Paliperidone Protects SH-SY5Y Cells Against MK-801-Induced Neuronal Damage Through Inhibition of Ca2+ Influx and Regulation of SIRT1/miR-134 Signal Pathway
Paliperidone Protects SH-SY5Y Cells Against MK-801-Induced Neuronal Damage Through Inhibition of Ca2+ Influx and Regulation of SIRT1/miR-134 Signal Pathway
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Paliperidone 通过抑制 Ca(2) 流入和调节 SIRT1/miR-134 信号通路来保护 SH-SY5Y 细胞免受 MK-801 诱导的神经元损伤。
DOI：
10.1007/s12035-015-9217-z
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发表时间：
2016-05-01
影响因子：
5.1
通讯作者：
Sun, Jinhao
中科院分区：
文献类型：
--
作者：
Zhu, Dexiao;Zhang, Jing;Sun, Jinhao
精神分裂症是一种严重的精神病。近年来，越来越多的证据支持精神分裂症患者脑内发生神经退行性变，并伴有进行性形态学改变。帕利哌酮是一种非典型的抗精神病药物，可减轻精神病症状，保护神经元免受各种应激。然而，其潜在的机制在很大程度上是未知的。在这项研究中，我们使用SH-SY 5 Y细胞来评估帕利哌酮对N-甲基-d-天冬氨酸受体拮抗剂MK-801诱导的神经毒性的神经保护能力。并对可能的分子机制进行了探讨。使用MTT和LDH测定，100 μ M MK-801的神经毒性降低了细胞活力，100 μ M帕潘立酮降低了神经毒性（均p < 0.05）。Hoechst 33342/PI双染色分析表明，暴露于MK-801（100 μ M）24 h导致30%的培养细胞死亡（p < 0.05）。采用膜片钳技术检测电压型钙通道的变化，结果表明帕利哌酮通过抑制电压型钙通道，有效地阻断了钙内流（p < 0.05）。此外，帕利哌酮显着逆转MK-801诱导的SIRT 1表达增加和miR-134表达减少（均p < 0.05）。最后，SIRT 1抑制剂烟酰胺阻断MK-801损伤效应并抑制miR-134表达。综上所述，我们的研究结果表明，帕潘立酮可以通过抑制Ca 2+内流和调节SIRT 1/miR-134途径来保护SH-SY 5 Y细胞免受MK-801诱导的神经毒性，为精神分裂症提供了一个有希望和潜在的治疗靶点。
Schizophrenia is a serious psychotic disease. Recently, increasing evidences support that neurodegeneration occurs in the brain of schizophrenia patients with progressive morphological changes. Paliperidone, an atypical antipsychotic drug, could attenuate psychotic symptom and protect neurons from different stressors. However, the underlying mechanisms are largely unknown. In this study, we used SH-SY5Y cells to evaluate the neuroprotective capability of paliperidone against the neurotoxicity induced by N-methyl-d-aspartate receptor antagonist, MK-801. And, we also explored the possible molecular mechanism. Neurotoxicity of 100 mu M MK-801, which reduced the cell viability, was diminished by 100 mu M paliperidone using MTT and LDH assays (both p < 0.05). Analysis with Hoechst 33342/PI double staining demonstrated that exposure to MK-801 (100 mu M) for 24 h led to the death of 30 % of cultured cells (p < 0.05). Moreover, the patch clamp technique was employed to detect voltage calcium channel changes; the results showed that paliperidone effectively blocked the Ca2+ influx through inhibiting the voltage-gated calcium channels (p < 0.05). Furthermore, paliperidone significantly reversed MK-801 induced increase of SIRT1 and decrease of miR-134 expression (both p < 0.05). Finally, SIRT1 inhibitor nicotinamide blocked MK-801 injury effects and suppressed miR-134 expression. Taken together, our results demonstrated that paliperidone could protect SH-SY5Y cells against MK-801 induced neurotoxicity via inhibition of Ca2+ influx and regulation of SIRT1/miR-134 pathway, providing a promising and potential therapeutic target for schizophrenia.