Brain-derived neurotrophic factor signalling mediates antidepressant effects of lamotrigine
Brain-derived neurotrophic factor signalling mediates antidepressant effects of lamotrigine
复制标题
脑源性神经营养因子信号传导介导拉莫三嗪的抗抑郁作用
DOI：
10.1017/s1461145710001082
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发表时间：
2011-09-01
影响因子：
4.8
通讯作者：
He, Shuchang
中科院分区：
文献类型：
--
作者：
Li, Nanxin;He, Xiaolu;He, Shuchang
抗惊厥药物拉莫三嗪已被证明对双相情感障碍患者具有抗抑郁作用。到目前为止，只有少数临床前研究在强迫游泳试验（FST）中使用拉莫三嗪治疗，强迫游泳试验是一种表面效度较低的抑郁症动物模型。拉莫三嗪发挥作用的潜在机制也尚未得到很好的阐释。本研究拓展了早期关于脑源性神经营养因子（BDNF）在调节拉莫三嗪抗抑郁作用中所起作用的研究。我们发现，在遭受慢性不可预测应激的大鼠中，长期给予30mg/kg拉莫三嗪可改善应激大鼠在蔗糖偏好试验（SPT）和新奇抑制摄食试验（NSFT）中的行为缺陷。同时，长期拉莫三嗪治疗可上调未应激和应激动物的额叶和海马BDNF蛋白表达，并恢复应激诱导的BDNF水平下调。此外，通过注入K252a（一种BDNF受体TrkB的抑制剂）抑制BDNF信号传导，可阻断拉莫三嗪在SPT、NSFT和FST中的抗抑郁作用。综上所述，本研究进一步证明BDNF是拉莫三嗪抗抑郁作用的关键介质。
The anticonvulsant drug lamotrigine has been shown to produce antidepressant effects in patients with bipolar disorder. To date, only a few preclinical studies have been conducted using lamotrigine treatment in the forced swim test (FST), an animal model of depression with low face validity. The underlying mechanisms by which lamotrigine works have not been well characterized either. This study extends earlier work on the role of brain-derived neurotrophic factor (BDNF) in regulating the antidepressant actions of lamotrigine. We showed that in rats subjected to chronic unpredictable stress, chronic administration of 30 mg/kg lamotrigine ameliorates behavioural deficits of stressed rats in both sucrose preference test (SPT) and novelty-suppressed feeding test (NSFT). In parallel, chronic lamotrigine treatment up-regulates frontal and hippocampal BDNF protein expression in both naive and stressed animals, and restores the stress-induced down-regulation of BDNF levels. In addition, inhibition of BDNF signalling by infusion of K252a, an inhibitor of the BDNF receptor TrkB, blocks the antidepressant effects of lamotrigine in SPT, NSFT and FST. Taken together, this study provides further evidence that BDNF is an essential mediator for the antidepressant effects of lamotrigine.