Background

The etiology of bipolar disorder (BD) is multifactorial, involving both environmental and genetic factors. Current pharmacological treatment is associated with several side effects, which are the main reason patients discontinue treatment. Epigenetic alterations have been studied for their role in the pathophysiology of BD, as they bridge the gap between gene and environment.

Objective

Evaluate the effects of histone deacetylase inhibitors on behavior and epigenetic enzymes activity in a rat model of mania induced by ouabain.

Methods

Adult male rats were subjected to a single intracerebroventricular injection of ouabain (10⁻³ M) followed by 7 days of valproate (200 mg/kg) or sodium butyrate (600 mg/kg) administration. Locomotor and exploratory activities were evaluated in the open-field test. Histone deacetylase, DNA methyltransferase, and histone acetyltransferase activity were assessed in the frontal cortex, hippocampus, and striatum.

Results

Ouabain induced hyperactivity in rats, which was reversed by valproate and sodium butyrate treatment. Ouabain did not alter the activity of any of the enzymes evaluated. However, valproate and sodium butyrate decreased the activity of histone deacetylase and DNA methyltransferase. Moreover, there was a positive correlation between these two enzymes.

Conclusion

These results suggest that targeting epigenetic mechanisms may play an important role in mania-like behavior management.

中文翻译：

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HDAC抑制剂可逆转由Ouabain引起的躁狂症动物模型中的躁狂症样行为并调节表观遗传调控酶。

背景

躁郁症（BD）的病因是多方面的，涉及环境和遗传因素。当前的药物治疗与多种副作用有关，这是患者停止治疗的主要原因。由于表观遗传改变在基因与环境之间的桥梁中起着重要作用，因此研究了它们在BD病理生理中的作用。

目的

评价组蛋白脱乙酰基酶抑制剂对哇巴因致躁狂症大鼠行为和表观遗传酶活性的影响。

方法

成年雄性大鼠单次脑室内注射哇巴因（10 ^-3  M），然后给予丙戊酸盐（200 mg / kg）或丁酸钠（600 mg / kg）7天。在野外试验中评估了运动和探索活动。评估额叶皮层，海马和纹状体中的组蛋白脱乙酰基酶，DNA甲基转移酶和组蛋白乙酰转移酶活性。

结果

瓦巴因诱导大鼠活动亢进，丙戊酸钠和丁酸钠治疗可逆转这种过度活动。瓦巴因没有改变任何评估酶的活性。但是，丙戊酸和丁酸钠会降低组蛋白脱乙酰基酶和DNA甲基转移酶的活性。此外，这两种酶之间存在正相关。

结论

这些结果表明靶向表观遗传机制可能在躁狂样行为管理中发挥重要作用。