L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors
L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors
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DOI：
10.1073/pnas.1216100110
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发表时间：
2013-03-19
影响因子：
11.1
通讯作者：
Nicoletti, Ferdinando
中科院分区：
文献类型：
--
作者：
Nasca, Carla;Xenos, Dionysios;Nicoletti, Ferdinando
表观遗传机制参与了抑郁症的病理生理学，是治疗干预的独特潜在靶点。乙酰化剂L-乙酰肉毒碱（LAC）是一种耐受性良好的药物，通过2型代谢型谷氨酸（mGlu 2）受体的表观遗传调节发挥抗抑郁药的作用。它在Flinders Sensitive Line大鼠和暴露于慢性不可预测压力的小鼠中引起快速和持久的抗抑郁作用，这两种动物分别模拟遗传和环境诱导的抑郁症。在这两种模型中，LAC增加了与Grm 2启动子结合的乙酰化H3 K27的水平，也增加了NF-κ B-p65亚基的乙酰化，从而增强了海马和前额皮质中编码mGlu 2受体的Grm 2基因的转录。重要的是，LAC减少不动时间在强迫游泳试验和增加蔗糖偏好早在3天的治疗，而14天的治疗需要氯丙咪嗪的抗抑郁作用。此外，对LAC的作用没有耐受性，停药后2 wk仍有抗抑郁作用。相反，NF-κ B B抑制阻止了LAC诱导的mGlu 2表达的增加，而组蛋白去乙酰化酶抑制剂的使用支持mGlu 2表达的表观遗传控制。最后，LAC对暴露于慢性不可预测的应激的mGlu 2敲除小鼠没有影响，并且单次注射mGlu 2/3受体拮抗剂LY 341495部分阻断LAC作用。LAC的快速和持久的抗抑郁作用强烈表明了一种独特的方法来检查人类抑郁症的表观遗传假说，为更有效的抗抑郁药和更快的起效铺平了道路。
Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a well-tolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-kappa B-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-kappa B inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.