Abstract P776: Post-Stroke Tenascin-C Induction Mediates the Ischemic Pathogenesis

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Bharath Chelluboina ◽  
Anil Kiran Chokkalla ◽  
Suresh L Mehta ◽  
Saivenkateshkomal Bathula ◽  
Robert J Dempsey ◽  
...  
Keyword(s):  
Matched Control ◽  
Gadobenate Dimeglumine ◽  
Cerebrovascular Diseases ◽  
Artery Occlusion ◽  
Tenascin C ◽  
Post Stroke ◽  
Adult Mice ◽  
Group Sex ◽  
Neurological Surgery ◽  
Cerebral Artery Occlusion

The mechanistic role of Tenascin-C (TNC) in the pathogenesis of acute ischemic stroke is not known despite its prognostic association with cerebrovascular diseases. We currently observed that transient middle cerebral artery occlusion (MCAO) upregulated cerebral TNC mRNA and protein expression between 3h and 24h reperfusion in adult mice of both sexes. We then evaluated the effect of TNC knockdown on ischemic outcome in adult mice of both sexes by treating with either TNC siRNA or control siRNA (intravenous) at 5 min of reperfusion following transient MCAO. TNC siRNA treatment significantly reduced the post-ischemic TNC protein induction tested at 72h reperfusion compared with the sex-matched control siRNA treated cohorts (n=6/group/sex). TNC siRNA cohorts showed significantly improved post-stroke motor function identified by beam walk test and rotarod test between days 1 and 14 of reperfusion compared with the sex-matched control siRNA cohorts (n=7/group/sex). TNC siRNA cohorts of both sexes also showed decreased post-ischemic BBB disruption (evaluated with T1-weighted MRI with gadobenate dimeglumine as contrast agent) and reduced infarction (assessed with T2-weighted MRI) at 3 days of reperfusion compared with the sex-matched control siRNA treated cohorts (n =4/group for BBB and n =12/group/sex for infarct). At day 21 of reperfusion, the survival rate was observed to be higher in the TNC siRNA treated mice compared with the control siRNA treated mice (n =7/group/sex). These studies thus show that induction of TNC during the acute period after stroke might be a mediator of ischemic brain damage and its knockdown is neuroprotective. Importantly this effect is independent of sex. The study was funded by the Department of Neurological Surgery, Univ. of Wisconsin-Madison.

Abstract T MP111: Gpr124 Regulates Post-Stroke Cerebrovascular Integrity

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Michael Mancuso ◽  
Junlei Chang ◽  
Carolina Maier-Albers ◽  
Cynthia Kosinski ◽  
Xibin Liang ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Blood Brain Barrier ◽  
Cerebral Artery ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Stroke Model ◽  
Post Stroke ◽  
Adult Mice ◽  
Cerebral Artery Occlusion

Introduction: GPR124/TEM5 is an orphan G-protein coupled receptor (GPCR) with a large extracellular domain. We and others have previously demonstrated that GPR124 exerts CNS-specific angiogenesis regulation with knockout mice exhibiting embryonic lethality from hemorrhagic glomeruloid vascular malformations in forebrain and neural tube (c.f. Kuhnert et al., Science , Nov 12;330(6006):985-9 . (2010)). Hypothesis: GPR124 regulates adult angiogenesis and blood-brain barrier (BBB) integrity during homeostasis or after stroke. Methods: To bypass GPR124 embryonic lethality, we generated GPR124 conditional knockout (cko) mice allowing temporally-regulated deletion. Tamoxifen treatment of GPR124 flox/- ; ROSA-CreER mice versus GPR124 flox/+; ROSA-CreER littermate controls allowed GPR124 cko versus heterozygosity, respectively, in adult mice. GPR124 deletion was followed by analyses of microvascular structure and patterning and blood-brain barrier (BBB) integrity). GPR124 cko mice versus controls were also subjected to 60 minute middle cerebral artery occlusion (MCAO) and effects on stroke volume, survival and microvascular structure assessed. Results: GPR124 deletion in neonatal or adult mice was well-tolerated without impairment of postnatal vascular patterning, BBB maturation or BBB integrity. However, GPR124 cko mice subjected to the middle cerebral artery occlusion (MCAO) stroke model exhibited impaired survival and a profound microvascular hemorrhagic transformation that was confined to the infarct region relative to wild-type controls. GPR124 cko stroke vasculature also exhibited numerous cellular and architectural defects relative to controls that will be discussed. Conclusions: GPR124 deletion is well tolerated in adult mice but results in marked hemorrhagic transformation in the MCAO stroke model. GPR124 represents a novel receptor whose function is essential for cerebrovascular integrity in the post-stroke setting, with attendant therapeutic implications.

scholarly journals Impact of Key Nicotinic AChR Subunits on Post-Stroke Pneumococcal Pneumonia

