Laboratório de Avaliação de Substâncias Bioativas, Departamento de Ciências Naturais, Universidade Regional de Blumenau, CEP 89030-903, Blumenau, Santa Catarina, Brazil.
Laboratório de Avaliação de Substâncias Bioativas, Departamento de Ciências Naturais, Universidade Regional de Blumenau, CEP 89030-903, Blumenau, Santa Catarina, Brazil; Programa de Pós-Graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
Chem Biol Interact. 2019 Dec 1;314:108843. doi: 10.1016/j.cbi.2019.108843. Epub 2019 Oct 3.
Depression is a common neuropsychiatric disorder whose pathophysiology has been associated with glutamatergic excitotoxicity. Thus, the research for new antidepressant strategies with the ability to mitigate glutamate toxicity has received growing attention. Given this background, the present study sought to investigate the antidepressant-like and neuroprotective effects of Morus nigra (MN) and its major phenolic, syringic acid (SA), against glutamate-induced damage, as well as, the role of the PI3K/Akt/GSK-3β signaling pathway in these effects. Treatment with MN (3 mg/kg) and SA (1 mg/kg) for 7 days, similar to fluoxetine (10 mg/kg), triggered an antidepressant-like effect. Moreover, the treatments evoked neuroprotection against glutamatergic excitotoxicity in hippocampal slices, and MN treatment also afforded protection in cerebrocortical slices. Notably, ex vivo neuroprotective effect of MN and SA was mediated, at least in part, by PI3K/Akt/GSK-3β signaling pathway. Furthermore, the ability of MN and SA to counteract the glutamate-induced damage were evaluated in three different in vitro experiments. The hippocampal slices pretreated with MN (0.05 and 0.1 μg/mL) or SA (0.01-0.1 μg/mL) as well as the concomitant treatment with MN (0.01 and 0.05 μg/mL) or SA (0.05 and 0.1 μg/mL) exhibited protection against glutamate toxicity. Interestingly, post-treatment with MN in all doses (0.01-0.1 μg/mL) and SA at dose of 0.1 μg/mL were capable of preventing glutamate-induced cell death. In vitro neuroprotective effect of SA, but not MN, involves the activation of Akt, since the pretreatment with LY294002 completely abolished the protective effect. Overall, MN and SA presented antidepressant-like and neuroprotective effects against glutamatergic excitotoxicity via PI3K/Akt/GSK-3β.
抑郁症是一种常见的神经精神疾病，其病理生理学与谷氨酸能兴奋性毒性有关。因此，寻找具有减轻谷氨酸毒性的新的抗抑郁策略的研究受到了越来越多的关注。基于这一背景，本研究旨在探讨桑（Morus nigra，MN）及其主要酚酸丁香酸（syringic acid，SA）对谷氨酸诱导损伤的抗抑郁样和神经保护作用，以及 PI3K/Akt/GSK-3β信号通路在这些作用中的作用。MN（3mg/kg）和 SA（1mg/kg）治疗 7 天，与氟西汀（10mg/kg）相似，可引发抗抑郁样作用。此外，这些治疗还引发了对海马切片中谷氨酸兴奋性毒性的神经保护作用，MN 治疗也对大脑皮质切片提供了保护作用。值得注意的是，MN 和 SA 的体外神经保护作用至少部分通过 PI3K/Akt/GSK-3β信号通路介导。此外，还在三种不同的体外实验中评估了 MN 和 SA 对抗谷氨酸诱导损伤的能力。MN（0.05 和 0.1μg/mL）或 SA（0.01-0.1μg/mL）预处理的海马切片以及 MN（0.01 和 0.05μg/mL）或 SA（0.05 和 0.1μg/mL）的伴随治疗均显示出对谷氨酸毒性的保护作用。有趣的是，MN 以所有剂量（0.01-0.1μg/mL）和 SA 剂量为 0.1μg/mL 的 post-treatment 能够预防谷氨酸诱导的细胞死亡。SA 的体外神经保护作用，但不是 MN，涉及 Akt 的激活，因为 LY294002 的预处理完全消除了保护作用。总体而言，MN 和 SA 对谷氨酸能兴奋性毒性具有抗抑郁样和神经保护作用，涉及 PI3K/Akt/GSK-3β。
