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  • 1
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    Online Resource
    Different effects of clazosentan on consequences of subarachnoid hemorrhage in rats
    Elsevier BV ; 2011
    In:  Brain Research Vol. 1392 ( 2011-05), p. 132-139
    Details
    In: Brain Research, Elsevier BV, Vol. 1392 ( 2011-05), p. 132-139
    Type of Medium: Online Resource
    ISSN: 0006-8993
    URL: Article
    DOI: 10.1016/j.brainres.2011.03.068
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2011
    detail.hit.zdb_id: 1462674-3
    SSG: 12
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  • 2
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    Abstract TMP70: Reduced Hippocampal Synapses Underlie Loss of Long-Term Potentiation after Experimental Subarachnoid Hemorrhage
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Stroke Vol. 44, No. suppl_1 ( 2013-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. suppl_1 ( 2013-02)
    Abstract: Background: Patients who survive aneurysmal subarachnoid hemorrhage (SAH) often have deficits in learning, memory and executive function, although structural brain damage may not be detectable. We previously reported that rodents with SAH develop cognitive deficits and loss of long-term potentiation (LTP), a probable electrophysiological correlate of learning and memory. We hypothesize that loss of LTP may be caused by diminished synapses and/or dysfunction of synaptic molecules responsible for LTP, and that this occurs without neuronal death. Methods: SAH was created by injection of 300 μl of fresh, unheparinized arterial blood into the prechiasmatic cistern of Sprague-Dawley rats (300-350g). Controls were injected with the same amount of saline. Cell death was detected with Fluoro-jade B and TUNEL staining. The number of synapses in dendritic layer of CA1 was quantified by double immunohistochemical staining of MAP2 and synaptophysin, or directly by transmission electron microscopy. Glutamate receptor subunits (GluR1/2) and CaM kinase II were quantified by immunohistochemical staining. Superoxide and nitric oxide (NO) concentrations in freshly homogenized hippocampal tissues were detected by spectrophotometry with DAF-2DA and MCLA dyes. Results: In the dendritic area of CA1, the number of synapses was significantly decreased after SAH compared to controls (54±4/image for SAH, 74±3 for controls, p 〈 0.001). Similarly, the expression of GluR1, GluR2 and CaM kinase II was decreased in SAH rats. Decreased superoxide (0.038±0.006 for SAH, 0.059±0.01 for control p 〈 0.001) but increased NO was detected in rats with SAH as compared to controls (1251±118 for SAH, 518±118 for controls, p 〈 0.001). Fluoro-jade B and TUNEL staining disclosed no to minimal CA1 cell death. Conclusions: Loss of LTP after SAH in rats may be due to a synaptic plasticity rather than cell death. Decreased immunoreactivity to GluR1, GluR2 and CaM kinase II suggests reduction in key proteins that mediator LTP may also contribute. Decreased superoxide and increased NO suggest oxidative stress is involved in the loss of LTP.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.44.suppl_1.ATMP70
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1467823-8
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  • 3
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    Abstract TP266: Platelet-Derived Glutamate Contributes to Neuronal Injury after Experimental Subarachnoid Hemorrhage
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Stroke Vol. 44, No. suppl_1 ( 2013-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. suppl_1 ( 2013-02)
    Abstract: Background: Glutamate toxicity (excitotoxicity) is well-studied in the pathogenesis of brain damage after cerebral ischemia and traumatic brain injury. Patients with subarachnoid hemorrhage (SAH) also have increased intracerebral glutamate as detected by microdialysis. While neurons and glia are potential sources of glutamate, platelets also release glutamate as part of their recruitment and might mediate neuronal damage. Studies have shown that intraluminal platelets escape into brain parenchyma after SAH. Therefore, we studied the hypothesis that formation of platelet microthrombi after SAH, and their subsequent extravasation releases glutamate that mediates excitotoxic brain injury and neuron dysfunction after SAH. Methods: We used two models, primary neuronal cultures exposed to activated platelets, and a model of SAH created by injection of 300 μl of fresh, unheparinized arterial blood into the prechiasmatic cistern of Sprague-Dawley rats (300-350 g). Glutamate was measured using amperometric microelectrode arrays. Propidium iodide was used to evaluate neuronal viability in neuronal cultures, and surface glutamate receptor immunohistochemical staining was used to evaluate the phenotype of platelet-exposed cultured neurons and brain after SAH. Microthrombi were stained with anti-fibrinogen antibodies. Results: We first demonstrated that thrombin-activated platelet-rich plasma releases glutamate in concentrations that exceed 300 μmol/l. When applied to neuronal cultures, this activated plasma was neurotoxic, and neurotoxicity was attenuated by glutamate receptor antagonism. Exposure of cultured neurons to thrombin-activated platelets induced a marked downregulation of the surface glutamate receptor GluR2, a marker of excitotoxicity and a possible mechanism of neuron dysfunction. Microthrombi were detected in rat cerebral cortex 7 days after SAH and linear regression demonstrated a strong correlation between proximity to microthrombi and reduction of surface glutamate GluR2 receptors. Conclusions: These correlative data support the novel hypothesis that platelet-mediated microthrombosis contributes to neuronal glutamate receptor dysfunction and might therefore influence clinical outcome following SAH.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.44.suppl_1.ATP266
