Relationship between thyroid hormone and sex hormone levels and non-suicidal self-injury in male adolescents with depression.

Objective: Non-suicidal self-injury (NSSI) is the intentional and repeated direct injury to one's bodily tissues or organs without the intent to die, which is not socially sanctioned and does not result in death. This study will be the first to explore the relationship between NSSI behavior and thyroid hormone and sex hormone levels in male adolescents with depression. Methods: Among the inpatients in the children's ward of Shandong Mental Health Center, eighty male patients with first-episode depressive disorder were randomly selected. Forty male adolescent depressed patients with NSSI behaviors were set as the NSSI group, and forty male adolescent depressed patients without NSSI behaviors were set as the No-NSSI group. Their thyroid hormones (free triiodothyronine, free thyroxine, and thyroid stimulating hormone) and sex hormones (estradiol, progesterone, and testosterone) were measured, and the severity of self-injury in the NSSI group was assessed using the Adolescent Self-Injury Questionnaire. The NSSI group was tested again after 6 weeks of sertraline treatment for biological indicators and assessed by the Self-Injury Questionnaire to compare the hormonal differences between the NSSI group and the No-NSSI group and compare the differences of each index before and after treatment in the NSSI group. Results: T3/T4 (p = 0.001) and FT3 (p = 0.023), TSH levels (p < 0.001) were lower in the NSSI group than in the No-NSSI group before treatment, and FT4 (p = 0.036) and T (p < 0.001) levels were higher than in the No-NSSI group. T3/T4 levels were higher in the NSSI group after treatment (p < 0.001). FT4 (p < 0.001) and T (p = 0.001) levels and self-injury questionnaire scores (p < 0.001) decreased after treatment in the NSSI group. In the NSSI group at baseline, FT4 levels were negatively correlated with self-injury questionnaire scores (r = -0.459, p = 0.003) and testosterone levels were positively correlated with self-injury questionnaire scores (r = 0.383, p = 0.015), and in the NSSI group after treatment, FT4 difference was negatively correlated with self-injury questionnaire score reduction rate (r = -0.037, p = 0.019), and testosterone difference was positively correlated with self-injury questionnaire score reduction rate (r = 0.424, p = 0.006). Logistic regression analysis showed that low TSH and high testosterone levels were independent risk factors for the development of non-suicidal self-harming behaviors in male adolescent depressed patients. Conclusion: Changes in thyroid hormone and sex hormone levels may be associated with non-suicidal self-injurious behavior in male adolescent depressed patients.

Associations of C-Reactive Protein, Free Triiodothyronine, Thyroid Stimulating Hormone and Creatinine Levels with Agitation in Patients with Schizophrenia: A Comparative Cross-Sectional Study.

PURPOSE: Agitation is prevalent among inpatients with schizophrenia. The aim of this study was to investigate whether biochemical parameters are associated with agitation in schizophrenia. PATIENTS AND METHODS: Agitation was evaluated by the Positive and Negative Syndrome Scale-Excited Component questionnaire (PANSS-EC). Fasting serum levels of C-reactive protein (CRP), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), uric acid (UA), creatinine, glucose and lipids were measured. RESULTS: The analysis included 154 inpatients with schizophrenia (71 with agitation, 83 without agitation) and 75 healthy control subjects. Patients with schizophrenia and agitation had higher serum levels of CRP, FT3, FT4 and UA as well as lower levels of serum TSH and creatinine than patients without agitation (all P < 0.05). Multivariate logistic regression analysis indicated that serum CRP (odds ratio [OR] = 1.470, P = 0.001), FT3 (OR = 13.026, P < 0.001), TSH (OR = 0.758, P = 0.033) and creatinine (OR = 0.965, P = 0.004) were significantly associated with agitation in schizophrenia. CRP, FT3, TSH and creatinine achieved an area under the ROC curve of 0.626, 0.728, 0.620 and 0.663 respectively in discriminating schizophrenia with or without agitation. CONCLUSION: Increased serum CRP and FT3 levels and decreased serum TSH and creatinine levels are independent risk factors for agitation in hospitalized patients with schizophrenia. Inflammation, thyroid hormones and renal function may be involved in the pathogenesis of agitation in schizophrenia.

