title: Paliperidone protects prefrontal cortical neurons from damages caused by MK-801 via Akt1/GSK3β signaling pathway.
abstract: Recent studies have suggested that neurodegeneration is involved in the pathogenesis of schizophrenia, and some atypical antipsychotics appear to prevent or retard progressive morphological brain changes. However, the underlying molecular mechanisms are largely unknown. Whether changes in intracellular signaling pathways are related to their neuroprotective effects remains undefined. In the present study, we used mouse embryonic prefrontal cortical neurons to examine the neuroprotection of paliperidone against the neuronal damage induced by exposure to the NMDA receptor antagonist, MK-801. Paliperidone inhibited MK-801 induced neurotoxicity both in MTT metabolism assay (p<0.01) and in lactate dehydrogenase (LDH) activity assay (p<0.01). Time course studies revealed that paliperidone effectively attenuated the elevation of intracellular free calcium concentration ([Ca(2+)]i) induced by exposure to MK-801 (p<0.01). Moreover, paliperidone could significantly retard MK-801-mediated inhibition of neurite outgrowth (p<0.01) and reverse MK-801-induced decreases of gene expression and phosphorylation of Akt1 and GSK3β (both p<0.01). Furthermore, these protective effects of paliperidone were blocked by pretreatment with a PI3K inhibitor LY294002. Taking together, our results demonstrated that paliperidone could protect prefrontal cortical neurons from MK-801-induced damages via Akt1/GSK3β signaling pathway.
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Peng
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Dexiao
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Feng
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Haiman
authors.initials: H
authors.lastname: Dong
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Yue
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Histology and Embryology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Histology and Embryology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Pharmacy, Shandong University School of Pharmacy, Jinan, Shandong 250012, China.
authors.forename: Xingzhen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Zengxun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China. Electronic address: sunjinhao@sdu.edu.cn.
authors.forename: Jinhao
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007555:Isoxazoles / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D016501:Neurites / Q000187:drug effects / Q000201:enzymology; D009474:Neurons / Q000187:drug effects*; D000068882:Paliperidone Palmitate; D017397:Prefrontal Cortex / Q000166:cytology*; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007555:Isoxazoles; D011743:Pyrimidines; D016291:Dizocilpine Maleate; D007770:L-Lactate Dehydrogenase; C514862:Akt1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000068882:Paliperidone Palmitate; D002118:Calcium