Agmatine, by Improving Neuroplasticity Markers and Inducing Nrf2, Prevents Corticosterone-Induced Depressive-Like Behavior in Mice
Agmatine, by Improving Neuroplasticity Markers and Inducing Nrf2, Prevents Corticosterone-Induced Depressive-Like Behavior in Mice
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DOI：
10.1007/s12035-015-9182-6
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发表时间：
2016-07-01
影响因子：
5.1
通讯作者：
Lopez, Manuela G.
中科院分区：
文献类型：
--
作者：
Freitas, Andiara E.;Egea, Javier;Lopez, Manuela G.
胍丁胺是一种内源性神经调节剂，是治疗抑郁症的辅助/单一疗法的潜在候选者。我们小组最近的一项研究表明，胍丁胺可诱导 Nrf2 并防止海马神经元细胞系中皮质酮的影响。本研究是先前研究的延伸，通过评估胍丁胺在小鼠皮质酮诱导的抑郁动物模型中的抗抑郁样作用。瑞士小鼠同时接受剂量为 0.1 mg/kg/天（口服）的胍丁胺或丙咪嗪和皮质酮治疗 21 天，并且在每日施用实验药物之前立即施用皮质酮（20 mg/kg/天，口服）。野生型 C57BL/6 小鼠 (Nrf2 (+/+)) 和 Nrf2 KO (Nrf2 (-/-)) 在 21 天内用胍丁胺（0.1 mg/kg/天，口服）或媒介物治疗。最后一次治疗后二十四小时，进行行为测试和生化测定。胍丁胺治疗 21 天能够消除皮质酮诱导的抑郁样行为以及成熟 BDNF 和突触结合蛋白 I 的免疫含量以及血清素和谷氨酸水平的变化。胍丁胺还消除了皮质酮引起的海马 CA1 区星形胶质细胞和小胶质细胞形态的变化。此外，对照小鼠的胍丁胺治疗增加了去甲肾上腺素、血清素和多巴胺水平、CREB磷酸化、成熟BDNF和突触结合蛋白I免疫含量，并降低了海马中的前BDNF免疫含量。胍丁胺产生抗抑郁样作用的能力在 Nrf2 (-/-) 小鼠中被消除。目前的结果强化了 Nrf2 在胍丁胺产生的抗抑郁样作用中的参与，并扩展了有关其作用机制的文献数据。
Agmatine, an endogenous neuromodulator, is a potential candidate to constitute an adjuvant/monotherapy for the management of depression. A recent study by our group demonstrated that agmatine induces Nrf2 and protects against corticosterone effects in a hippocampal neuronal cell line. The present study is an extension of this previous study by assessing the antidepressant-like effect of agmatine in an animal model of depression induced by corticosterone in mice. Swiss mice were treated simultaneously with agmatine or imipramine at a dose of 0.1 mg/kg/day (p.o.) and corticosterone for 21 days and the daily administrations of experimental drugs were given immediately prior to corticosterone (20 mg/kg/day, p.o.) administrations. Wild-type C57BL/6 mice (Nrf2 (+/+)) and Nrf2 KO (Nrf2 (-/-)) were treated during 21 days with agmatine (0.1 mg/kg/day, p.o.) or vehicle. Twenty-four hours after the last treatments, the behavioral tests and biochemical assays were performed. Agmatine treatment for 21 days was able to abolish the corticosterone-induced depressive-like behavior and the alterations in the immunocontent of mature BDNF and synaptotagmin I, and in the serotonin and glutamate levels. Agmatine also abolished the corticosterone-induced changes in the morphology of astrocytes and microglia in CA1 region of hippocampus. In addition, agmatine treatment in control mice increased noradrenaline, serotonin, and dopamine levels, CREB phosphorylation, mature BDNF and synaptotagmin I immunocontents, and reduced pro-BDNF immunocontent in the hippocampus. Agmatine's ability to produce an antidepressant-like effect was abolished in Nrf2 (-/-) mice. The present results reinforce the participation of Nrf2 in the antidepressant-like effect produced by agmatine and expand literature data concerning its mechanisms of action.