Effect of Molybdenum on the Impact Toughness of Heat-Affected Zone in High-Strength Low-Alloy Steel.

The microstructure, precipitates, and austenite grain in high-strength low-alloy steel were characterized by optical microscope, transmission electron microscope, and laser scanning confocal microscopy to investigate the effect of Mo on the toughness of steel. The microstructure was refined and the toughness was enhanced after the addition of 0.07% Mo in steel. The addition of Mo can suppress the Widmanstätten ferrite (WF) formation and promote the transformation of acicular ferrite (AF), leading to the fine transformed products in the heat-affected zone (HAZ). The chemical composition of precipitates changed from Nb(C, N) to (Nb, Mo)(C, N) because of the addition of Mo. The calculated lattice misfit between Nb(C, N) and ferrite was approximately 11.39%, while it was reduced to 5.40% for (Nb, Mo)(C, N), which significantly affected the size and number density of precipitates. A detailed analysis of the precipitates focusing on the chemical composition, size, and number density has been undertaken to understand the contribution of Mo on the improvement of steel toughness.

Astragalus protects PC12 cells from 6-hydroxydopamine-induced neuronal damage: A serum pharmacological study.

Accumulating evidence has already indicated that traditional Chinese medicine (TCM) possesses tremendous potential for treating neurodegenerative diseases. Astragalus, also named Huangqi, is a famous traditional medical herb that can be applied to treat cerebral ischemia and prevent neuronal degeneration. Nevertheless, the underlying mechanisms remain largely unexplored. In the present study, Astragalus-containing serum (ASMES) was prepared and added into the culture medium of PC12 cells to explore its neuroprotective effect on 6-hydroxydopamine (6-OHDA)-caused neuronal toxicity. Our data showed that ASMES significantly ameliorated the cellular viability of cultured PC12 cells against the neurotoxicity induced by 6-OHDA (P < 0.05). Moreover, ASMES significantly decreased the cell apoptosis triggered by 6-OHDA (P < 0.01). Furthermore, 2',7'-dichlorofluorescin diacetate assay was performed to detect the changes in oxidative stress, and we showed that 6-OHDA elevated the production of reactive oxygen species (ROS), whereas ASMES significantly reversed these changes (P < 0.01). Besides, mitochondrial membrane potential (MMP) assay showed that ASMES could restore 6-OHDA-damaged MMP in cultured PC12 cells (P < 0.05). In conclusion, Astragalus could protect PC12 cells from 6-OHDA-caused neuronal toxicity, and possibly, the ROS-mediated apoptotic pathway participated in this process. Collectively, our findings provided valuable insights into the potential in treatment of neurodegenerative diseases.

Transplantation of fecal microbiota from patients with alcoholism induces anxiety/depression behaviors and decreases brain mGluR1/PKC ε levels in mouse.

Recent studies have revealed that the gut microbiota participates in the psychiatric behavior changes in disorders associated with alcohol. But it still remains unknown whether alcoholism is involved in changes in gut microbiota and its underlying mechanism is also not clear. Here, we tested the gut microbiota of patients with alcoholism and conducted fecal microbiota transplantation (FMT) from patients with alcoholism to C57BL/6J mice whose gut microbiota had been sharply suppressed with antibiotics (ABX). Then we evaluated their alcohol preference degree, anxiety, and depression-like behaviors and social interaction behaviors, together with molecular changes in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). Our data indicated that the gut microbiota of patients with alcoholism was drastically different from those of the healthy adults. The abundance of p_Firmicutes was significantly increased whereas p_Bacteroidetes was decreased. Compared to mice transplanted with fecal microbiota from healthy male adults, the mice accepting fecal microbiota from patients with alcoholism showed (a) anxiety-like and depression-like behaviors, (b) decreased social interaction behaviors, (c) spontaneous alcohol preference, and (d) decreased brain-derived neurotrophic factor (BDNF), alpha 1 subunit of GABA type A receptor (α1GABAA R) in mPFC and decreased metabotropic glutamate receptors 1 (mGluR1), protein kinase C (PKC) ε in NAc. Overall, our results suggest that fecal microbiota from patients with alcoholism did induce a status like alcohol dependence in C57BL/6J mice. The decreased expression of BDNF, α1GABAA R, and mGluR1/ PKC ε may be the underlying mechanism.

