Abcc8 (sulfonylurea receptor-1) knockout mice exhibit reduced axonal injury, cytotoxic edema and cognitive dysfunction vs. wild-type in a cecal ligation and puncture model of sepsis.
Abcc8 (sulfonylurea receptor-1) knockout mice exhibit reduced axonal injury, cytotoxic edema and cognitive dysfunction vs. wild-type in a cecal ligation and puncture model of sepsis.
复制标题
DOI：
10.1186/s12974-023-02692-2
复制
发表时间：
2023-01-21
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
脓毒症相关脑损伤（SABI）的特点是精神状态的急性恶化，导致脓毒症幸存者的认知障碍和获得新的和持续的功能限制。先前，我们报道了脓毒症小鼠在没有血脑屏障破坏的情况下，有轴突损伤、小胶质细胞活跃和大脑皮层、丘脑和海马细胞毒性水肿的证据。该领域的一个关键概念进展是发现磺酰脲受体1 (SUR1)，它是三磷酸腺苷（ATP）结合盒蛋白超家族的成员，与瞬时受体电位美拉他汀4 （TRPM4）阳离子通道相关，在脑水肿的发展中起关键作用。因此，我们假设Abcc8 （Sur1基因）敲除（KO）与脓毒症小鼠盲肠结扎和穿刺（CLP）模型中小胶质细胞激活减少、脑水肿和神经行为改善有关。用CLP诱导4 - 6周龄Abcc8 KO和野生型（WT）同窝对照雄性小鼠脓毒症。我们使用免疫组织化学来定义神经病理学和小胶质细胞激活，同时使用磁共振成像进行平行研究，重点关注CLP后第1天和第4天的脑水肿。与WT相比，Abcc8 KO小鼠在第1天表现出轴突损伤和细胞毒性水肿的减少。与WT相比，Abcc8 KO小鼠大脑皮层的小胶质细胞激活也减少。这些发现与CLP后7-8天空间记忆的改善有关。我们的研究挑战了败血症的一个关键概念，表明脑损伤可能不仅仅是全身性炎症的延伸。我们进一步推进了这一领域，并证明了SUR1基因的缺失改善了败血症的中枢神经系统病理生物学，包括水肿、轴突损伤、神经炎症和行为缺陷。Abcc8 KO在小鼠CLP模型中的益处值得研究Abcc8的药理学抑制作为SABI的一种新的潜在治疗策略。
Sepsis-associated brain injury (SABI) is characterized by an acute deterioration of mental status resulting in cognitive impairment and acquisition of new and persistent functional limitations in sepsis survivors. Previously, we reported that septic mice had evidence of axonal injury, robust microglial activation, and cytotoxic edema in the cerebral cortex, thalamus, and hippocampus in the absence of blood–brain barrier disruption. A key conceptual advance in the field was identification of sulfonylurea receptor 1 (SUR1), a member of the adenosine triphosphate (ATP)-binding cassette protein superfamily, that associates with the transient receptor potential melastatin 4 (TRPM4) cation channel to play a crucial role in cerebral edema development. Therefore, we hypothesized that knockout (KO) of Abcc8 (Sur1 gene) is associated with a decrease in microglial activation, cerebral edema, and improved neurobehavioral outcomes in a murine cecal ligation and puncture (CLP) model of sepsis. Sepsis was induced in 4–6-week-old Abcc8 KO and wild-type (WT) littermate control male mice by CLP. We used immunohistochemistry to define neuropathology and microglial activation along with parallel studies using magnetic resonance imaging, focusing on cerebral edema on days 1 and 4 after CLP. Abcc8 KO mice exhibited a decrease in axonal injury and cytotoxic edema vs. WT on day 1. Abcc8 KO mice also had decreased microglial activation in the cerebral cortex vs. WT. These findings were associated with improved spatial memory on days 7–8 after CLP. Our study challenges a key concept in sepsis and suggests that brain injury may not occur merely as an extension of systemic inflammation. We advance the field further and demonstrate that deletion of the SUR1 gene ameliorates CNS pathobiology in sepsis including edema, axonal injury, neuroinflammation, and behavioral deficits. Benefits conferred by Abcc8 KO in the murine CLP model warrant studies of pharmacological Abcc8 inhibition as a new potential therapeutic strategy for SABI.
登录
查看更多内容
影响因子：
3.7
作者：
Ehler, Johannes;Petzold, Axel;Sauer, Martin
通讯作者：
Sauer, Martin
影响因子：
2.5
作者：
Bennett RE;Mac Donald CL;Brody DL
通讯作者：
Brody DL
影响因子：
2.5
作者：
Bhagat, Yusuf A.;Hussain, Muhammad S.;Beaulieu, Christian
通讯作者：
Beaulieu, Christian
影响因子：
4.1
作者：
Farris, Reid W. D.;Weiss, Noel S.;Zimmerman, Jerry J.
通讯作者：
Zimmerman, Jerry J.
影响因子：
38.9
作者：
Elison, Sarah;Shears, Dan;Garralda, M. Elena
通讯作者：
Garralda, M. Elena