A Novel Mouse Model for Cerebral Venous Sinus Thrombosis

Bourrienne, Marie‐Charlotte; Loyau, Stéphane; Benichi, Sandro; Gay, Juliette; Solo-Nomenjanahary, Mialitiana; Journé, Clément; Meglio, Lucas Di; Seckendorff, Aurélien Freiherr von; Desilles, Jean‐Philippe; Ho‐Tin‐Noé, Benoît; Ajzenberg, Nadine; Mazighi, Mikaël

doi:10.1007/s12975-021-00898-1

Cited by 9 publications

(21 citation statements)

References 47 publications

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“…Cerebral venous sinus thrombosis (CVST) is an underrated and potentially fatal cause of stroke with a reported mortality of 5–10% worldwide. The impaired venous drainage attributed to thrombus obstruction largely leads to ischemia, cerebral edema, and parenchymal lesions that can be complicated by infarction or hemorrhage reported in approximately 60% of cases [ 1 – 3 ]. Unfortunately, in addition to anticoagulant and thrombolytic therapy, effective treatments targeting the damaged brain parenchyma after CVST remain limited to date [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Activating cGAS–STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis

Ding

Liu

et al. 2022

J Neuroinflammation

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Background Neuroinflammation-induced injury is intimately associated with poor prognosis in patients with cerebral venous sinus thrombosis (CVST). The cyclic GMP-AMP synthase–stimulator of interferon gene (cGAS–STING) axis is a cytoplasmic double-stranded DNA (dsDNA) sensing pathway has recently emerged as a crucial mediator of neuroinflammation in ischemic stroke. However, the role of the cGAS–STING pathway in modulating post-CVST inflammation and the underlying mechanisms involved remain unclear. Methods A CVST model was induced by ferric chloride in male C57BL/6J mice. The selective cGAS inhibitor RU.521, STING agonist 2′3′-cGAMP, and STING siRNA were delivered by intranasal administration or intraventricular injection. Post-CVST assessments included rotarod test, TUNEL staining, Fluoro-Jade C staining, dihydroethidium staining, western blotting, qPCR, immunofluorescence, immunohistochemistry, ELISA and flow cytometry. Results cGAS, STING, NLRP3 and GSDMD were significantly upregulated after CVST and mostly in the microglia of the mouse brain. CVST triggered the release of dsDNA into the cytoplasm and elicited an inflammatory response via activating the cGAS–STING axis. RU.521 decreased the levels of 2′3′-cGAMP, STING and downstream inflammatory cytokines, and suppressed the expressions of NLRP3 inflammasome and pyroptosis-pertinent components containing cleaved caspase-1, GSDMD, GSDMD-C, pro- and cleaved IL-1β, and cleaved IL-1β/pro-IL-1β. Besides, RU.521 treatment also reduced oxidative stress, lessened the numbers of microglia and neutrophils, and ameliorated neuronal apoptosis, degeneration along with neurological deficits post-CVST. 2′3'-cGAMP delivery enhanced the expressions of STING and related inflammatory mediators, NLRP3 inflammasome and pyroptosis-relevant proteins, whereas these alterations were significantly abrogated by the silencing of STING by siRNA. Conclusions Our data demonstrate that repression of the cGAS–STING pathway diminishes the neuroinflammatory burden of CVST and highlight this approach as a potential therapeutic tactic in CVST-mediated pathologies.

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Section: Introductionmentioning

confidence: 99%

Activating cGAS–STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis

Ding

Liu

et al. 2022

J Neuroinflammation

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“…Furthermore, few studies have reported neurological function and mental status in the context of CVST. Bourrienne et al established a CVST animal model and observed dysfunction of neurological sensory-motor functions [ 10 ]. Similarly, admission scores (GCS, NIHSS, and mRS) in the present study suggest that patients with CVST exhibit neurological deficits, while behavioural tests suggested anxiety and depression-like changes in model rats.…”

Section: Discussionmentioning

confidence: 99%

“…Animal models that appropriately recapitulate the clinical symptoms are essential for understanding CVST pathophysiology. Over the past few years, several types of CVST models have been established, including those generated via superior sagittal sinus (SSS) ligation [ 8 , 9 ], injection of thrombi or procoagulants [ 10 – 12 ], thrombus models induced using ferric chloride, and SSS occlusion via a self-made plug [ 13 , 14 ]. Despite the various modelling methods, each model has explained the pathophysiology of CVST from a different perspective.…”