Chronic alcohol exposure induced gut microbiota dysbiosis and its correlations with neuropsychic behaviors and brain BDNF/Gabra1 changes in mice.

Alcohol addiction can cause brain dysfunction and many other diseases. Recently, increasing evidences have suggested that gut microbiota plays a vital role in regulating alcohol addiction. However, the exact mechanism has not yet been elucidated. Here, our study focused on the intestinal bacteria alternations and their correlations with alcohol-induced neuropsychic behaviors. When consuming alcohol over 3-week period, animals gradually displayed anxiety/depression-like behaviors. Moreover, 16S rRNA sequencing showed significant intestinal microflora dysbiosis and distinct community composition. Actinobacteria and Cyanobacteria were both increased at the phylum level. At the genus level, Adlercreutzia spp., Allobaculum spp., and Turicibacter spp. were increased whereas Helicobacter spp. was decreased. We also found that the distances in inner zone measured by open field test and 4% (v/v) alcohol preference percentages were significantly correlated with Adlercreutzia spp. The possible mechanisms were explored and we found the expression of brain-derived neurotrophic factor (BDNF) and α1 subunit of γ-aminobutyric acid A receptor (Gabra1) were both decreased in prefrontal cortex (PFC). Especially, further correlation analyses demonstrated that decreased Adlercreutzia spp. was positively correlated with alcohol preference and negatively correlated with anxiety-like behavior and BDNF/Gabra1 changes in PFC. Similar relationships were observed between Allobaculum spp. and alcohol preference and BDNF changes. Helicobacter spp. and Turicibacter spp. were also correlated with PFC BDNF and hippocampus Gabra1 level. Taken together, our study showed that gut microbiota dysbiosis during chronic alcohol exposure was closely correlated with alcohol-induced neuropsychic behaviors and BDNF/Gabra1 expression, which provides a new perspective for understanding underlying mechanisms in alcohol addiction. © 2018 BioFactors, 45(2):187-199, 2019.

Fecal Microbiota Transplantation from Healthy Donors Reduced Alcohol-induced Anxiety and Depression in an Animal Model of Chronic Alcohol Exposure.

Alcohol addiction can cause brain dysfunction and threatens both individuals and society. Recently, emerging studies have suggested the dysbiosis of gut microbiota induced by alcohol exposure contributed to the reward-seeking behaviors as well as anxiety, depression. In the current study, animal model of chronic alcohol exposure was established by providing mice with gradient concentrations of alcohol from 2%, 4%, and 6% to 8% for 21 days. Moreover, three fecal microbiota transplantation (FMT) plans were innovatively designed to explore the potential effects of FMT from 3 healthy donors on alcohol-induced neuropsychic behaviors. To our knowledge, for the first time, we found that anxiety and depression after alcohol intake were gradually relieved with the extension of transplantation. Although the two-week FMT starting at the end of alcohol treatment had few effects, the transplantation started at 8% ethanol exposure alleviated alcohol-induced depression in tail suspension test. More importantly, accompanied by three-week exposure, the five-week FMT significantly decreased anxiety-like behaviors in open field test and depression in tail suspension test. These data validated the role of gut microbiota in alcohol addiction and indicated the modulation of healthy donor FMT on alcohol-related anxiety and depression, providing a new target for treating alcohol addiction by targeting microbiota.

Escitalopram augmentation improves negative symptoms of treatment resistant schizophrenia patients - A randomized controlled trial.

