Upregulation of mGlu2 Receptors via NF-κB p65 Acetylation Is Involved in the Proneurogenic and Antidepressant Effects of Acetyl-L-Carnitine
Upregulation of mGlu2 Receptors via NF-κB p65 Acetylation Is Involved in the Proneurogenic and Antidepressant Effects of Acetyl-L-Carnitine
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DOI：
10.1038/npp.2013.121
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发表时间：
2013-10-01
影响因子：
7.6
通讯作者：
Grilli, Mariagrazia
中科院分区：
文献类型：
--
作者：
Cuccurazzu, Bruna;Bortolotto, Valeria;Grilli, Mariagrazia
乙酰-L-肉毒碱（ALC）是一种天然存在的分子，在细胞生物能量学中具有重要作用，并作为蛋白质（包括NF-κ B p65）的乙酰基供体。在人类中，外源性给予ALC已被证明对情绪障碍有效，具有良好的耐受性。目前还没有关于ALC在抑郁症动物模型中的抗抑郁作用以及这种作用所涉及的假定机制的信息。在这里，我们报告说，ALC是一个前神经分子，其对成年海马神经祖细胞的神经元分化的影响是独立的神经保护活性。ALC的体外前神经发生作用似乎是通过NF-κ B B途径的激活介导的，特别是通过p65乙酰化，以及随后NF-κ B介导的代谢型谷氨酸受体2（mGlu 2）表达的上调。在体内测试时，慢性ALC治疗可以逆转由不可预测的慢性轻度应激引起的抑郁样行为，这是一种具有高表面有效性和预测性的抑郁症啮齿动物模型，其行为效应与应激小鼠大脑中mGlu 2受体表达上调相关。此外，慢性，但不是急性或亚慢性，药物治疗显着增加成年出生的神经元在应激和非应激小鼠的背侧海马。我们现在提出，这种机制可能潜在地参与了ALC在人类中的抗抑郁作用。从临床角度来看，这些结果具有潜在的相关性，因为其高耐受性特征，ALC可能理想地用于对经典抗抑郁药相关副作用敏感的患者亚群。
Acetyl-L-carnitine (ALC) is a naturally occurring molecule with an important role in cellular bioenergetics and as donor of acetyl groups to proteins, including NF-kappa B p65. In humans, exogenously administered ALC has been shown to be effective in mood disturbances, with a good tolerability profile. No current information is available on the antidepressant effect of ALC in animal models of depression and on the putative mechanism involved in such effect. Here we report that ALC is a proneurogenic molecule, whose effect on neuronal differentiation of adult hippocampal neural progenitors is independent of its neuroprotective activity. The in vitro proneurogenic effects of ALC appear to be mediated by activation of the NF-kappa B pathway, and in particular by p65 acetylation, and subsequent NF-kappa B-mediated upregulation of metabotropic glutamate receptor 2 (mGlu2) expression. When tested in vivo, chronic ALC treatment could revert depressive-like behavior caused by unpredictable chronic mild stress, a rodent model of depression with high face validity and predictivity, and its behavioral effect correlated with upregulated expression of mGlu2 receptor in hippocampi of stressed mice. Moreover, chronic, but not acute or subchronic, drug treatment significantly increased adult born neurons in hippocampi of stressed and unstressed mice. We now propose that this mechanism could be potentially involved in the antidepressant effect of ALC in humans. These results are potentially relevant from a clinical perspective, as for its high tolerability profile ALC may be ideally employed in patient subpopulations who are sensitive to the side effects associated with classical antidepressants.