Activation of the sigma-1 receptor by haloperidol metabolites facilitates brain-derived neurotrophic factor secretion from human astroglia.
Activation of the sigma-1 receptor by haloperidol metabolites facilitates brain-derived neurotrophic factor secretion from human astroglia.
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DOI：
10.1016/j.neuint.2017.02.003
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发表时间：
2017-05
影响因子：
4.2
通讯作者：
Schetz JA
中科院分区：
文献类型：
--
作者：
Dalwadi DA;Kim S;Schetz JA
神经胶质细胞在神经元支持中起关键作用，包括神经营养因子脑源性神经营养因子（BDNF）的产生和释放。sigma-1受体（S1 R）的激活已被证明可以减轻炎症应激介导的脑损伤，并且有新的证据表明这可能涉及BDNF依赖性机制。在这份报告中，我们研究了S1 R介导的BDNF从人星形胶质细胞的释放。星形胶质细胞表达S1 R，当用原型S1 R激动剂4-PPBP和（+）-SKF 10047刺激时，S1 R介导BDNF释放。这种作用可被选择性浓度的S1 R拮抗剂BD 1063所拮抗。已知氟哌啶醇与S1 R具有高亲和力的相互作用，但它不能促进BDNF的释放。然而，值得注意的是，发现氟哌啶醇的两种代谢产物氟哌啶醇I和氟哌啶醇II（还原氟哌啶醇）促进BDNF分泌，并且这种作用被BD 1063拮抗。通过qPCR评估，4-PPBP和氟哌啶醇代谢产物均不影响BDNF mRNA的水平。这些结果首次证明，氟哌啶醇代谢产物I和II通过作为功能选择性S1 R激动剂促进星形胶质细胞分泌BDNF。
Glial cells play a critical role in neuronal support which includes the production and release of the neurotrophin brain-derived neurotrophic factor (BDNF). Activation of the sigma-1 receptor (S1R) has been shown to attenuate inflammatory stress-mediated brain injuries, and there is emerging evidence that this may involve a BDNF-dependent mechanism. In this report we studied S1R-mediated BDNF release from human astrocytic glial cells. Astrocytes express the S1R, which mediates BDNF release when stimulated with the prototypical S1R agonists 4-PPBP and (+)-SKF10047. This effect could be antagonized by a selective concentration of the S1R antagonist BD1063. Haloperidol is known to have high affinity interactions with the S1R, yet it was unable to facilitate BDNF release. Remarkably, however, two metabolites of haloperidol, haloperidol I and haloperidol II (reduced haloperidol), were discovered to facilitate BDNF secretion and this effect was antagonized by BD1063. Neither 4-PPBP, nor either of the haloperidol metabolites affected the level of BDNF mRNA as assessed by qPCR. These results demonstrate for the first time that haloperidol metabolites I and II facilitate the secretion of BDNF from astrocytes by acting as functionally selective S1R agonists.