Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, Brazil.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Eur J Neurosci. 2021 Jan;53(2):649-662. doi: 10.1111/ejn.14922. Epub 2020 Aug 19.
It is known that bipolar disorder has a multifactorial aetiology where the interaction between genetic and environmental factors is responsible for its development. Because of this, epigenetics has been largely studied in psychiatric disorders. The present study aims to evaluate the effects of histone deacetylase inhibitors on epigenetic enzyme alterations in rats or mice submitted to animal models of mania induced by dextro-amphetamine or sleep deprivation, respectively. Adult male Wistar rats were subjected to 14 days of dextro-amphetamine administration, and from the eighth to the fourteenth day, the animals were treated with valproate and sodium butyrate in addition to dextro-amphetamine injections. Adult C57BL/6 mice received 7 days of valproate or sodium butyrate administration, being sleep deprived at the last 36 hr of the protocol. Locomotor and exploratory activities of rats and mice were evaluated in the open-field test, and histone deacetylase, DNA methyltransferase, and histone acetyltransferase activities were assessed in the frontal cortex, hippocampus, and striatum. Dextro-amphetamine and sleep deprivation induced hyperactivity and increased histone deacetylase and DNA methyltransferase activities in the animal's brain. Valproate and sodium butyrate were able to reverse hyperlocomotion induced by both animal models, as well as the alterations on histone deacetylase and DNA methyltransferase activities. There was a positive correlation between enzyme activities and number of crossings for both models. Histone deacetylase and DNA methyltransferase activities also presented a positive correlation between theirselves. These results suggest that epigenetics can play an important role in BD pathophysiology as well as in its treatment.
已知双相情感障碍具有多因素病因，遗传和环境因素的相互作用导致其发病。正因为如此，表观遗传学在精神疾病中得到了广泛的研究。本研究旨在评估组蛋白去乙酰化酶抑制剂对分别由右旋苯丙胺或睡眠剥夺诱导的躁狂动物模型中的大鼠或小鼠中表观遗传酶改变的影响。成年雄性 Wistar 大鼠接受 14 天的右旋苯丙胺给药，从第 8 天到第 14 天，除右旋苯丙胺注射外，动物还接受丙戊酸钠和丁酸钠治疗。成年 C57BL/6 小鼠接受 7 天的丙戊酸钠或丁酸钠给药，在方案的最后 36 小时内被剥夺睡眠。通过旷场试验评估大鼠和小鼠的运动和探索活动，并在前额皮质、海马体和纹状体评估组蛋白去乙酰化酶、DNA 甲基转移酶和组蛋白乙酰转移酶活性。右旋苯丙胺和睡眠剥夺诱导动物大脑过度活跃，并增加组蛋白去乙酰化酶和 DNA 甲基转移酶活性。丙戊酸钠和丁酸钠能够逆转两种动物模型引起的过度运动，以及组蛋白去乙酰化酶和 DNA 甲基转移酶活性的改变。两种模型的酶活性与穿越次数之间呈正相关。组蛋白去乙酰化酶和 DNA 甲基转移酶活性之间也存在正相关。这些结果表明，表观遗传学可能在双相情感障碍的病理生理学及其治疗中发挥重要作用。
