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

Abstract

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.

Reversible cerebral vasoconstriction syndrome: Considerable differential diagnosis

“…Corresponding to these most common ways of treating CVST, chemical thrombolysis, and mechanical thrombectomy is favorable to be used in severe stage. [16]…”

State of the art in cerebral venous sinus thrombosis animal models

“…In contrast, thread‐embolism models (silicone, plastic) consist in a transient occlusion of the SSS 46–48 . These models allow studying mechanisms involved during occlusion and recanalization (after thread removal) while potentially varying the occlusion time.…”

“…In the acute phase, Bederson scale and rotarod test have been commonly used to assess neurological functions. However, they could be less sensitive than implementation of different sensorimotor tests to detect slight neurological impairment 26,35,37,48,53 . In contrast, long‐term models of CVST are rarely implemented, and data on the assessment of neurological function are therefore limited 33,41,46 .…”

“…45 In contrast, thread-embolism models (silicone, plastic) consist in a transient occlusion of the SSS. [46][47][48] These models allow studying mechanisms involved during occlusion and recanalization (after thread removal) while potentially varying the occlusion time. The latter models induce brain edema and angiogenesis following SSS occlusion, but they do not involve occlusion of other draining veins (i.e., cortical veins), which may account for the absence of observed ischemic lesions or ICH.…”

“…However, they could be less sensitive than implementation of different sensorimotor tests to detect slight neurological impairment. 26,35,37,48,53 In contrast, long-term models of CVST are rarely implemented, and data on the assessment of neurological function are therefore limited. 33,41,46 Only one study has shown that CVST was associated with long-term locomotor activity deficits using the measurement of wheel running activity.…”