PDF(Pubmed)
Abstract：
There is some evidence that the serotonin receptor subtype 7 (5-HT7) could be new therapeutic target for neuroprotection. The aim of this study was to compare the neuroprotective and neurite outgrowth potential of new 5-HT7 receptor agonists (AH-494, AGH-238, AGH-194) with 5-CT (5-carboxyamidotryptamine) in human neuroblastoma SH-SY5Y cells. The results revealed that 5-HT7 mRNA expression was significantly higher in retinoic acid (RA)-differentiated cells when compared to undifferentiated ones and it was higher in cell cultured in neuroblastoma experimental medium (DMEM) compared to those placed in neuronal (NB) medium. Furthermore, the safety profile of compounds was favorable for all tested compounds at concentration used for neuroprotection evaluation (up to 1 μM), whereas at higher concentrations (above 10 μM) the one of the tested compounds, AGH-194 appeared to be cytotoxic. While we observed relatively modest protective effects of 5-CT and AH-494 in UN-SH-SY5Y cells cultured in DMEM, in UN-SH-SY5Y cells cultured in NB medium we found a significant reduction of H2O2-evoked cell damage by all tested 5-HT7 agonists. However, 5-HT7-mediated neuroprotection was not associated with inhibition of caspase-3 activity and was not observed in RA-SH-SY5Y cells exposed to H2O2. Furthermore, none of the tested 5-HT7 agonists altered the damage induced by 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenylpyridinium ion (MPP +) and doxorubicin (Dox) in UN- and RA-SH-SY5Y cells cultured in NB. Finally we showed a stimulating effect of AH-494 and AGH-194 on neurite outgrowth. The obtained results provide insight into neuroprotective and neurite outgrowth potential of new 5-HT7 agonists.
摘要：
有证据表明5-羟色胺受体亚型7（5-HT7）可能是神经保护的新治疗靶标。这项研究的目的是比较新的5-HT7受体激动剂（AH-494，AGH-238，AGH-194）与5-CT（5-羧基酰胺胺）在人神经母细胞瘤SH-SY5Y细胞中的神经保护和神经突生长潜力。结果表明，与未分化的细胞相比，视黄酸（RA）分化的细胞中的5-HT7mRNA表达明显更高，而在神经母细胞瘤实验培养基（DMEM）中培养的细胞中的5-HT7mRNA表达高于神经元（NB）培养基。此外，在用于神经保护评估的浓度（高达1μM）下，化合物的安全性对所有测试化合物都是有利的，而在较高浓度（高于10μM）的测试化合物之一，AGH-194似乎是细胞毒性的。虽然我们观察到5-CT和AH-494在DMEM中培养的UN-SH-SY5Y细胞中的相对适度的保护作用，在NB培养基中培养的UN-SH-SY5Y细胞中，我们发现所有测试的5-HT7激动剂均显着降低了H2O2诱发的细胞损伤。然而,5-HT7介导的神经保护与caspase-3活性的抑制无关，并且在暴露于H2O2的RA-SH-SY5Y细胞中未观察到。此外，所测试的5-HT7激动剂均未改变6-羟基多巴胺（6-OHDA）诱导的损伤，在NB中培养的UN-和RA-SH-SY5Y细胞中的1-甲基-4-苯基吡啶鎓离子（MPP）和多柔比星（Dox）。最后，我们显示了AH-494和AGH-194对神经突生长的刺激作用。获得的结果提供了对新的5-HT7激动剂的神经保护和神经突生长潜力的洞察。
