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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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Abstract

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 μM MK-801, which reduced the cell viability, was diminished by 100 μM paliperidone using MTT and LDH assays (both p < 0.05). Analysis with Hoechst 33342/PI double staining demonstrated that exposure to MK-801 (100 μM) 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.

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Abbreviations

MK-801:

Dizocilpine

LDH:

Lactate dehydrogenase

MTT:

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide

RT-PCR:

Real-time polymerase chain reaction

CREB:

cAMP-response element binding protein

miR-134:

MicroRNA-134

SIRT1:

Sirtuin 1

NMDA:

N-Methyl-d-aspartic acid

NCS-1:

Neuronal calcium sensor-1

CaV2.1:

Calcium channel, voltage-dependent, P/Q type, alpha 1A subunit

TTX:

Tetrodotoxin

IRS-2:

Insulin receptor substrates-2

Erk:

Extracellular signal-regulated kinase 1/2

MEK:

Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase

IGF-1:

Insulin-like growth factor 1

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Acknowledgments

We thank Guibao Li for applying technical supports in the work. This experiment was supported by the following grants, a grant from the National Natural Science Foundation of China with no.81371471, grants from Natural Science Foundation of Shandong Province with no. ZR2010HM051 and no. ZR2012HM026, and a grant from Shandong Provincial Science and Technology Development Plan with no. 2011GSF11810.

Conflict of Interest

We, all authors, declare that we have no conflicts of interest.

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Authors and Affiliations

  1. Department of Anatomy, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province, 250012, People’s Republic of China

    Dexiao Zhu, Jing Zhang, Jintao Wu, Guibao Li & Jinhao Sun

  2. Department of Physiology, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province, 250012, People’s Republic of China

    Wei Yao

  3. Department of Histology and Embryology, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province, 250012, People’s Republic of China

    Jing Hao

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  1. Dexiao Zhu
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Correspondence to Jinhao Sun.

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Zhu, D., Zhang, J., Wu, J. et al. Paliperidone Protects SH-SY5Y Cells Against MK-801-Induced Neuronal Damage Through Inhibition of Ca2+ Influx and Regulation of SIRT1/miR-134 Signal Pathway. Mol Neurobiol 53, 2498–2509 (2016). https://doi.org/10.1007/s12035-015-9217-z

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