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Paliperidone protects prefrontal cortical neurons from damages caused by MK-801 via Akt1/GSK3β signaling pathway

Schizophrenia Research, 1, 147, pages 14 - 23

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 reveled that paliperidone effectively attenuated the elevation of intracellular free calcium concentration ([Ca2 +]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 (bothp < 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.

Keywords: Paliperidone, Protection, Schizophrenia, Prefrontal cortical neurons.

Footnotes

a Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China

b Department of Histology and Embryology, Shandong University School of Medicine, Jinan, Shandong 250012, China

c Department of Pharmacy, Shandong University School of Pharmacy, Jinan, Shandong 250012, China

d Department of Psychiatry, Shandong University School of Medicine, Jinan, Shandong 250012, China

lowast Corresponding author. Tel./fax: + 86 531 88382093.