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 253
Author(s):  
Sandra Jagdmann ◽  
Claudia Dames ◽  
Daniel Berchtold ◽  
Katarzyna Winek ◽  
Luis Weitbrecht ◽  
...  
Keyword(s):  
Artery Occlusion ◽  
Experimental Stroke ◽  
Medical Complication ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Post Stroke ◽  
Cholinergic Signaling ◽  
Cerebral Artery Occlusion ◽  
Pathogen Clearance ◽  
The Impact ◽  
Alveolar Capillary

Pneumonia is the most frequent severe medical complication after stroke. An overactivation of the cholinergic signaling after stroke contributes to immunosuppression and the development of spontaneous pneumonia caused by Gram-negative pathogens. The α7 nicotinic acetylcholine receptor (α7nAChR) has already been identified as an important mediator of the anti-inflammatory pathway after stroke. However, whether the α2, α5 and α9/10 nAChR expressed in the lung also play a role in suppression of pulmonary innate immunity after stroke is unknown. In the present study, we investigate the impact of various nAChRs on aspiration-induced pneumonia after stroke. Therefore, α2, α5, α7 and α9/10 nAChR knockout (KO) mice and wild type (WT) littermates were infected with Streptococcus pneumoniae (S. pneumoniae) three days after middle cerebral artery occlusion (MCAo). One day after infection pathogen clearance, cellularity in lung and spleen, cytokine secretion in bronchoalveolar lavage (BAL) and alveolar-capillary barrier were investigated. Here, we found that deficiency of various nAChRs does not contribute to an enhanced clearance of a Gram-positive pathogen causing post-stroke pneumonia in mice. In conclusion, these findings suggest that a single nAChR is not sufficient to mediate the impaired pulmonary defense against S. pneumoniae after experimental stroke.

scholarly journals Stent retriever for iatrogenic cerebral thromboembolism treatment

2014 ◽  
Vol 95 (1) ◽  
pp. 118-120
Author(s):  
M U Volodyukhin
Keyword(s):  
Blood Flow ◽  
Cerebral Angiography ◽  
Clinical Case ◽  
Severe Disabilities ◽  
Cerebrovascular Diseases ◽  
Artery Occlusion ◽  
Stent Retriever ◽  
Circulation System ◽  
Complete Restoration ◽  
Cerebral Artery Occlusion

Thromboembolism is one of the dangerous complications of cerebrovascular endovascular surgeries, often resulting in severe disabilities. A clinical case of using stent retriever for treating iatrogenic cerebral thromboembolism occurred as a complication of diagnostic cerebral angiography is presented. Patient M., 49 years, was admitted in the department of neurology with referral diagnosis of subarachnoid hematoma. No pathologic changes of intracranial arteries were revealed on multi-spiral computed tomography, so cerebral angiography was administered. After administration of heparin (100 U/kg), selective cerebral angiography of all the intracranial vascular beds was performed using a diagnostic cerebral catheter with some technical difficulties. After the intervention was finished, the patient developed non-focal neurological symptoms, left-sided hemianopsia. Angiography of posterior circulation system was repeated immediately, left posterior cerebral artery occlusion was found. Stent retriever was used to restore the intracranial blood flow. An intracranial stent retriever Solitaire (EV3) was delivered to the occlusion and deployed with exposition of 5 minutes and further removal. Control angiography showed complete restoration of the intracranial blood flow without signs of distal embolism. The neurologic deficit had completely resolved during first 24 hours after the surgery. The presented clinical case illustrates the effect of stent retriever use to to restore the intracranial blood flow and stresses the need for such devices availability in departments performing cerebral surgeries in patients with cerebrovascular diseases.

scholarly journals Enhanced Bioavailability of Dihydrotanshinone I–Bovine Serum Albumin Nanoparticles for Stroke Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanru Ren ◽  
Yicheng Feng ◽  
Kunyao Xu ◽  
Saisai Yue ◽  
Tiantian Yang ◽  
...  
Keyword(s):  
Bovine Serum Albumin ◽  
Serum Albumin ◽  
Bovine Serum ◽  
Salvia Miltiorrhiza ◽  
Cerebrovascular Diseases ◽  
Artery Occlusion ◽  
Stroke Therapy ◽  
Significant Efficacy ◽  
The Central Nervous System ◽  
Cerebral Artery Occlusion

