Early BBB breakdown and subacute inflammasome activation and pyroptosis as a result of cerebral venous thrombosis

Sherif Rashad, Kuniyasu Niizuma, Mika Sato-Maeda, Miki Fujimura, Ahmed Mansour, Hidenori Endo, Shuntaro Ikawa, Teiji Tominaga

研究成果: Article査読

26 被引用数 (Scopus)

抄録

Cerebral venous thrombosis (CVT) is a rare form of cerebral stroke that causes a variety of symptoms, ranging from mild headache to severe morbidity or death in the more severe forms. The use of anti-coagulant or thrombolytic agents is the classical treatment for CVT. However, the development of new therapies for the treatment of the condition has not been the focus. In this study, we aimed to analyze the pathophysiology of CVT and to identify the pathways associated with its pathology. Moreover, mechanisms that are potential drug targets were identified. Our data showed the intense activation of immune cells, particularly the microglia, along with the increase in macrophage activity and NLRP3 inflammasome activation that is indicated by NLRP3, IL-1β and IL-18 gene and caspase-1 upregulation and cleavage as well as pyroptotic cell death. Leukocytes were observed in the brain parenchyma, indicating a role in CVT-induced inflammation. In addition, astrocytes were activated, and they induced glial scar leading to parenchymal contraction during the subacute stage and tissue loss. MMP9 was responsible primarily for the BBB breakdown after CVT and it is mainly produced by pericytes. MMP9 activation was observed before inflammatory changes, indicating that BBB breakdown is the initial driver of the pathology of CVT. These results show an inflammation driven pathophysiology of CVT that follows MMP9-mediated BBB breakdown, and identified several targets that can be targeted by pharmaceutical agents to improve the neuroinflammation that follows CVT, such as MMP9, NLRP3, and IL-1β. Some of these pharmaceutical agents are already in clinical practice or under clinical trials indicating a good potential for translating this work into patient care.

本文言語English
ページ(範囲)54-68
ページ数15
ジャーナルBrain research
1699
DOI
出版ステータスPublished - 2018 11 15

ASJC Scopus subject areas

  • 神経科学(全般)
  • 分子生物学
  • 臨床神経学
  • 発生生物学

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