Tricyclic antidepressant amitriptyline indirectly increases the proliferation of adult dentate gyrus-derived neural precursors: an involvement of astrocytes.
Tricyclic antidepressant amitriptyline indirectly increases the proliferation of adult dentate gyrus-derived neural precursors: an involvement of astrocytes.
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DOI：
10.1371/journal.pone.0079371
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Takebayashi M
中科院分区：
文献类型：
--
作者：
Boku S;Hisaoka-Nakashima K;Nakagawa S;Kato A;Kajitani N;Inoue T;Kusumi I;Takebayashi M
抗抑郁药可增加成年齿状回神经前体细胞的增殖，这被认为与抗抑郁药的治疗作用有关。然而，其背后的机制仍不清楚。通过使用培养的成年大鼠DG衍生的神经前体（ADP），我们已经表明，抗抑郁药对ADP没有直接影响。因此，抗抑郁药可能通过未知的间接机制增加成年DG中神经前体细胞的增殖。我们还发现，阿米替林（AMI），三环类抗抑郁药，诱导GDNF，BDNF，FGF 2和VEGF，常见的神经源性因子，在原代培养的星形胶质细胞（PCA）的表达。这些结果表明，AMI诱导的星形胶质细胞因子可能会增加成年DG神经前体细胞的增殖。为了验证这一假设，我们研究了AMI诱导的因素和条件培养基（CM）从PCA处理AMI对ADP增殖的影响。用BrdU免疫细胞化学法检测CM及各因素对ADP增殖的影响。ADP细胞表达GDNF、BDNF和FGF 2受体，但不表达VEGF。FGF2显著增加ADP增殖，但不增加BDNF和GDNF。此外，FGF受体特异性抑制剂和抗FGF2抗体均能显著抵消CM对ADP增殖的促进作用。此外，脑中的FGF 2主要来源于星形胶质细胞，星形胶质细胞是成年DG中神经源性龛的关键组分。这表明AMI可能通过PCA间接增加ADP增殖，并且FGF2可能是介导AMI通过星形胶质细胞对ADP增殖的这种间接作用的潜在候选者。
Antidepressants increase the proliferation of neural precursors in adult dentate gyrus (DG), which is considered to be involved in the therapeutic action of antidepressants. However, the mechanism underlying it remains unclear. By using cultured adult rat DG-derived neural precursors (ADP), we have already shown that antidepressants have no direct effects on ADP. Therefore, antidepressants may increase the proliferation of neural precursors in adult DG via unknown indirect mechanism. We have also shown that amitriptyline (AMI), a tricyclic antidepressant, induces the expressions of GDNF, BDNF, FGF2 and VEGF, common neurogenic factors, in primary cultured astrocytes (PCA). These suggest that AMI-induced factors in astrocytes may increase the proliferation of neural precursors in adult DG. To test this hypothesis, we examined the effects of AMI-induced factors and conditioned medium (CM) from PCA treated with AMI on ADP proliferation. The effects of CM and factors on ADP proliferation were examined with BrdU immunocytochemistry. AMI had no effect on ADP proliferation, but AMI-treated CM increased it. The receptors of GDNF, BDNF and FGF2, but not VEGF, were expressed in ADP. FGF2 significantly increased ADP proliferation, but not BDNF and GDNF. In addition, both of a specific inhibitor of FGF receptors and anti-FGF2 antibody significantly counteracted the increasing effect of CM on ADP proliferation. In addition, FGF2 in brain is mainly derived from astrocytes that are key components of the neurogenic niches in adult DG. These suggest that AMI may increase ADP proliferation indirectly via PCA and that FGF2 may a potential candidate to mediate such an indirect effect of AMI on ADP proliferation via astrocytes.
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