Sub-Acute Treatment of Curcumin Derivative J147 Ameliorates Depression-Like Behavior Through 5-HT1A-Mediated cAMP Signaling
Sub-Acute Treatment of Curcumin Derivative J147 Ameliorates Depression-Like Behavior Through 5-HT1A-Mediated cAMP Signaling
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DOI：
10.3389/fnins.2020.00701
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发表时间：
2020-07-08
影响因子：
4.3
通讯作者：
Yu, Yingcong
中科院分区：
文献类型：
--
作者：
Li, Jianxin;Chen, Ling;Yu, Yingcong
重度抑郁症（MDD）是一种严重的精神障碍，与单胺类神经递质缺乏有关，特别是与5-羟色胺（5-羟色胺，5-羟色胺）及其受体异常有关。我们之前的研究表明，一种新的姜黄素衍生物J147通过增加小鼠海马中的脑源性神经营养因子（BDNF）水平，在急性治疗中表现出抗抑郁样作用。本研究扩展了我们之前的研究结果，并研究了J147亚急性治疗3天对雄性ICR小鼠的抗抑郁样作用及其与5-HT（1A）和5-HT（1B）受体和下游cAMP-BDNF信号传导的可能相关性。方法J147按1、3、9 mg/kg灌胃给药3 d，记录强制游泳和悬尾试验（FST和TST）的抗静止时间。采用放射配体结合法测定J147对5-HT（1A）和5-HT（1B）受体的亲和力。此外，使用5-HT（1A）或5-HT（1B）激动剂或其拮抗剂来确定哪种5-HT受体亚型参与J147的抗抑郁样作用。测定下游信号分子cAMP、PKA、pCREB、BDNF的作用机制。结果J147亚急性处理显著降低了大鼠FST和TST的静止时间，且呈剂量依赖性。J147对小鼠皮质组织制备的5-HT（1A）受体具有较高的体外亲和性，对5-HT（1B）受体的亲和性较低。J147的这些作用被5-HT（1A）拮抗剂nad299预处理阻断，并被5-HT（1A）拮抗剂8-OH-DPAT增强。然而，5-HT（1B）受体拮抗剂NAS-181并没有明显改变J147对抑郁样行为的影响。此外，nad299预处理阻断了J147诱导的海马cAMP、PKA、pCREB和BDNF表达的增加，而8-OH-DPAT增强了J147对这些蛋白表达的影响。结论J147在3 d的治疗期内可诱导快速的抗抑郁样作用，且不诱导药物耐受。这些作用可能是由5- ht1a依赖性cAMP/PKA/pCREB/BDNF信号介导的。
Background Major depressive disorder (MDD) is a severe mental disorder related to the deficiency of monoamine neurotransmitters, particularly to abnormalities of 5-HT (5-hydroxytryptamine, serotonin) and its receptors. Our previous study suggested that acute treatment with a novel curcumin derivative J147 exhibited antidepressant-like effects by increasing brain derived neurotrophic factor (BDNF) level in the hippocampus of mice. The present study expanded upon our previous findings and investigated the antidepressant-like effects of sub-acute treatment of J147 for 3 days in male ICR mice and its possible relevancy to 5-HT(1A)and 5-HT(1B)receptors and downstream cAMP-BDNF signaling. Methods J147 at doses of 1, 3, and 9 mg/kg (via gavage) was administered for 3 days, and the anti-immobility time in the forced swimming and tail suspension tests (FST and TST) was recorded. The radioligand binding assay was used to determine the affinity of J147 to 5-HT(1A)and 5-HT(1B)receptor. Moreover, 5-HT(1A)or 5-HT(1B)agonist or its antagonist was used to determine which 5-HT receptor subtype is involved in the antidepressant-like effects of J147. The downstream signaling molecules such as cAMP, PKA, pCREB, and BDNF were also measured to determine the mechanism of action. Results The results demonstrated that sub-acute treatment of J147 remarkably decreased the immobility time in both the FST and TST in a dose-dependent manner. J147 displayed high affinityin vitroto 5-HT(1A)receptor prepared from mice cortical tissue and was less potent at 5-HT(1B)receptor. These effects of J147 were blocked by pretreatment with a 5-HT(1A)antagonist NAD-299 and enhanced by a 5-HT(1A)agonist 8-OH-DPAT. However, 5-HT(1B)receptor antagonist NAS-181 did not appreciably alter the effects of J147 on depression-like behaviors. Moreover, pretreatment with NAD-299 blocked J147-induced increases in cAMP, PKA, pCREB, and BDNF expression in the hippocampus, while 8-OH-DPAT enhanced the effects of J147 on these proteins' expression. Conclusion The results suggest that J147 induces rapid antidepressant-like effects during a 3-day treatment period without inducing drug tolerance. These effects might be mediated by 5-HT1A-dependent cAMP/PKA/pCREB/BDNF signaling.