Pre-clinical effects of highly potent MEK1/2 inhibitors on rat cerebral vasculature after organ culture and subarachnoid haemorrhage

2019 ◽  
Vol 133 (16) ◽  
pp. 1797-1811 ◽  
Author(s):  
Simon T. Christensen ◽  
Kristian A. Haanes ◽  
Stine Spray ◽  
Anne-Sofie Grell ◽  
Karin Warfvinge ◽  
...  
Keyword(s):  
Organ Culture ◽  
Subarachnoid Haemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Mitogen Activated Protein Kinase ◽  
Neurological Deficits ◽  
Aneurysmal Subarachnoid Haemorrhage ◽  
Clinical Effects ◽  
Potential Candidate ◽  
The Impact

Abstract Background: Aneurysmal subarachnoid haemorrhage (SAH) is a variant of haemorrhagic stroke with a striking 50% mortality rate. In addition to the initial insult, secondary delayed brain injury may occur days after the initial ischemic insult and is associated with vasospasms leading to delayed cerebral ischemia. We have previously shown that the MEK1/2 inhibitor U0126 improves neurological assessment after SAH in rats. Aim: The purpose of the present study was to analyse the impact of a broad selection of high potency MEK1/2 inhibitors in an organ culture model and use the IC50 values obtained from the organ culture to select highly potent inhibitors for pre-clinical in vivo studies. Results: Nine highly potent mitogen activated protein kinase kinase (MEK1/2) inhibitors were screened and the two most potent inhibitors from the organ culture screening, trametinib and PD0325901, were tested in an in vivo experimental rat SAH model with intrathecal injections. Subsequently, the successful inhibitor trametinib was administered intraperitoneally in a second in vivo study. In both regimens, trametinib treatment caused significant reductions in the endothelin-1 induced contractility after SAH, which is believed to be associated with endothelin B receptor up-regulation. Trametinib treated rats showed improved neurological scores, evaluated by the ability to traverse a rotating pole, after induced SAH. Conclusion: The PD0325901 treatment did not improve the neurological score after SAH, nor showed any beneficial therapeutic effect on the contractility, contrasting with the reduction in neurological deficits seen after trametinib treatment. These data show that trametinib might be a potential candidate for treatment of SAH.

scholarly journals Impaired Cerebral Autoregulation After Subarachnoid Hemorrhage: A Quantitative Assessment Using a Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Masayo Koide ◽  
Hannah R. Ferris ◽  
Mark T. Nelson ◽  
George C. Wellman
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Laser Doppler Flowmetry ◽  
Cerebral Autoregulation ◽  
Cerebrovascular Disorders ◽  
Delayed Cerebral Ischemia ◽  
Laser Doppler ◽  
Neurological Deficits ◽  
Doppler Flowmetry ◽  
The Impact

Subarachnoid hemorrhage (SAH) is a common form of hemorrhagic stroke associated with high rates of mortality and severe disability. SAH patients often develop severe neurological deficits days after ictus, events attributed to a phenomenon referred to as delayed cerebral ischemia (DCI). Recent studies indicate that SAH-induced DCI results from a multitude of cerebral circulatory disturbances including cerebral autoregulation malfunction. Cerebral autoregulation incorporates the influence of blood pressure (BP) on arterial diameter in the homeostatic regulation of cerebral blood flow (CBF), which is necessary for maintaining constant brain perfusion during physiological swings in systemic BP. In this study, we quantitatively examined the impact of SAH on cerebral autoregulation using a mouse endovascular perforation model and a newly developed approach combining absolute and relative CBF measurements. This method enables a direct quantitative comparison of cerebral autoregulation between individual animals (e.g., SAH vs. control or sham-operated mice), which cannot be done solely using relative CBF changes by laser Doppler flowmetry. Here, absolute CBF was measured via injection of fluorescent microspheres at a baseline BP. In separate groups of animals, in vivo laser Doppler flowmetry was used to measure relative CBF changes over a range of BP using phlebotomy and the pressor phenylephrine to lower and raise BP, respectively. Absolute CBF measurements from microspheres were then used to calibrate laser Doppler measurements to calculate the relationship between CBF and BP, i.e., “cerebral autoregulation curves.” Un-operated and sham-operated groups exhibited similar cerebral autoregulatory curves, showing comparable levels of relatively constant CBF over a range of BP from ~80 mmHg to ~130 mmHg. In contrast, SAH animals exhibited a narrower autoregulatory range of BP, which was primarily due to a decrease in the upper limit of BP whereby cerebral autoregulation was maintained. Importantly, SAH animals also exhibited a marked decrease in CBF throughout the entire range of BP. In sum, this study provides evidence of the dramatic reduction in cortical CBF and the diminished range of autoregulation after SAH. Furthermore, this novel methodology should pave the way for future studies examining pathological mechanisms and/or therapeutic strategies targeting impaired cerebral autoregulation, a pathology common to many cardiovascular and cerebrovascular disorders.

