Interleukin)-15 Bridges Astrocyte-Microglia Crosstalk and Exacerbates Brain Injury Following Intracerebral Hemorrhage

Stroke ◽  
2020 ◽  
Vol 51 (3) ◽  
pp. 967-974 ◽  
Author(s):  
Samuel X. Shi ◽  
Yu-Jing Li ◽  
Kaibin Shi ◽  
Kristofer Wood ◽  
Andrew F. Ducruet ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Autologous Blood ◽  
Brain Slices ◽  
Neurological Deficits ◽  
Transgenic Mouse Line ◽  
Il Interleukin ◽  
Targeted Expression ◽  
Interleukin 15

Background and Purpose— Microglia are among the first cells to respond to intracerebral hemorrhage (ICH), but the mechanisms that underlie their activity following ICH remain unclear. IL (interleukin)-15 is a proinflammatory cytokine that orchestrates homeostasis and the intensity of the immune response following central nervous system inflammatory events. The goal of this study was to investigate the role of IL-15 in ICH injury. Methods— Using brain slices of patients with ICH, we determined the presence and cellular source of IL-15. A transgenic mouse line with targeted expression of IL-15 in astrocytes was generated to determine the role of astrocytic IL-15 in ICH. The expression of IL-15 was controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15 tg ). ICH was induced by intraparenchymal injection of collagenase or autologous blood. Results— In patients with ICH and wild-type mice subjected to experimental ICH, we found a significant upregulation of IL-15 in astrocytes. In GFAP-IL-15 tg mice, we found that astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. This aggravated ICH injury in GFAP-IL-15 tg mice is accompanied by increased microglial accumulation in close proximity to astrocytes in perihematomal tissues. Additionally, microglial expression of CD86, IL-1β, and TNF-α is markedly increased in GFAP-IL-15 tg mice following ICH. Furthermore, depletion of microglia using a colony stimulating factor 1 receptor inhibitor diminishes the exacerbation of ICH injury in GFAP-IL-15 tg mice. Conclusions— Our findings identify IL-15 as a mediator of the crosstalk between astrocytes and microglia that exacerbates brain injury following ICH.

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

Stroke ◽  
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.

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