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
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  • 4
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    Abstract WP262: Therapeutically Targeting TNFa-S1P Signaling Restores Microvascular Reactivity after Experimental Subarachnoid Hemorrhage
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Stroke Vol. 44, No. suppl_1 ( 2013-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. suppl_1 ( 2013-02)
    Abstract: Background: Subarachnoid hemorrhage (SAH) is characterized by an initial hemorrhagic and ischemic brain injury followed by delayed macro- and microvascular constriction. Large-artery vasospasm and enhanced microcirculatory myogenic tone may contribute to delayed cerebral ischemia. Although this implies that therapeutic interventions must specifically correct the SAH-induced myogenic tone enhancement, current therapeutic approaches non-selectively interfere with vasoconstriction and risk disrupting cerebral autoregulation. This may explain why most interventions do not improve clinical outcome. This study identifies the molecular basis for exacerbated cerebrovascular constriction and validates new targets for SAH treatment. Methods: Wild-type, tumor necrosis factor α (TNFα) knockout, sphingosine-1-kinase (Sphk1) knockout and inducible, smooth muscle cell-targeted TNFα knockout mice were used. SAH was created by injection of 80 μl of arterial blood into the prechiasmatic cistern. Myogenic tone in the olfactory artery was assessed with a myograph system. Standard procedures for fluorescent immunolocalization, Western blotting and assessment of apoptosis were used. Results: SAH increased myogenic tone and vascular wall TNFα expression, without enhancing overall vascular contractility in response to phenylephrine. Knockout of TNFα globally or smooth muscle cell-specifically prevented SAH-induced increased myogenic tone. Inhibition of TNFα-shedding (TAPI, 50 μmol/L) or receptor-binding (etanercept, 10 mg/ml) eliminated SAH-mediated myogenic tone augmentation. Cystic fibrosis transmembrane regulator (CFTR) protein expression was down-regulated in cerebral arteries after SAH, which was abolished by antagonism of TNFα. Genetic mouse models confirmed that S1P signaling mediates the myogenic tone augmentation in SAH. Finally, disrupting TNFα signaling attenuated neuronal apoptosis in SAH animals. Conclusion: We identify a novel smooth muscle cell autocrine/paracrine signaling network that augments myogenic tone in SAH. It links TNFα, CFTR and sphingosine-1-phosphate (S1P) signaling. Targeting TNFα and the S1P 2 receptor subtype are potential therapeutic options to improve clinical outcome in SAH.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.44.suppl_1.AWP262
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1467823-8
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  • 5
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    Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Stroke Vol. 46, No. 8 ( 2015-08), p. 2260-2270
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 46, No. 8 ( 2015-08), p. 2260-2270
    Abstract: Subarachnoid hemorrhage (SAH) is a complex stroke subtype characterized by an initial brain injury, followed by delayed cerebrovascular constriction and ischemia. Current therapeutic strategies nonselectively curtail exacerbated cerebrovascular constriction, which necessarily disrupts the essential and protective process of cerebral blood flow autoregulation. This study identifies a smooth muscle cell autocrine/paracrine signaling network that augments myogenic tone in a murine model of experimental SAH: it links tumor necrosis factor-α (TNFα), the cystic fibrosis transmembrane conductance regulator, and sphingosine-1-phosphate signaling. Methods— Mouse olfactory cerebral resistance arteries were isolated, cannulated, and pressurized for in vitro vascular reactivity assessments. Cerebral blood flow was measured by speckle flowmetry and magnetic resonance imaging. Standard Western blot, immunohistochemical techniques, and neurobehavioral assessments were also used. Results— We demonstrate that targeting TNFα and sphingosine-1-phosphate signaling in vivo has potential therapeutic application in SAH. Both interventions (1) eliminate the SAH-induced myogenic tone enhancement, but otherwise leave vascular reactivity intact; (2) ameliorate SAH-induced neuronal degeneration and apoptosis; and (3) improve neurobehavioral performance in mice with SAH. Furthermore, TNFα sequestration with etanercept normalizes cerebral perfusion in SAH. Conclusions— Vascular smooth muscle cell TNFα and sphingosine-1-phosphate signaling significantly enhance cerebral artery tone in SAH; anti-TNFα and anti–sphingosine-1-phosphate treatment may significantly improve clinical outcome.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.114.006365