Section: Introductionmentioning

confidence: 99%

A novel rat model for cerebral venous sinus thrombosis: verification of similarity to human disease via clinical analysis and experimental validation

Lin

et al. 2022

J Transl Med

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Background Cerebral venous sinus thrombosis (CVST) is a rare neurovascular disorder with highly variable manifestations and clinical courses. Animal models properly matched to the clinical form of CVST are necessary for elucidating the pathophysiology of the disease. In this study, we aimed to establish a rat model that accurately recapitulates the clinical features of CVST in human patients. Methods This study consisted of a clinical analysis and animal experiments. Clinical data for two centres obtained between January 2016 and May 2021 were collected and analysed retrospectively. In addition, a Sprague–Dawley rat model of CVST was established by inserting a water-swellable rubber device into the superior sagittal sinus, following which imaging, histological, haematological, and behavioural tests were used to investigate pathophysiological changes. Principal component analysis and hierarchical clustering heatmaps were used to evaluate the similarity between the animal models and human patients. Results The imaging results revealed the possibility of vasogenic oedema in animal models. Haematological analysis indicated an inflammatory and hypercoagulable state. These findings were mostly matched with the retrospective clinical data. Pathological and serological tests further revealed brain parenchymal damage related to CVST in animal models. Conclusions We successfully established a stable and reproducible rat model of CVST. The high similarity between clinical patients and animal models was verified via cluster analysis. This model may be useful for the study of CVST pathophysiology and potential therapies.

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“…Illustration of the different techniques for assessing cerebral venous sinus thrombosis (CVST)‐related damage in superior sagittal sinus (SSS)‐injected thrombus mouse model (adapted from Bourrienne et al 53 ). A, Serial coronal T2‐weighted images from mouse 1 day after CVST induction, demonstrating localized ischemia in cortical parenchyma (white asterisk).…”

Section: Relevant Endpoints For Cvst Modelsmentioning

confidence: 99%

“…In the clot-injected model, thrombus constitutes both pro-coagulant and pro-inflammatory surfaces, as observed with thrombus early growth through new platelet and leukocyte recruitment. 53 Experimental models constitute also a useful tool for novel therapy testing and require, in this case, a model characterized by thrombosis formed into an open sinus channel. Thrombus composition and time of exposure to anticoagulant therapy also affects recanalization.…”

Section: Advantag E S Limitati On S and Appli C Ati On S Of C Vs T ...mentioning

confidence: 99%

State of the art in cerebral venous sinus thrombosis animal models

Bourrienne

Gay

Mazighi

et al. 2022

Journal of Thrombosis and Haemostasis

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Cerebral venous sinus thrombosis (CVST) is an uncommon location of venous thromboembolism (VTE) that represents a distinct cause of stroke primarily affecting young adults. 1,2 Predisposing factors for CVST are multiple, including those described in VTE and specific local causes (regional infections, brain tumors, and cranial trauma). 3 Beyond thrombosis, CVST-related parenchymal injuries include edema, ischemic strokes, and intra-cerebral hemorrhage (ICH; i.e., parenchymal/subdural hematomas and subarachnoid hemorrhages), which are identified in 40%-60% of patients. [4][5][6][7] Diagnosis and prognosis are still challenging due to the non-specificity and high variability of clinical course. Clinical symptoms result from increased intracranial pressure due to impaired venous drainage and CVST-related brain injury. Clinical symptoms range from isolated headaches (the most frequent one at presentation ≈90%), to focal deficits, seizure, and coma. 4,5,7,8 Recent studies reported higher incidence of CVST than previously estimated (13-17.5 vs. 3-5 million per year, respectively) with an overall death and dependency rate ≈15%. 1,2,6 This may be the result, at least in part, of the improved

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A Novel Mouse Model for Cerebral Venous Sinus Thrombosis

Cited by 9 publications

References 47 publications

Activating cGAS–STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis

Activating cGAS–STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis

A novel rat model for cerebral venous sinus thrombosis: verification of similarity to human disease via clinical analysis and experimental validation

State of the art in cerebral venous sinus thrombosis animal models

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