Doxycycline at subantimicrobial dose combined with escitalopram reverses depressive-like behavior and neuroinflammatory hippocampal alterations in the lipopolysaccharide model of depression
Doxycycline at subantimicrobial dose combined with escitalopram reverses depressive-like behavior and neuroinflammatory hippocampal alterations in the lipopolysaccharide model of depression
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DOI：
10.1016/j.jad.2021.05.083
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发表时间：
2021-06-20
影响因子：
6.6
通讯作者：
Macedo, Danielle S.
中科院分区：
文献类型：
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作者：
Ferreira Mello, Bruna Stefania;Maia Chaves Filho, Adriano Jose;Macedo, Danielle S.
强力霉素（Doxycycline， DOXY）是具有抗炎和神经保护作用的第二代四环素。促炎谱似乎可以预测抑郁症状的严重程度。在本研究中，我们旨在确定亚抗菌剂量多西环素（DOXY, 10mg/ kg）的抗炎作用，单独使用或与抗抑郁药艾司西酞普兰（ESC）联合使用，是否可以恢复脂多糖诱导的小鼠抑郁样改变。雄性瑞士小鼠连续10天接受生理盐水或脂多糖（LPS）。从LPS暴露第6天开始，小鼠分别接受DOXY 10 mg/kg、ESC 4 mg/kg、DOXY 10 mg/kg +ESC 4 mg/kg （DOXY+ESC）或生理盐水处理。在第10天，我们评估了行为绝望（强迫游泳测试）、快感缺乏（蔗糖偏好测试）、脑氧化应激标志物以及与抑郁相关的炎症和保护途径，如NF-kB和磷酸- creb。我们的研究结果表明，DOXY单独或联合ESC可降低海马Iba-1表达和白细胞介素(IL)-113水平。只有DOXY+ESC成功逆转了lps诱导的NF-kBp65表达和TNF α水平的升高。DOXY引起海马磷酸化- creb和GSH浓度的表达显著增加。DOXY和DOXY+ESC显示出调节丝裂原活化激酶p42-44 （Phospho-p44/ 42 MAPK）和糖原合成酶激酶3 β (GSK313)磷酸化形式的功能状态的趋势，显示出对炎症的保护作用。总之，SDD联合ESC似乎是恢复炎症变化和预防抑郁症的好策略。
Doxycycline (DOXY) is a second-generation tetracycline with anti-inflammatory and neuroprotective effects. A proinflammatory profile seems to predict the severity of depressive symptoms. In the present study, we aimed at determining whether the anti-inflammatory action of subantimicrobial-dose doxycycline (SDD) (DOXY, 10mg/ kg), alone or combined with the antidepressant escitalopram (ESC), could revert lipopolysaccharide-induced depressive-like alterations in mice. Male Swiss mice received saline or lipopolysaccharide (LPS) for ten consecutive days. From the 6th day of LPS exposure, they were treated with DOXY 10 mg/kg, ESC 4 mg/kg, DOXY 10 mg/kg plus ESC 4 mg/kg (DOXY+ESC), or saline. On the 10th day, we assessed behavioral despair (forced swimming test), anhedonia (sucrose preference test), brain oxidative stress markers, and inflammatory and protective pathways related to depression, such as NF-kB and phospho-CREB. Our results showed that DOXY alone or combined with ESC reduced hippocampal Iba-1 expression and interleukin (IL)-113 levels. Only DOXY+ESC successfully reversed the LPS-induced increase in NF-kBp65 expression and TNF alpha levels. DOXY caused a marked increase in the hippocampal expression of phospho-CREB and GSH concentrations. DOXY and DOXY+ESC showed a tendency to modulate the functional status of mitogen-activated kinase p42-44 (Phospho-p44/ 42 MAPK) and of the phosphorylated form of glycogen synthase kinase 3 beta (GSK313), revealing a protective profile against inflammation. In conclusion, SDD, combined with ESC, seems to be a good strategy for reverting inflammatory changes and protecting against depression.