Department of Emergency Medicine Center, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
Department of Emergency Medicine Center, Lanling Hospital, Linyi, Shandong, China.
Inhal Toxicol. 2020 Feb;32(2):79-85. doi: 10.1080/08958378.2020.1741739. Epub 2020 Mar 18.
Acute carbon monoxide （CO）poisoning can cause delayed neurological sequelae (DNS). Glycogen synthase kinase 3β (GSK-3β) /Tau protein pathway is reported to play a key role in neurological abnormalities. In the present study, we aimed to determine the role of GSK-3β/Tau in DNS following acute CO poisoning. 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a specific non-competitive inhibitor of GSK-3β, was used to inhibit GSK-3β. Twenty-four male Sprague-Dawley rats were randomly assigned to the three groups: Control group, CO group and CO-TDZD-8 group. Rats breathed 1000 ppm CO for 40 minutes and then 3000 ppm for up to 20 minutes until they lost consciousness. TDZD-8 (1 mg/kg) was administered intravenously three times after the end of CO exposure at 0, 24, 48 hours late. Learning and memory abilities were observed using the Morris Water Maze (MWM). Brain histological changes were evaluated by hematoxylin-eosin staining. Moreover, the expression levels of Tau and GSK-3β were detected after acute carbon monoxide poisoning. TDZD-8 significantly attenuated the learning and memory dysfunction induced by acute CO poisoning, ameliorated the histology structure of damaged neural cells in cortex and hippocampus CA1 area. TDZD-8 clearly decreased p-Tau expression, reversed the reduction of p-GSK-3β induced by acute CO poisoning. The therapeutic effect of TDZD-8 in alleviating DNS caused by acute CO poisoning is related to the inactivation of Tau by intensifying the level of GSK-3β phosphorylation.
急性一氧化碳（CO）中毒可引起迟发性神经后遗症（DNS）。糖原合酶激酶 3β（GSK-3β）/Tau 蛋白通路被报道在神经异常中发挥关键作用。在本研究中，我们旨在确定 GSK-3β/Tau 在急性 CO 中毒后 DNS 中的作用。4-苄基-2-甲基-1,2,4-噻二唑烷-3,5-二酮（TDZD-8）是 GSK-3β 的特异性非竞争性抑制剂，用于抑制 GSK-3β。24 只雄性 Sprague-Dawley 大鼠随机分为三组：对照组、CO 组和 CO-TDZD-8 组。大鼠吸入 1000ppm CO 40 分钟，然后吸入 3000ppm CO 长达 20 分钟，直至失去意识。CO 暴露结束后 0、24、48 小时静脉注射 TDZD-8（1mg/kg）3 次。使用 Morris 水迷宫（MWM）观察学习和记忆能力。通过苏木精-伊红染色评估脑组织学变化。此外，急性一氧化碳中毒后检测 Tau 和 GSK-3β 的表达水平。TDZD-8 显著减轻急性 CO 中毒引起的学习和记忆功能障碍，改善皮质和海马 CA1 区受损神经细胞的组织学结构。TDZD-8 明显降低 p-Tau 表达，逆转急性 CO 中毒引起的 p-GSK-3β 减少。TDZD-8 减轻急性 CO 中毒引起的 DNS 的治疗效果与 Tau 的失活有关，通过增强 GSK-3β 磷酸化水平来减轻 DNS。