The impact of hypopituitarism on function and performance in subjects with recent history of traumatic brain injury and aneurysmal subarachnoid haemorrhage

Brain Injury ◽  
2009 ◽  
Vol 23 (7-8) ◽  
pp. 639-648 ◽  
Author(s):  
Lakshmi Srinivasan ◽  
Brian Roberts ◽  
Tamara Bushnik ◽  
Jeffrey Englander ◽  
David A. Spain ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Subarachnoid Haemorrhage ◽  
Recent History ◽  
Aneurysmal Subarachnoid Haemorrhage ◽  
History Of ◽  
And Performance ◽  
The Impact

scholarly journals Zebrafish Cancer Predisposition Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Kim Kobar ◽  
Keon Collett ◽  
Sergey V. Prykhozhij ◽  
Jason N. Berman
Keyword(s):  
Large Scale ◽  
Genetic Manipulation ◽  
Bone Marrow Failure ◽  
Cancer Predisposition ◽  
Potential Candidate ◽  
Cancer Evolution ◽  
High Fecundity ◽  
Cancer Models ◽  
The Impact

Cancer predisposition syndromes are rare, typically monogenic disorders that result from germline mutations that increase the likelihood of developing cancer. Although these disorders are individually rare, resulting cancers collectively represent 5–10% of all malignancies. In addition to a greater incidence of cancer, affected individuals have an earlier tumor onset and are frequently subjected to long-term multi-modal cancer screening protocols for earlier detection and initiation of treatment. In vivo models are needed to better understand tumor-driving mechanisms, tailor patient screening approaches and develop targeted therapies to improve patient care and disease prognosis. The zebrafish (Danio rerio) has emerged as a robust model for cancer research due to its high fecundity, time- and cost-efficient genetic manipulation and real-time high-resolution imaging. Tumors developing in zebrafish cancer models are histologically and molecularly similar to their human counterparts, confirming the validity of these models. The zebrafish platform supports both large-scale random mutagenesis screens to identify potential candidate/modifier genes and recently optimized genome editing strategies. These techniques have greatly increased our ability to investigate the impact of certain mutations and how these lesions impact tumorigenesis and disease phenotype. These unique characteristics position the zebrafish as a powerful in vivo tool to model cancer predisposition syndromes and as such, several have already been created, including those recapitulating Li-Fraumeni syndrome, familial adenomatous polyposis, RASopathies, inherited bone marrow failure syndromes, and several other pathogenic mutations in cancer predisposition genes. In addition, the zebrafish platform supports medium- to high-throughput preclinical drug screening to identify compounds that may represent novel treatment paradigms or even prevent cancer evolution. This review will highlight and synthesize the findings from zebrafish cancer predisposition models created to date. We will discuss emerging trends in how these zebrafish cancer models can improve our understanding of the genetic mechanisms driving cancer predisposition and their potential to discover therapeutic and/or preventative compounds that change the natural history of disease for these vulnerable children, youth and adults.

scholarly journals Do transfusion requirements increase after the diagnosis of vasospasm in patients with aneurysmal subarachnoid haemorrhage?

