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A Novel Mouse Model for Cerebral Venous Sinus Thrombosis

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Abstract

Cerebral venous sinus thrombosis (CVST) is an uncommon cause of stroke resulting in parenchymal injuries associated with heterogeneous clinical symptoms and prognosis. Therefore, an experimental animal model is required to further study underlying mechanisms involved in CVST. This study is aimed at developing a novel murine model suitable and relevant for evaluating injury patterns during CVST and studying its clinical aspects. CVST was achieved in C57BL/6J mice by autologous clot injection into the superior sagittal sinus (SSS) combined with bilateral ligation of external jugular veins. Clot was prepared ex vivo using thrombin before injection. On days 1 and 7 after CVST, SSS occlusion and associated-parenchymal lesions were monitored using different modalities: in vivo real-time intravital microscopy, magnetic resonance imaging (MRI), and immuno-histology. In addition, mice were subjected to a neurological sensory-motor evaluation. Thrombin-induced clot provided fibrin- and erythrocyte-rich thrombi that lead to reproducible SSS occlusion at day 1 after CVST induction. On day 7 post-CVST, venous occlusion monitoring (MRI, intravital microscopy) showed that initial injected-thrombus size did not significantly change demonstrating no early spontaneous recanalization. Microscopic histological analysis revealed that SSS occlusion resulted in brain edema, extensive fibrin-rich venular thrombotic occlusion, and ischemic and hemorrhagic lesions. Mice with CVST showed a significant lower neurological score on post-operative days 1 and 7, compared to the sham-operated group. We established a novel clinically CVST-relevant model with a persistent and reproducible SSS occlusion responsible for symptomatic ischemic and hemorrhagic lesions. This method provides a reliable model to study CVST physiopathology and evaluation of therapeutic new regimens.

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Data Availability

The corresponding author (Marie-Charlotte Bourrienne) takes full responsibility for the data, the analyses and interpretation, and the conduct of the research of the present study and has full access to all of the data.

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Software application or custom code: not applicable.

Funding

Dr. Bourrienne is the recipient of a grant poste d’accueil INSERM. This study was supported by INSERM.

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Authors and Affiliations

  1. Laboratory for Vascular Translational Science (LVTS), INSERM UMR 1148, Université de Paris, 75018, Paris, France

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

  2. Pediatric Neurosurgery Department, AP-HP, Necker Children Hospital, Paris, France

    Sandro Benichi

  3. Fédération de Recherche en Imagerie Multimodalités (FRIM), Faculté de Médecine X. Bichat, INSERM UMS34, Université de Paris, 75018, Paris, France

    Clément Journé

  4. Department of Interventional Neuroradiology, Rothschild Foundation Hospital, Paris, France

    Jean-Philippe Desilles & Mikaël Mazighi

  5. Laboratory of Hematology, AP-HP, Bichat Hospital, 75877, Paris Cedex 18, France

    Nadine Ajzenberg

  6. Department of Neurology, AP-HP, Lariboisière Hospital, Paris, France

    Mikaël Mazighi

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  1. Marie-Charlotte Bourrienne
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  2. Stéphane Loyau
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  4. Juliette Gay
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Correspondence to Marie-Charlotte Bourrienne.

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All scientific procedures using animals were conducted according to French veterinary guidelines and those formulated by the European Community for experimental animal use (L358-86/609EEC) and were approved by the Committee on the Ethics of Animal Experiments (Paris Nord no. 121, approval number no. 14070). This article does not contain any studies with human participants performed by any of the authors. Consent to participate is not applicable.

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Bourrienne, MC., Loyau, S., Benichi, S. et al. A Novel Mouse Model for Cerebral Venous Sinus Thrombosis. Transl. Stroke Res. 12, 1055–1066 (2021). https://doi.org/10.1007/s12975-021-00898-1

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