Serum interleukin (IL)-6 levels in schizophrenia correlate with the severity of negative symptoms. This study aimed to explore the potential immune mechanism of SSRI augmentation in the management of patients with treatment-resistant schizophrenia, assessing changes in IL-6 and CRP amounts. This was a randomized double-blind, placebo-controlled, 8-week study of escitalopram augmentation in 62 schizophrenic patients treated in 2016-2017 at the Shandong Mental Health Center. Twenty-nine healthy controls were also included. Patients received add-on escitalopram or placebo for 8 weeks. Serum IL-6 and CRP were measured at baseline and 8 weeks. The primary outcome was the Positive and Negative Syndrome Scale (PANSS). After 8 weeks of treatment, reductions in total PANSS, negative subscore, and affective subscore were more important in escitalopram treated patients than in the placebo group (all P < 0.05). Escitalopram significantly decreased CRP and IL-6 levels (both P < 0.05). At baseline, IL-6's effects on negative and cognitive symptoms represented 16.2% and 20.1%, respectively; at week 8, these effects were 22.7% and 20.8% on negative and cognitive symptoms, respectively. CRP had no impact on any PANSS score. Overall, escitalopram augmentation may be a useful addition for schizophrenic patients with persistent negative symptoms. Changes in IL-6 may be associated with negative and cognitive symptoms.

Resveratrol Suppresses Rotenone-induced Neurotoxicity Through Activation of SIRT1/Akt1 Signaling Pathway.

Rotenone is a common pesticide and has been reported as one of the risk factors for Parkinson disease. Rotenone can cause neuronal death or apoptosis through inducing oxidative injury and inhibiting mitochondrial function. As a natural polyphenolic compound, resveratrol possesses the antioxidant capacity and neuroprotective effect. However, the mechanism underlying the neuroprotective effect of resveratrol against rotenone-induced neurotoxicity remains elusive. Here, we treated PC12 cells with rotenone to induce neurotoxicity, and the neurotoxic cells were subjected to resveratrol treatment. The CCK8 and LDH activity assays demonstrated that resveratrol could suppress neurotoxicity induced by rotenone (P < 0.01). The DCFH-DA assay indicated that resveratrol reduced the production of reactive oxygen species (ROS). JC-1 and Hoechst 33342/PI staining revealed that resveratrol attenuated mitochondrial dysfunction and cell apoptosis. Moreover, resveratrol reversed rotenone-induced decrease in SIRT1 expression and Akt1 phosphorylation (P < 0.05). Furthermore, when the SIRT1 and Akt1 activity was inhibited by niacinamide and LY294002, respectively, the neuroprotective effect of resveratrol was remarkably attenuated, which implied that SIRT1 and Akt1 could mediate this process and may be potential molecular targets for intervening rotenone-induced neurotoxicity. In summary, our study demonstrated that resveratrol reduced rotenone-induced oxidative damage, which was partly mediated through activation of the SIRT1/Akt1 signaling pathway. Our study launched a promising avenue for the potential application of resveratrol as a neuroprotective therapeutic agent in Parkinson disease. Anat Rec, 301:1115-1125, 2018. © 2018 Wiley Periodicals, Inc.

The maintenance of modified electroconvulsive therapy combined with risperidone is better than risperidone alone in preventing relapse of schizophrenia and improving cognitive function.

OBJECTIVE: To evaluate the effect of maintenance modified electroconvulsive therapy (MECT) on schizophrenic patients. METHODS: From June 2012 to June 2014, 62 patients with schizophrenia, who had recovered from a successful course of acute MECT, were recruited. Thirty-one patients received maintenance MECT and risperidone, as the experimental group. Another 31 patients were enrolled in the control group, and received risperidone only. The effects on cognitive functions, clinical symptoms and relapse rate were determined. RESULTS: Patients in the experimental group had a lower relapse rate and longer relapse-free survival time than the controls. Relative to the baseline evaluation, patients showed statistically significant improvement in verbal memory and visual memory. At the final assessment, the scores of verbal and visual memory were remarkably lower in the experimental group than the controls but there was no significant difference in other tests. CONCLUSION: Maintenance MECT plus medication is superior to medication alone in preventing relapse and improving cognitive function.

