Department of Natural and Life Sciences, Faculty of Exact Sciences and Natural and Life Sciences, University Mohamed Khider of Biskra, BP 145 RP, 07000, Biskra, Algeria; Laboratory of Biotechnology, National Higher School of Biotechnology, Ville universitaire Ali Mendjeli, BP E66 25100, Constantine, Algeria.
Department of Oral and Maxillofacial Surgery, University of California, San Francisco, 707 Parnassus Ave Suite D-1201, San Francisco, CA, 94143, USA.
Biomed Pharmacother. 2021 Mar;135:111246. doi: 10.1016/j.biopha.2021.111246. Epub 2021 Feb 1.
Growing evidence suggests that a high fat diet (HFD) induces oxidative stress on the central nervous system (CNS), which predisposes to mood disorders and neuroinflammation. In this study we postulated that in addition to improving mood, antidepressant therapy would reverse inflammatory changes in the brain of rats exposed to a HFD. To test our hypothesis, we measured the effect of the antidepressant agomelatine (AGO) on anxiety- and depressive-like behaviors, as well as on CNS markers of inflammation in rats rendered obese. Agomelatine is an agonist of the melatonin receptors MT1 and MT2 and an antagonist of the serotonin receptors 5HT2B and 5HT2C. A subset of rats was also treated with lipopolysaccharides (LPS) to determine how additional neuroinflammation alters behavior and affects the response to the antidepressant. Specifically, rats were subjected to a 14-week HFD, during which time behavior was evaluated twice, first at the 10th week prior to LPS and/or agomelatine, and then at the 14th week after a bi-weekly exposure to LPS (250 μg/kg) and daily treatment with agomelatine (40 mg/kg). Immediately after the second behavioral testing we measured the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β), markers of oxidative stress thiobarbituric acid reactive substances (TABRS), catalase (CAT) and glutathione peroxidase (GPx), the growth factor BDNF, as well as the apoptosis marker caspase-3. Our results show that a HFD induced an anxiety-like behavior in the open field test (OFT) at the 10th week, followed by a depressive-like behavior in the forced swim test (FST) at the 14th week. In the prefrontal and hippocampal cortices of rats exposed to a HFD we noted an overproduction of TNF-α, IL-6, IL-1β, and TABRS, together with an increase in caspase-3 activity. We also observed a decrease in BDNF, as well as reduced CAT and GPx activity in the same brain areas. Treatment with agomelatine reversed the signs of anxiety and depression, and decreased the cytokines (TNF-α, IL-6 and IL-1β), TABRS, as well as caspase-3 activity. Agomelatine also restored BDNF levels and the activity of antioxidant enzymes CAT and GPx. Our findings suggest that the anxiolytic/antidepressant effect of agomelatine in obese rats could result from a reversal of the inflammatory and oxidative stress brought about by their diet.
越来越多的证据表明高脂肪饮食（HFD）会对中枢神经系统（CNS）造成氧化应激，从而导致情绪障碍和神经炎症。在这项研究中，我们假设抗抑郁治疗除了改善情绪外，还会逆转暴露于 HFD 的大鼠大脑中的炎症变化。为了验证我们的假设，我们测量了抗抑郁药阿戈美拉汀（AGO）对焦虑和抑郁样行为以及大鼠肥胖时 CNS 炎症标志物的影响。阿戈美拉汀是褪黑素受体 MT1 和 MT2 的激动剂，5-羟色胺受体 5HT2B 和 5HT2C 的拮抗剂。一部分大鼠还接受了脂多糖（LPS）治疗，以确定额外的神经炎症如何改变行为并影响对抗抑郁药的反应。具体来说，大鼠接受了为期 14 周的 HFD，在此期间，在 LPS 和/或阿戈美拉汀之前的第 10 周进行了两次行为评估，然后在每周两次暴露于 LPS（250μg/kg）和每天接受阿戈美拉汀（40mg/kg）治疗后的第 14 周进行了评估。在第二次行为测试后，我们立即测量了促炎细胞因子肿瘤坏死因子-α（TNF-α）、白细胞介素 6（IL-6）和白细胞介素 1β（IL-1β）、氧化应激硫代巴比妥酸反应物质（TABRS）、过氧化氢酶（CAT）和谷胱甘肽过氧化物酶（GPx）、生长因子 BDNF 以及凋亡标志物半胱天冬酶-3。我们的结果表明，HFD 在第 10 周的开阔场测试（OFT）中引起了焦虑样行为，然后在第 14 周的强迫游泳测试（FST）中引起了抑郁样行为。在暴露于 HFD 的大鼠的前额叶和海马皮层中，我们观察到 TNF-α、IL-6、IL-1β 和 TABRS 的过度产生，同时伴有 caspase-3 活性增加。我们还观察到 BDNF 减少，以及同一脑区的 CAT 和 GPx 活性降低。阿戈美拉汀治疗可逆转焦虑和抑郁症状，并降低细胞因子（TNF-α、IL-6 和 IL-1β）、TABRS 以及 caspase-3 活性。阿戈美拉汀还恢复了 BDNF 水平和抗氧化酶 CAT 和 GPx 的活性。我们的发现表明，阿戈美拉汀在肥胖大鼠中的抗焦虑/抗抑郁作用可能是由于其饮食引起的炎症和氧化应激的逆转所致。
Biomed Pharmacother. 2021-3
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