2015 ◽  
Vol 02 (01) ◽  
pp. 038-043
Author(s):  
Lashmikumar Venkatraghavan ◽  
Sarah Tymianski ◽  
Jeffrey Singh
Keyword(s):  
Multivariate Analysis ◽  
Subarachnoid Haemorrhage ◽  
Clinical Outcomes ◽  
Oxygen Delivery ◽  
Univariate Analysis ◽  
Delayed Cerebral Ischemia ◽  
Aneurysmal Subarachnoid Haemorrhage ◽  
Cerebral Oxygen ◽  
Transfusion Threshold ◽  
Transfusion Requirements

Abstract Background: Many patients experience impaired cerebral oxygen delivery secondary to vasospasm and delayed cerebral ischemia following aneurysmal subarachnoid haemorrhage (SAH). Anaemia is common after SAH affecting up to 50% patients, which may decrease cerebral oxygen delivery and is associated with worse clinical outcomes. Transfusion of allogeneic red cells increases the oxygen content of the blood but it not consistently associated with improved physiologic markers of clinical outcomes. The threshold for transfusion is not clear in patients with SAH. A recent survey found that most physicians would alter their transfusion threshold in SAH patients who develop delayed ischemia. The objective of our study is to identify the predictors of transfusion and to determine if the diagnosis of delayed ischemia increases the transfusion rates in patients with aneurysmal subarachnoid haemorrhage. Materials and Methods: We retrospectively reviewed the charts of 100 consecutive patients with SAH who were admitted to ICU for mechanical ventilation, and collected demographic and clinical data. Data were analyzed for the association between clinical factors and transfusion the differences in transfusion between the patients with and without vasospasm. Statistical methods included the t-test, univariate analysis and multivariate analysis. Results: Data from 96 patients were included in the analysis. Incidence of anaemia haemoglobin (Hb) < 100 gm/l and vasospasm were 67% (64/96) and 39% (38/96) respectively. Of 64 patients with anaemia, 27 patients received transfusion, while 38 patients did not receive a transfusion. The transfusion rates were similar between those who had vasospasm and who did not. However, out of the 14 patients with vasospasm who received a transfusion, 11 patients had been transfused after experiencing vasospasm, while only 3 were transfused before. On multivariate analysis only female sex, starting Hb levels and lowest Hb levels were found to be predictors of transfusion. Presence or absence of vasospasm was not found to be a predictor. Conclusions: From our retrospective review, we conclude that the incidence of anaemia is higher in patients with vasospasm. Sex and starting and lowest Hb levels were the only predictors of transfusion likelihood in aneurysmal subarachnoid haemorrhage while presence of vasospasm was not.

scholarly journals Impact of Resolvin E1 on Murine Neutrophil Phagocytosis in Type 2 Diabetes

2014 ◽  
Vol 83 (2) ◽  
pp. 792-801 ◽  
Author(s):  
Bruno S. Herrera ◽  
Hatice Hasturk ◽  
Alpdogan Kantarci ◽  
Marcelo O. Freire ◽  
Olivia Nguyen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Transgenic Animals ◽  
Genetically Engineered ◽  
Mitogen Activated Protein Kinase ◽  
Air Pouch ◽  
Content Type ◽  
Genetically Engineered Mice ◽  
The Impact

Diabetic complications involve inflammation-mediated microvascular and macrovascular damage, disruption of lipid metabolism, glycosylation of proteins, and abnormalities of neutrophil-mediated events. Resolution of inflamed tissues to health and homeostasis is an active process mediated by endogenous lipid agonists, including lipoxins and resolvins. This proresolution system appears to be compromised in type 2 diabetes (T2D). The goal of this study was to investigate unresolved inflammation in T2D. Wild-type (WT) and genetically engineered mice, including T2D mice (db/db), transgenic mice overexpressing the human resolvin E1 (RvE1) receptor (ERV1), and a newly bred strain ofdb/ERV1mice, were used to determine the impact of RvE1 on the phagocytosis ofPorphyromonas gingivalisin T2D. Neutrophils were isolated and incubated with fluorescein isothiocyanate-labeledP. gingivalis, and phagocytosis was measured in a fluorochrome-based assay by flow cytometry. Mitogen-activated protein kinase (MAPK) (p42 and p44) and Akt (Thr308 and Ser473) phosphorylation was analyzed by Western blotting. The mouse dorsal air pouch model was used to evaluate thein vivoimpact of RvE1. Results revealed that RvE1 increased the neutrophil phagocytosis ofP. gingivalisin WT animals but had no impact indb/dbanimals. InERV1-transgenic andERV1-transgenic diabetic mice, phagocytosis was significantly increased. RvE1 decreased Akt and MAPK phosphorylation in the transgenic animals.In vivodorsal air pouch studies revealed that RvE1 decreases neutrophil influx into the pouch and increases neutrophil phagocytosis ofP. gingivalisin the transgenic animals; cutaneous fat deposition was reduced, as was macrophage infiltration. The results suggest that RvE1 rescues impaired neutrophil phagocytosis in obese T2D mice overexpressingERV1.