Dihydrotanshinone I (DHT) is a natural component in Salvia miltiorrhiza and has been widely researched for its multiple bioactivities. However, poor solubility and biocompatibility of DHT limit its desirable application for clinical purposes. Herein, DHT was encapsulated with bovine serum albumin (BSA) to enhance bioavailability. Compared to free DHT, DHT–BSA NPs (nanoparticles) showed an improved solubility in normal saline and increased protection against hydrogen peroxide–induced oxidative damage in PC12 cells. In addition, DHT–BSA NPs administered by intravenous injection displayed a significant efficacy in the middle cerebral artery occlusion/reperfusion models, without any impact on the cerebral blood flow. In summary, DHT–BSA NPs show an enhanced bioavailability compared with free DHT and a successful penetration into the central nervous system for stroke therapy, demonstrating their application potential in cardio–cerebrovascular diseases.

scholarly journals Sensory Stimulation-Induced Astrocytic Calcium Signaling in Electrically Silent Ischemic Penumbra

2019 ◽  
Author(s):  
Reena P. Murmu ◽  
Jonas C. Fordsmann ◽  
Changsi Cai ◽  
Alexey Brazhe ◽  
Kirsten J. Thomsen ◽  
...  
Keyword(s):  
Sensory Stimulation ◽  
Artery Occlusion ◽  
Ischemic Penumbra ◽  
Somatosensory Stimulation ◽  
Two Photon Microscopy ◽  
Adult Mice ◽  
Dynamic Variations ◽  
Somatosensory Input ◽  
Cerebral Artery Occlusion ◽  
Old Mice

AbstractMiddle cerebral artery occlusion (MCAO) induces ischemia characterized by a densely ischemic focus, and a less densely ischemic penumbral zone in which neurons and astrocytes display age-dependent dynamic variations in spontaneous Ca2+ activities. However, it is unknown whether penumbral nerve cells respond to sensory stimulation early after stroke onset, which is critical for understanding stimulation-induced stroke therapy. In this study, we investigated the ischemic penumbra’s capacity to respond to somatosensory input. We examined adult (3- to 4-month-old) and old (18- to 24-month-old) male mice at 2–4 hours after MCAO, using two-photon microscopy to record somatosensory stimulation-induced neuronal and astrocytic Ca2+ signals in the ischemic penumbra. In both adult and old mice, MCAO abolished spontaneous and stimulation-induced electrical activity in the penumbra, and strongly reduced stimulation-induced Ca2+ responses in neuronal somas (35–82%) and neuropil (92–100%) in the penumbra. In comparison, after stroke, stimulation-induced astrocytic Ca2+ responses in the penumbra were only moderately reduced (by 54–62%) in adult mice, and were even better preserved (reduced by 31–38%) in old mice.Our results suggest that somatosensory stimulation evokes astrocytic Ca2+ activity in the ischemic penumbra. We hypothesize that the relatively preserved excitability of astrocytes, most prominent in aged mice, may modulate protection from ischemic infarcts during early somatosensory activation of an ischemic cortical area. Future neuroprotective efforts in stroke may target spontaneous or stimulation-induced activity of astrocytes in the ischemic penumbra.

scholarly journals A New NF-κB Inhibitor, MEDS-23, Reduces the Severity of Adverse Post-Ischemic Stroke Outcomes in Rats

2021 ◽  
Vol 12 (1) ◽  
pp. 35
Author(s):  
Elina Rubin ◽  
Agnese C. Pippione ◽  
Matthew Boyko ◽  
Giacomo Einaudi ◽  
Stefano Sainas ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Artery Occlusion ◽  
Brain Inflammation ◽  
Neurological Deficits ◽  
Stroke Outcomes ◽  
Post Stroke ◽  
Factor Α ◽  
Cerebral Artery Occlusion ◽  
First Time

Aim: Nuclear factor kappa B (NF-κB) is known to play an important role in the inflammatory process which takes place after ischemic stroke. The major objective of the present study was to examine the effects of MEDS-23, a potent inhibitor of NF-κB, on clinical outcomes and brain inflammatory markers in post-ischemic stroke rats. Main methods: Initially, a Toxicity Experiment was performed to determine the appropriate dose of MEDS-23 for use in animals, as MEDS-23 was analyzed in vivo for the first time. We used the middle cerebral artery occlusion (MCAO) model for inducing ischemic stroke in rats. The effects of MEDS-23 (at 10 mg/kg, ip) on post-stroke outcomes (brain inflammation, fever, neurological deficits, mortality, and depression- and anxiety-like behaviours) was tested in several efficacy experiments. Key findings: MEDS-23 was found to be safe and significantly reduced the severity of some adverse post-stroke outcomes such as fever and neurological deficits. Moreover, MEDS-23 significantly decreased prostaglandin E2 levels in the hypothalamus and hippocampus of post-stroke rats, but did not prominently alter the levels of interleukin-6 and tumor necrosis factor-α. Significance: These results suggest that NF-κB inhibition is a potential therapeutic strategy for the treatment of ischemic stroke.

