title: Paliperidone Protects SH-SY5Y Cells Against MK-801-Induced Neuronal Damage Through Inhibition of Ca(2+) Influx and Regulation of SIRT1/miR-134 Signal Pathway.
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 Ca(2+) 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 Ca(2+) influx and regulation of SIRT1/miR-134 pathway, providing a promising and potential therapeutic target for schizophrenia.
authors.affiliation: Department of Anatomy, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province, 250012, People's Republic of China.
authors.forename: Dexiao
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Anatomy, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province, 250012, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Anatomy, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province, 250012, People's Republic of China.
authors.forename: Jintao
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Anatomy, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province, 250012, People's Republic of China.
authors.forename: Guibao
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Physiology, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province, 250012, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Histology and Embryology, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province, 250012, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Anatomy, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong Province, 250012, People's Republic of China. sunjinhao@gmail.com.
authors.forename: Jinhao
authors.initials: J
authors.lastname: Sun
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D009536:Niacinamide / Q000494:pharmacology; D000068882:Paliperidone Palmitate / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015220:Calcium Channels; C569273:MIRN134 microRNA, human; D035683:MicroRNAs; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009536:Niacinamide; D016291:Dizocilpine Maleate; D056564:Sirtuin 1; D000068882:Paliperidone Palmitate; D002118:Calcium
keywords: MK-801; Neuroprotection; Paliperidone; Schizophrenia