Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan.
Department of Pharmacology, School of Pharmacy at Fukuoka, International University of Health and Welfare, 137-1 Enokizu, Okawa, Fukuoka 831-8501, Japan.
Neurosci Lett. 2022 Jan 1;766:136340. doi: 10.1016/j.neulet.2021.136340. Epub 2021 Nov 10.
Recent reports have implied that aberrant biochemical processes in the brain are frequently accompanied by subtle shifts in the cellular epigenetic profile that might underlie the pathogenic progression of psychiatric disorders. The aim of the present study was to examine the effect of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, on the emotional abnormality induced by maladaptation to stress in mice. Mice were exposed to repeated restraint stress for 240 min/day for 14 days. We applied dosing schedules. In one schedule, from the 3rd day of stress exposure, mice were treated with TSA (1650 μM/4 μL, i.c.v.) immediately after the daily exposure to restraint stress. In the other schedule, from the 1st day of stress exposure, mice were treated with TSA 2 h before exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated using the hole-board test. Mice that were exposed to restraint stress for 240 min/day for 14 days showed a decrease in head-dipping behavior. This decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with TSA 2 h before daily exposure to restraint stress, which confirmed the development of stress adaptation. On the other hand, no such stress adaptation was observed under chronic treatment with TSA immediately after daily stress exposure. A biochemical study showed that tryptophan hydroxylase, the rate-limiting enzyme in serotonin (5-HT) synthesis, was increased in midbrain containing raphe nuclei obtained from stress-adapted mice that were chronically treated with TSA 2 h before daily stress exposure. These findings suggest that an HDAC inhibitor may have a beneficial effect on stress adaptation by affecting 5-HT neural function in the brain and alleviate the emotional abnormality under conditions of excessive stress.
最近的报告表明，大脑中的异常生化过程常常伴随着细胞表观遗传特征的微妙变化，而这些变化可能是精神疾病发病进展的基础。本研究旨在探讨组蛋白去乙酰化酶（HDAC）抑制剂曲古抑菌素 A（TSA）对适应不良应激引起的小鼠情绪异常的影响。将小鼠暴露于重复束缚应激 240 分钟/天，持续 14 天。我们应用了两种给药方案。在一种方案中，从应激暴露的第 3 天开始，每天暴露于束缚应激后，立即用 TSA（1650μM/4μL，脑室内）处理小鼠。在另一种方案中，从应激暴露的第 1 天开始，在暴露于束缚应激之前 2 小时用 TSA 处理小鼠。在最后一次暴露于束缚应激后，使用洞板测试评估小鼠的情绪。每天暴露于束缚应激 240 分钟/天持续 14 天的小鼠出现低头行为减少。应激适应不良小鼠中观察到的这种情绪降低通过慢性 TSA 治疗（在每天暴露于束缚应激之前 2 小时）得到显著恢复，这证实了应激适应的发展。另一方面，在每天应激暴露后立即进行慢性 TSA 治疗时，没有观察到这种应激适应。生化研究表明，色氨酸羟化酶，即 5-羟色胺（5-HT）合成的限速酶，在慢性 TSA 治疗（在每天应激暴露前 2 小时）的应激适应小鼠的中脑含有中缝核的部位增加。这些发现表明，HDAC 抑制剂可能通过影响大脑中的 5-HT 神经功能对应激适应产生有益影响，并在过度应激条件下缓解情绪异常。