Abstract 113: GSK360A Inhibits Prolyl 4-Hydroxylase, Upregulates Hypoxia Inducible Factors (HIF) and Provides Protection from Ischemic Stroke-Induced Injury and Sensory-Motor-Cognitive Deficits

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Jin Zhou ◽  
Jie Li ◽  
Daniel Rosenbaum ◽  
Robert Willette ◽  
John Lepore ◽  
...  
Keyword(s):  
Motor Activity ◽  
Brain Infarction ◽  
Methyl Cellulose ◽  
Artery Occlusion ◽  
Hypoxia Inducible Factors ◽  
Sprague Dawley ◽  
Dose Selection ◽  
Post Stroke ◽  
Beneficial Effects ◽  
Cerebral Artery Occlusion

Background: Hypoxia inducible factors (HIFs) are transcription factors that are upregulated by decreased oxygen tension and ischemic preconditioning. HIFs increase angiogenesis, erythropoiesis, cell proliferation/survival and energy metabolism and decrease inflammation. GSK360A is a novel, orally active prolyl 4-hydroxylase (PHD) inhibitor that upregulates HIF-1α signaling and can protect the failing heart. Since GSK360A upregulates systems involved in ischemic tolerance, its administration prior to surgery/ischemia could be beneficial. GSK360A effects in cerebral ischemia have not been explored. Method: Male Sprague Dawley rats received 2 hours transient middle cerebral artery occlusion (tMCAO) followed by 22 hours of reperfusion. GSK dose selection was based on previous pharmacodynamic data on HIF system upregulation that was verified in these studies. Vehicle (1% Methyl cellulose) or GSK360A (30 mg/kg) was administered by oral gavage at 18 and 5 hr prior to tMCAO. Measurements were made of kidney erythropoietin (EPO) mRNA and protein over 1 day, modified neurological severity score (mNSS) over 5 and 24 hrs, cognitive performance (Active Place Avoidance; APA) and motor activity at 3-4 weeks and terminal brain infarction were made. Different groups of rats (N=5-10 per group) were studied over 1 day to 4 weeks. Results: GSK360A increased kidney EPO mRNA and protein up to 80-fold (p<0.01) by 5 hr post-stroke. Stroke increased mNNS that was reduced by GSK360A (31% and 20%, p<0.05) at 5 and 24 hr post-stroke onset. Stroke-induced decreases in APA performance, reflecting cognitive dysfunction, was reduced (p<0.01) by GSK360A without affecting motor activity. GSK360A also reduced brain infarction (30%, p<0.05). Conclusions: This is the first demonstration of GSK360A brain protection and long-term improvement in post-stroke neurological outcome, including beneficial effects to reduce stroke-induced loss in cognitive function. These data suggest that pre-stroke administration of GSK360A can produce PHD inhibition that stimulates HIF signaling useful for high-stroke-risk situations. In addition, its use prior to surgery might reduce the probability of post-surgical cognitive decline.

Abstract TMP29: Mesenchymal Stromal Cell Administration Attenuates Post-Stroke Susceptibility to Spontaneous Infection Through Prevention of Caspase-1-Dependent Splenic Marginal Zone B Cell Death

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Yinong Huang ◽  
Zhengqi Lu
Keyword(s):  
Marginal Zone ◽  
Artery Occlusion ◽  
Mice Model ◽  
Mortality And Morbidity ◽  
Post Stroke ◽  
Caspase 1 ◽  
Mitochondrial Transfer ◽  
Splenic Atrophy ◽  
Cerebral Artery Occlusion ◽  
Spontaneous Infection

Spontaneous infection is one of most common complications of acute ischemic stroke (AIS) and leads to increased mortality and morbidity in stroke patients. However, current interventions fail to improve clinical outcomes in these patients. Since stroke-induced immunodeficiency is thought to contribute to the risk of infections, we suppose mesenchymal stromal cells (MSCs) therapy, based on its potent immunomodulatory capacities, could be a potential solution to this problem. Here, we show MSCs administration successfully ameliorates post-stroke infections and reduces the mortality in mouse middle cerebral artery occlusion (MCAO) model of AIS. Additionally, the intravenously infused MSCs preferentially migrate to the spleen and mainly distribute around the marginal zone (MZ). These grafted MSCs rescue stroke-induced splenic atrophy, especially the marginal zone B (MZB) cells loss, a subset of innate-like lymphocytes localized in MZ. Using the CD19-deficient mice model lacking MZB cells, we found that MSCs transplantation could not reduce post-stroke infections or mortality in CD19 -/- mice, reconfirming MZB cells are indispensable for the immunoprotective effects of MSCs. In terms of mechanism, we demonstrate that MSCs attenuate caspase-1-dependent MZB cells death partially through direct mitochondrial transfer and subsequent inhibition of NLRP3 activation. Taken together, this study suggests MSCs administration alleviates post-stroke immunodepression and spontaneous infections via MZB cells protection.

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