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1467823-8
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  • 6
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    Circadian Rhythmicity in Cerebral Microvascular Tone Influences Subarachnoid Hemorrhage–Induced Injury
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Stroke Vol. 53, No. 1 ( 2022-01), p. 249-259
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 53, No. 1 ( 2022-01), p. 249-259
    Abstract: Circadian rhythms influence the extent of brain injury following subarachnoid hemorrhage (SAH), but the mechanism is unknown. We hypothesized that cerebrovascular myogenic reactivity is rhythmic and explains the circadian variation in SAH-induced injury. Methods: SAH was modeled in mice with prechiasmatic blood injection. Inducible, smooth muscle cell–specific Bmal1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1) gene deletion (smooth muscle–specific Bmal1 1 knockout [sm-Bmal1 KO]) disrupted circadian rhythms within the cerebral microcirculation. Olfactory cerebral resistance arteries were functionally assessed by pressure myography in vitro; these functional assessments were related to polymerase chain reaction/Western blot data, brain histology (Fluoro-Jade/activated caspase-3), and neurobehavioral assessments (modified Garcia scores). Results: Cerebrovascular myogenic vasoconstriction is rhythmic, with a peak and trough at Zeitgeber times 23 and 11 (ZT23 and ZT11), respectively. Histological and neurobehavioral assessments demonstrate that higher injury levels occur when SAH is induced at ZT23, compared with ZT11. In sm-Bmal1 KO mice, myogenic reactivity is not rhythmic. Interestingly, myogenic tone is higher at ZT11 versus ZT23 in sm-Bmal1 KO mice; accordingly, SAH-induced injury in sm-Bmal1 KO mice is more severe when SAH is induced at ZT11 compared to ZT23. We examined several myogenic signaling components and found that CFTR (cystic fibrosis transmembrane conductance regulator) expression is rhythmic in cerebral arteries. Pharmacologically stabilizing CFTR expression in vivo (3 mg/kg lumacaftor for 2 days) eliminates the rhythmicity in myogenic reactivity and abolishes the circadian variation in SAH-induced neurological injury. Conclusions: Cerebrovascular myogenic reactivity is rhythmic. The level of myogenic tone at the time of SAH ictus is a key factor influencing the extent of injury. Circadian oscillations in cerebrovascular CFTR expression appear to underlie the cerebrovascular myogenic reactivity rhythm.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.121.036950
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467823-8
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  • 7
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    Online Resource
    Platelet-mediated changes to neuronal glutamate receptor expression at sites of microthrombosis following experimental subarachnoid hemorrhage : Laboratory investigation
    Journal of Neurosurgery Publishing Group (JNSPG) ; 2014
    In:  Journal of Neurosurgery Vol. 121, No. 6 ( 2014-12), p. 1424-1431
    Details
    In: Journal of Neurosurgery, Journal of Neurosurgery Publishing Group (JNSPG), Vol. 121, No. 6 ( 2014-12), p. 1424-1431
    Abstract: Glutamate is important in the pathogenesis of brain damage after cerebral ischemia and traumatic brain injury. Notably, brain extracellular and cerebrospinal fluid as well as blood glutamate concentrations increase after experimental and clinical trauma. While neurons are one potential source of glutamate, platelets also release glutamate as part of their recruitment and might mediate neuronal damage. This study investigates the hypothesis that platelet microthrombi release glutamate that mediates excitotoxic brain injury and neuron dysfunction after subarachnoid hemorrhage (SAH). Methods The authors used two models, primary neuronal cultures exposed to activated platelets, as well as a whole-animal SAH preparation. Propidium iodide was used to evaluate neuronal viability, and surface glutamate receptor staining was used to evaluate the phenotype of platelet-exposed neurons. Results The authors demonstrate that thrombin-activated platelet-rich plasma releases glutamate, at concentrations that can exceed 300 μM. When applied to neuronal cultures, this activated plasma is neurotoxic, and the toxicity is attenuated in part by glutamate receptor antagonists. The authors also demonstrate that exposure to thrombin-activated platelets induces marked downregulation of the surface glutamate receptor glutamate receptor 2, a marker of excitotoxicity exposure and a possible mechanism of neuronal dysfunction. Linear regression demonstrated that 7 days after SAH in rats there was a strong correlation between proximity to microthrombi and reduction of surface glutamate receptors. Conclusions The authors conclude that platelet-mediated microthrombosis contributes to neuronal glutamate receptor dysfunction and might mediate brain injury after SAH.
    Type of Medium: Online Resource
    ISSN: 0022-3085 , 1933-0693
    URL: Article
    DOI: 10.3171/2014.3.JNS132130
    RVK:
    XA 10000
    RVK:
    XA 55270
    Language: Unknown
    Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
    Publication Date: 2014
    detail.hit.zdb_id: 2026156-1
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