The maintenance of modified electroconvulsive therapy combined with risperidone is better than risperidone alone in preventing relapse of schizophrenia and improving cognitive function / Manutenção de eletroconvulsoterapia modificada combinada com risperidona é melhor do que a risperidona isoladamente na prevenção de recidivas de esquizofrenia e melhoras da função cognitiva

ABSTRACT Objective To evaluate the effect of maintenance modified electroconvulsive therapy (MECT) on schizophrenic patients. Methods From June 2012 to June 2014, 62 patients with schizophrenia, who had recovered from a successful course of acute MECT, were recruited. Thirty-one patients received maintenance MECT and risperidone, as the experimental group. Another 31 patients were enrolled in the control group, and received risperidone only. The effects on cognitive functions, clinical symptoms and relapse rate were determined. Results Patients in the experimental group had a lower relapse rate and longer relapse-free survival time than the controls. Relative to the baseline evaluation, patients showed statistically significant improvement in verbal memory and visual memory. At the final assessment, the scores of verbal and visual memory were remarkably lower in the experimental group than the controls but there was no significant difference in other tests. Conclusion Maintenance MECT plus medication is superior to medication alone in preventing relapse and improving cognitive function.

RESUMO Objetivo Avaliar o efeito da manutenção de eletroconvulsoterapia modificada (ECTM) em pacientes com esquizofrenia. Métodos Entre junho de 2012 a junho de 2014, 62 pacientes, com esquizofrenia e que apresentaram recuperação bem-sucedida após ECTM aguda, foram recrutados. Um grupo experimental de trinta e um pacientes recebeu ECTM de manutenção e risperidona. Os demais pacientes foram incluídos no grupo controle, recebendo apenas a risperidona. Determinou-se os efeitos sobre as funções cognitivas, os sintomas clínicos e a taxa de recidiva. Resultados Os pacientes do grupo experimental tiveram menor taxa de recidiva e maior tempo de sobrevida livre de recidiva do que os do grupo controle. Em relação à avaliação inicial, os pacientes apresentaram melhora estatisticamente significativa da memória verbal e da memória visual. Na avaliação final, os escores de memória verbal e visual foram extraordinariamente menores no grupo experimental do que no grupo controle, mas não se observou diferenças significativas em outros testes. Conclusão A ECTM de manutenção combinada à medicação é superior ao uso apenas de medicação na prevenção de recidivas e na melhora da função cognitiva.

The risk of male adult alcohol dependence: The role of the adverse childhood experiences and ecological executive function.

OBJECTIVE: To explore the association between male adult alcohol dependence and their adverse childhood experiences as well as ecological executive function. METHODS: The questionnaires of Adverse Childhood Experiences (ACEs) and Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) were adopted for the assessments of 102 alcohol dependent patients who were diagnosed according to the criteria defined by the International Classification of diseases and related health problems (ICD-10) and 106 healthy volunteers, and the differences between patients and healthy volunteers were analyzed. RESULTS: The percentage of adverse childhood experiences in alcohol dependent patients was significantly higher than that in healthy volunteers (χ(2)=17.28, P<0.01); and the incidences of emotional abuse, physical neglect, violence witness, and substance abuse were significantly higher in alcohol dependent patients than those in healthy volunteers (χ(2)=4.59, 4.46, 10.51, and 44.09 respectively; P<0.05). The ecological executive function analysis showed that the BRIEF total score and scores for each item were all significantly higher in alcohol dependent patients than those of healthy volunteers (P<0.01). CONCLUSIONS: The adult alcohol dependence was associated with their adverse childhood experiences and ecological executive function. Then physical neglect and substance abuse of parents in childhood, and emotional control defect in the ecological executive function showed strong association with adult alcohol dependence.

Melatonin treatment during the incubation of sensitization attenuates methamphetamine-induced locomotor sensitization and MeCP2 expression.

