Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou 510630, PR China.
Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510632, PR China.
Brain Res. 2019 Sep 15;1719:40-48. doi: 10.1016/j.brainres.2019.05.009. Epub 2019 May 7.
Sepsis-associated encephalopathy (SAE) is a common and serious complication of sepsis, which is thought to be caused by neuroinflammation. In our previous study, ubiquitin-specific protease 8 (USP8), was reported to regulate inflammation in vitro. In the current study, we investigated whether increased USP8 expression would ameliorate the cognitive and motor impairments induced by cecal ligation and puncture (CLP) in mice, a model of SAE. Male adult mice were randomly divided into four groups: control, sham, CLP, and CLP + USP8 groups. The CLP + USP8 mice showed reduced weight loss on day 4 post-CLP, with a slight increase noted on day 7. The mortality rate in the CLP group was 70% 48 h after CLP; however, USP8 significantly improved survival after CLP. USP8 modulated the neurobehavioral scores in CLP mice. Our results also indicate that USP8 attenuated the CLP-induced cognitive and motor impairments, based on the performance of mice in the Morris water maze (MWM), pole-climbing, and wire suspension tests. USP8 suppressed the release of pro-inflammatory mediators, including prostaglandin E(PGE) in the serum and nitric oxide (NO) in brain tissue, as well as levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in brain tissue. Immunofluorescence experiments revealed that USP8 inhibited CLP-induced increases in microglial size and density in the hippocampus, and protected hippocampal neurons. Our findings indicate that neuroinflammation occurs in the brains of CLP mice, and that USP8 exerts protective effects against CLP-induced neuroinflammation and cognitive and motor impairments, which may aid in the development of novel therapeutic strategies for SAE.
脓毒症相关性脑病 (SAE) 是脓毒症的一种常见且严重的并发症，被认为是由神经炎症引起的。在我们之前的研究中，泛素特异性蛋白酶 8 (USP8) 被报道可在体外调节炎症。在目前的研究中，我们研究了增加 USP8 表达是否会改善结扎盲肠穿刺 (CLP) 诱导的小鼠 SAE 模型中的认知和运动障碍。成年雄性小鼠随机分为四组：对照组、假手术组、CLP 组和 CLP+USP8 组。CLP+USP8 组小鼠在 CLP 后第 4 天体重减轻减少，第 7 天略有增加。CLP 组的死亡率在 CLP 后 48 小时为 70%；然而，USP8 显著提高了 CLP 后的存活率。USP8 调节 CLP 小鼠的神经行为评分。我们的结果还表明，USP8 减轻了 CLP 诱导的认知和运动障碍，这基于小鼠在 Morris 水迷宫 (MWM)、爬杆和悬线测试中的表现。USP8 抑制了促炎介质的释放，包括血清中的前列腺素 E(PGE)和脑组织中的一氧化氮 (NO)，以及脑组织中诱导型一氧化氮合酶 (iNOS) 和环氧化酶-2 (COX-2) 的水平。免疫荧光实验表明，USP8 抑制了 CLP 诱导的海马中小胶质细胞大小和密度的增加，并保护了海马神经元。我们的研究结果表明，CLP 小鼠的大脑中发生了神经炎症，USP8 对 CLP 诱导的神经炎症和认知及运动障碍具有保护作用，这可能有助于开发治疗 SAE 的新策略。
