Department of Neurosurgery, Chi Mei Medical Center, Taiwan University of Science and Technology, Tainan, Taiwan.
J Neurotrauma. 2013 Jul 15;30(14):1223-31. doi: 10.1089/neu.2012.2689. Epub 2013 Jul 2.
Traumatic brain injury (TBI) is the most common cause of death and acquired disability among children and young adults in the developed countries. In clinical studies, the incidence of depression is high after TBI, and the mechanisms behind TBI-induced depression remain unclear. In the present study, we subjected rats to a moderate fluid percussion into the closed cranial cavity to induce TBI. After 3 days of recovery, injured rats were given a forced swim test (FST) and novelty-suppressed feeding tests. We found that TBI rats exhibited increased duration of immobility and longer latency to begin chewing food in a new environment compared with sham-operated rats. Western blot analysis showed that TBI led to a decrease in the phosphorylated levels of extracellular signal regulated kinases (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK). Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), significantly reduced the duration of immobility when administered once per day for 14 days. Consistent with behavioral tests, fluoxetine treatment reversed TBI-induced decrease in p-ERK1/2 and p-p38 MAPK levels. Pre-treatment with a selective tryptophan hydroxylase inhibitor para-chlorophenylalanine (PCPA) blocked the antidepressant effect of fluoxetine. PCPA also prevented the effect of fluoxetine on ERK1/2 phosphorylation without affecting p38 MAPK phosphorylation. Pre-treatment with ERK inhibitor SL327 but not p38 MAPK inhibitor SB203580 prevented the antidepressant effect of fluoxetine. These results suggest that ERK1/2 plays a critical role in TBI-induced depression.
创伤性脑损伤 (TBI) 是发达国家儿童和青年人群中最常见的死亡和后天残疾原因。在临床研究中，TBI 后抑郁的发病率很高，而 TBI 引起抑郁的机制尚不清楚。在本研究中，我们采用闭合性颅脑损伤方法诱导大鼠中度颅脑损伤。恢复 3 天后，对损伤大鼠进行强迫游泳试验 (FST) 和新异环境摄食抑制试验。结果发现，与假手术大鼠相比，TBI 大鼠在新异环境中的静止时间延长，开始咀嚼食物的潜伏期延长。Western blot 分析显示，TBI 导致细胞外信号调节激酶 (ERK1/2) 和 p38 丝裂原活化蛋白激酶 (p38 MAPK) 的磷酸化水平降低。选择性 5-羟色胺再摄取抑制剂 (SSRI) 氟西汀，每日给药 14 天，可显著减少不动时间。与行为测试一致，氟西汀治疗逆转了 TBI 诱导的 p-ERK1/2 和 p-p38 MAPK 水平降低。先用色氨酸羟化酶选择性抑制剂对氯苯丙氨酸 (PCPA) 预处理，可阻断氟西汀的抗抑郁作用。PCPA 还可阻止氟西汀对 ERK1/2 磷酸化的影响，而不影响 p38 MAPK 磷酸化。ERK 抑制剂 SL327 预处理而非 p38 MAPK 抑制剂 SB203580 可预防氟西汀的抗抑郁作用。这些结果表明 ERK1/2 在 TBI 诱导的抑郁中起关键作用。
