Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, 88806-000, Brazil.
Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Mol Neurobiol. 2021 Jun;58(6):2724-2733. doi: 10.1007/s12035-021-02294-0. Epub 2021 Jan 25.
Sepsis is an organ dysfunction caused by a host's unregulated response to infection, causing long-term brain dysfunction with microglial activation, the release of inflammatory components, and mitochondrial changes. Neuroinflammation can increase the expression of the 18-kD translocator protein (TSPO) in the mitochondria, leading to the activation of the microglia and the release of inflammatory components. The antagonist PK-11195 can modulate TSPO and reduce microglial activation and cognitive damage presented in an animal model of sepsis. The aim of this was to evaluate the effects of PK-11195 on long-term brain inflammation and cognitive impairment in an animal model of sepsis. Wistar rats, 60 days old, were submitted to cecal ligation and puncture (CLP) surgery, divided into groups control/saline, control/PK-11195, sepsis/saline, and sepsis/PK-11195. Immediately after surgery, the antagonist PK-11195 was administered at a dose of 3 mg/kg. Ten days after CLP surgery, the animals were submitted to behavioral tests and determination of brain inflammatory parameters. The sepsis/saline group presented cognitive damage. However, there was damage prevention in animals that received PK-11195. Besides, the sepsis increased the levels of cytokines and M1 microglia markers and caused oxidative damage. However, PK-11195 had the potential to decrease inflammation. These events show that the modulation of neuroinflammation during sepsis by PK-11195, possibly related to changes in TSPO, improves mitochondrial function in the animals' brains. In conclusion, the antagonist PK-11195 attenuated brain inflammation and prevented cognitive impairment in animals subjected to sepsis.
脓毒症是一种器官功能障碍，由宿主对感染的失控反应引起，导致小胶质细胞激活、炎症成分释放和线粒体改变引起的长期脑功能障碍。神经炎症可增加线粒体中 18-kD 转位蛋白（TSPO）的表达，导致小胶质细胞激活和炎症成分释放。PK-11195 拮抗剂可调节 TSPO，减少小胶质细胞激活和脓毒症动物模型中认知损伤。本研究旨在评估 PK-11195 对脓毒症动物模型中大脑长期炎症和认知障碍的影响。60 天大的 Wistar 大鼠接受盲肠结扎和穿孔（CLP）手术，分为对照组/生理盐水、对照组/PK-11195、脓毒症/生理盐水和脓毒症/PK-11195 组。手术后立即给予拮抗剂 PK-11195 剂量为 3mg/kg。CLP 手术后 10 天，对动物进行行为测试和脑炎症参数测定。脓毒症/生理盐水组表现出认知损伤。然而，接受 PK-11195 的动物有预防损伤的作用。此外，脓毒症增加了细胞因子和 M1 小胶质细胞标志物的水平，并导致氧化损伤。然而，PK-11195 具有降低炎症的潜力。这些事件表明，PK-11195 对脓毒症期间的神经炎症的调节，可能与 TSPO 的变化有关，改善了动物大脑的线粒体功能。总之，拮抗剂 PK-11195 减轻了脓毒症动物的大脑炎症并预防了认知障碍。