Causes of neurological deficits following clipping of 200 consecutive ruptured aneurysms in patients with good-grade aneurysmal subarachnoid haemorrhage

2010 ◽  
Vol 153 (2) ◽  
pp. 295-303 ◽  
Author(s):  
Diederik O. Bulters ◽  
Thomas Santarius ◽  
H. Ling Chia ◽  
Richard A. Parker ◽  
Rikin Trivedi ◽  
...  
Keyword(s):  
Subarachnoid Haemorrhage ◽  
Neurological Deficits ◽  
Aneurysmal Subarachnoid Haemorrhage ◽  
Ruptured Aneurysms ◽  
Good Grade

scholarly journals Literature Review of Aneurysmal Subarachnoid Hemorrhage from Incidence to Treatment Options

2020 ◽  
Vol 18 (1) ◽  
pp. 70-78
Author(s):  
Ieva Buce-Satoba ◽  
Daina Rozkalne ◽  
Jevgenijs Stepanovs ◽  
Biruta Mamaja ◽  
Gaida Krumina ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cerebral Ischemia ◽  
Literature Review ◽  
Glasgow Coma Scale ◽  
Subarachnoid Haemorrhage ◽  
Cerebral Vasospasm ◽  
Treatment Options ◽  
Delayed Cerebral Ischemia ◽  
Late Complications ◽  
Aneurysmal Subarachnoid Haemorrhage

SummaryIntroductionAneurysmal subarachnoid haemorrhage (SAH) is associated with high mortality and morbidity. Rebleeding, cerebral vasospasm (VS) with delayed cerebral ischemia (DCI) are major complications after SAH associated with poor neurological outcome.Aim of the studyTo summarize the existing research data on the SAH from incidence, risk factors and clinical presentation to diagnostic, monitoring and treatment options after SAH.Materials and MethodsLiterature review was carried out to identify factors associated with SAH using specific keywords (aneurysmal subarachnoid haemorrhage, rebleeding, cerebral vasospasm, delayed cerebral ischemia) in the PUBMED database. In the time period from 2000 to 2019, 34 full articles were reviewed.ResultsAccording to the literature, the key risk factors for cerebral aneurysms and the SAH are hypertension, smoking, chronic alcohol abuse, family history of intracranial aneurysms in first-degree relatives and female sex. The key risk factor for early complication - rebleeding after SAH - is hypertension. The factors responsible for late complications - cerebral VS and DCI after SAH - are initially lower Glasgow coma scale and higher grades of Fisher scale, where grade IV and III predict cerebral VS in 31–37%. Furthermore, hyperglycaemic state, hyponatremia, hypotension and cerebral hypoperfusion, increased level of Troponin correlate with the incidence of cerebral VS and DCI. Although the golden standard to detect cerebral VS is digital subtraction angiography, CT angiography has become a routine examination. Transcranial doppler sonography is recommended and regional cerebral oximetry also seems to be promising. To avoid rebleeding for wide-necked, gigantic aneurysms or when SAH is combined with intraparenchymal hematoma, surgical clipping is preferred. For posterior circulation aneurisms, poor grade SAH and patients with age >70 years superior is endovascular treatment. To avoid late complications, the pharmacological method is used with Nimodipine.ConclusionsSAH is still associated with poor clinical outcome due to the development of early and late complications. The highest risk patients are those with low Glasgow coma scale and high grades of Fisher scale. Timely performed obliteration methods of the ruptured aneurysm are crucial and Nimodipine is the main agent to prevent cerebral VS and DCI.

