Chemistry & Biology：抗抑郁药阿米替林可促进大脑发育

美国埃默里大学科研人员最近研究发现，被广泛用作抗抑郁药物和止痛剂的阿米替林可直接刺激脑部神经细胞生长，从而促进大脑发育。

实验表明，阿米替林能直接促进大脑中“神经生长因子”的发展，维持神经细胞中的含氧量和葡萄糖含量，从而激发神经细胞向外伸展神经突，以连结其他神经细胞。另外，阿米替林还能抑制神经毒素红藻氨酸的产生。这显示了它不同于很多抗抑郁药物的药效机制。

阿米替林是一种三环类抗抑郁剂，目前被广泛用于治疗偏头痛和由糖尿病引发的神经性疾病。

这项研究结果将发表在最新一期美国《化学与生物学》杂志上。（生物谷Bioon.com）

生物谷推荐原始出处：

Chemistry & Biology, Volume 16, Issue 6, 644-656, 26 June 2009 doi:10.1016/j.chembiol.2009.05.010

Amitriptyline is a TrkA and TrkB Receptor Agonist that Promotes TrkA/TrkB Heterodimerization and Has Potent Neurotrophic Activity

Sung-Wuk Jang1,Xia Liu1,Chi-Bun Chan1,David Weinshenker2,Randy A. Hall3,Ge Xiao4andKeqiang Ye1,,

1 Department of Pathology and Laboratory Medicine, Emory University, 615 Michael Street, Atlanta, GA 30322, USA
2 Department of Human Genetics, Emory University, 615 Michael Street, Atlanta, GA 30322, USA
3 Department of Pharmacology, Emory University, 615 Michael Street, Atlanta, GA 30322, USA
4 Centers for Disease Control and Prevention, 4770 Buford Highway, Atlanta, GA 30341, USA

Neurotrophins, the cognate ligands for the Trk receptors, are homodimers and induce Trk dimerization through a symmetric bivalent mechanism. We report here that amitriptyline, an antidepressant drug, directly binds TrkA and TrkB and triggers their dimerization and activation. Amitriptyline, but not any other tricyclic or selective serotonin reuptake inhibitor antidepressants, promotes TrkA autophosphorylation inprimary neurons and induces neurite outgrowth in PC12 cells. Amitriptyline binds the extracellular domain of both TrkA and TrkB and promotes TrkA-TrkB receptor heterodimerization. Truncation of amitriptyline binding motif on TrkA abrogates the receptor dimerization by amitriptyline. Administration of amitriptyline to mice activates both receptors and significantly reduces kainic acid-triggered neuronal cell death. Inhibition of TrkA, but not TrkB, abolishes amitriptyline's neuroprotective effect without impairing its antidepressant activity. Thus, amitriptyline acts as a TrkA and TrkB agonist and possesses marked neurotrophic activity.