Department of Histology and Embryology, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, Shandong, China.
Department of Intensive Care Unit, Yantai Yuhuangding Hospital Qingdao University, Yantai, 264000, Shandong, China.
Psychopharmacology (Berl). 2021 Oct;238(10):2923-2936. doi: 10.1007/s00213-021-05908-6. Epub 2021 Jul 7.
Post-traumatic stress disorder (PTSD) is a serious stress-related neuropsychiatric disorder caused by major traumatic events. Abnormal activity of the locus coeruleus (LC)-noradrenergic system is related to the development of PTSD-like symptoms. Our previous studies have indicated that endoplasmic reticulum (ER) stress induced neuronal apoptosis of LC in rats with PTSD. The purpose of this study was to further investigate the role of ER stress pathways in LC neuronal dysfunction and elucidate the effect of the bioactive component tetramethylpyrazine (TMP) against ER stress response. We used an acute exposure to single prolonged stress (SPS) to model PTSD in rats. There were higher norepinephrine (NE) levels in the brain, increased tyrosine hydroxylase expression in LC, and enhanced anxiety-like behaviors in rats exposed to SPS, which were observed by enzyme-linked immunosorbent assay, western blot analysis and elevated plus maze test, respectively. In addition, the three major pathways of ER stress were activated by SPS exposure, which may be involved in the dysregulation of the LC-noradrenergic system of rats with PTSD. Furthermore, we found that TMP administration significantly suppressed the increased responsiveness of LC-noradrenergic system, effectively reduced the anxiety response of SPS rats, and selectively attenuated the activation of pro-apoptotic ER stress pathways. The results suggest that TMP was efficient in improving the LC-NE dysfunction induced by excessive ER stress. TMP exhibited a significant neuroprotective effect and potential therapeutics on PTSD-like symptoms.
创伤后应激障碍（PTSD）是一种由重大创伤性事件引起的严重应激相关神经精神障碍。蓝斑（LC）-去甲肾上腺素能系统的异常活动与 PTSD 样症状的发展有关。我们之前的研究表明，创伤后应激障碍大鼠 LC 中的内质网（ER）应激诱导神经元凋亡。本研究的目的是进一步探讨 ER 应激途径在 LC 神经元功能障碍中的作用，并阐明活性成分川芎嗪（TMP）对 ER 应激反应的影响。我们使用单次延长应激（SPS）急性暴露来建立 PTSD 大鼠模型。通过酶联免疫吸附试验、western blot 分析和高架十字迷宫试验，分别观察到 SPS 暴露的大鼠大脑中去甲肾上腺素（NE）水平升高、LC 中酪氨酸羟化酶表达增加以及焦虑样行为增强。此外，SPS 暴露激活了 ER 应激的三大途径，这可能与 PTSD 大鼠 LC-去甲肾上腺素能系统的失调有关。此外，我们发现 TMP 给药显著抑制了 LC-去甲肾上腺素能系统的反应性增加，有效降低了 SPS 大鼠的焦虑反应，并选择性减弱了促凋亡 ER 应激途径的激活。结果表明，TMP 能有效改善由过度 ER 应激引起的 LC-NE 功能障碍。TMP 对 PTSD 样症状具有显著的神经保护作用和潜在的治疗作用。