scholarly journals Aneurysmal Subarachnoid Haemorrhage After COVID-19 Infection

2020 ◽  
Author(s):  
Sajjad Muhammad ◽  
Soheil Naderi ◽  
Mostafa Ahmadi ◽  
Askar Ghorbani ◽  
Daniel Hänggi
Keyword(s):  
Subarachnoid Haemorrhage ◽  
Systemic Inflammation ◽  
Artery Aneurysm ◽  
Neurological Deficits ◽  
Coagulation System ◽  
Anterior Communicating Artery ◽  
Aneurysmal Subarachnoid Haemorrhage ◽  
Low Oxygen ◽  
First Case ◽  
History Of

Abstract BackgroundSARS-CoV-2 virus infection leads to a severe and dysbalanced inflammatory response with hypercytokinemia and immunodepression. Systemic inflammation due to viral infections can potentially cause vascular damage including disruption of blood-brain barrier (BBB) and alterations in coagulation system that may also lead to cardiovascular and neurovascular events. Here, we report the first case of COVID-19 infection leading to aneurysmal subarachnoid haemorrhage (aSAH). Case DescriptionA 61-year-old woman presented with dyspnea, cough and fever. She was over weight with Body mass-index of 34 and history of hypertension. No history of subarachnoid hemorrhage in the family. She was admitted in ICU due to low oxygen saturation (89%). A chest CT showed typical picture of COVID-19 pneumonia. Oropharyngeal swab with a PCR-based testing was COVID-19 positive. She was prescribed with favipiravir and hydroxychloroquine in Addition to oxygen support. On second day she experienced sudden headache and losst conciousness. A computer tomography (CT) with CT-angiography revealed subarachnoid haemorrhage in basal cisterns from a ruptured anterior communicating artery aneurysm. The aneurysm was clipped microsurgically through a standard pterional approach and the patient was admitted again to intensive care unit for further intensive medical treatment. Post-operative the patient showed slight motor dysphasia. No other neurological deficits.ConclusionAneurysmal subarachnoid haemorrhage secondary to COVID-19 infection might be triggered by systemic inflammation. COVID-19 infection could be one of the risk factors leading to instability and rupture of intracranial aneurysm.

scholarly journals DAPK1 loss triggers tumor invasion in colorectal tumor cells

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Sara Steinmann ◽  
Philipp Kunze ◽  
Chuanpit Hampel ◽  
Markus Eckstein ◽  
Jesper Bertram Bramsen ◽  
...  
Keyword(s):  
Chorioallantoic Membrane ◽  
Gene Expression Signature ◽  
Predictive Biomarker ◽  
Cancer Type ◽  
Potential Candidate ◽  
Metastatic Progression ◽  
Death Associated Protein Kinase ◽  
The Impact

AbstractColorectal cancer (CRC) is one of the leading cancer-related causes of death worldwide. Despite the improvement of surgical and chemotherapeutic treatments, as of yet, the disease has not been overcome due to metastasis to distant organs. Hence, it is of great relevance to understand the mechanisms responsible for metastasis initiation and progression and to identify novel metastatic markers for a higher chance of preventing the metastatic disease. The Death-associated protein kinase 1 (DAPK1), recently, has been shown to be a potential candidate for regulating metastasis in CRC. Hence, the aim of the study was to investigate the impact of DAPK1 protein on CRC aggressiveness. Using CRISPR/Cas9 technology, we generated DAPK1-deficient HCT116 monoclonal cell lines and characterized their knockout phenotype in vitro and in vivo. We show that loss of DAPK1 implemented changes in growth pattern and enhanced tumor budding in vivo in the chorioallantoic membrane (CAM) model. Further, we observed more tumor cell dissemination into chicken embryo organs and increased invasion capacity using rat brain 3D in vitro model. The novel identified DAPK1-loss gene expression signature showed a stroma typical pattern and was associated with a gained ability for remodeling the extracellular matrix. Finally, we suggest the DAPK1-ERK1 signaling axis being involved in metastatic progression of CRC. Our results highlight DAPK1 as an anti-metastatic player in CRC and suggest DAPK1 as a potential predictive biomarker for this cancer type.

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