Behavior sensitization is a long-lasting enhancement of locomotor activity after exposure to psychostimulants. Incubation of sensitization is a phenomenon of remarkable augmentation of locomotor response after withdrawal and reflects certain aspects of compulsive drug craving. However, the mechanisms underlying these phenomena remain elusive. Here we pay special attention to the incubation of sensitization and suppose that the intervention of this procedure will finally decrease the expression of sensitization. Melatonin is an endogenous hormone secreted mainly by the pineal gland. It is effective in treating sleep disorder, which turns out to be one of the major withdrawal symptoms of methamphetamine (MA) addiction. Furthermore, melatonin can also protect neuronal cells against MA-induced neurotoxicity. In the present experiment, we treated mice with low dose (10mg/kg) of melatonin for 14 consecutive days during the incubation of sensitization. We found that melatonin significantly attenuated the expression of sensitization. In contrast, the vehicle treated mice showed prominent enhancement of locomotor activity after incubation. MeCP2 expression was also elevated in the vehicle treated mice and melatonin attenuated its expression. Surprisingly, correlation analysis suggested significant correlation between MeCP2 expression in the nucleus accumbens (NAc) and locomotion in both saline control and vehicle treated mice, but not in melatonin treated ones. MA also induced MeCP2 over-expression in PC12 cells. However, melatonin failed to reduce MeCP2 expression in vitro. Our results suggest that melatonin treatment during the incubation of sensitization attenuates MA-induced expression of sensitization and decreases MeCP2 expression in vivo.

Lithium protects against methamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3ß/mTOR pathway.

Methamphetamine (MA) is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to MA causes psychosis and increases the risk of Parkinson's disease. Lithium (Li) is a known mood stabilizer and has neuroprotective effects. Previous studies suggest that MA exposure decreases the phosphorylation of Akt/GSK3ß pathway in vivo, whereas Li facilitates the phosphorylation of Akt/GSK3ß pathway. Moreover, GSK3ß and mTOR are implicated in the locomotor sensitization induced by psychostimulants and mTOR plays a critical role in MA induced toxicity. However, the effect of MA on Akt/GSK3ß/mTOR pathway has not been fully investigated in vitro. Here, we found that MA exposure significantly dephosphorylated Akt/GSK3ß/mTOR pathway in PC12 cells. In addition, Li remarkably attenuated the dephosphorylation effect of MA exposure on Akt/GSK3ß/mTOR pathway. Furthermore, Li showed obvious protective effects against MA toxicity and LY294002 (Akt inhibitor) suppressed the protective effects of Li. Together, MA exposure dephosphorylates Akt/GSK3ß/mTOR pathway in vitro, while lithium protects against MA-induced neurotoxicity via phosphorylation of Akt/GSK3ß/mTOR pathway.

Neuroprotection of resveratrol against neurotoxicity induced by methamphetamine in mouse mesencephalic dopaminergic neurons.

Resveratrol is originally extracted from huzhang, a Chinese herbal medicine. Recently, resveratrol has attracted a great of attention due to its antioxidant and antiapoptotic properties. Although the neuroprotection of resveratrol on neural damages in various models has been well characterized, little is known about the role of resveratrol in methamphetamine (MA) induced neurotoxicity in mesencephalic dopaminergic neurons. Dopaminergic neurons were isolated from midbrain of mouse embryos at embryonic day 15 and cultured in the presence of MA and resveratrol. Cell viability was examined by MTT assay and the apoptosis was assessed using Hoechst33342/PI double staining. To evaluate the Oxidative damage, ROS assay was performed. Moreover, the changes of time course of intracellular free calcium concentration ([Ca(2+) ]i) were analyzed with Fluo-3/AM tracing. The data showed that MA induced the neurotoxicity of cultured cells in a dose-dependent manner. Resveratrol significantly increased cellular viability and retarded cell apoptosis. Furthermore, resveratrol also attenuated MA induced ROS production and intracellular free calcium overload. Our results suggest that resveratrol protects dopaminergic neurons from MA-induced neuronal cytotoxicity, which, at least partly, is mediated by inhibition of [Ca(2+) ]i and oxidative stress. © 2015 BioFactors 41(4):252-260, 2015.

HIV transactivator of transcription enhances methamphetamine-induced Parkinson's-like behavior in the rats.

Abuse of methamphetamine (MA) increases the risk of infection of HIV-1, induces considerable neurotoxicity in several brain regions, and impairs the motor and cognitive function in individuals. HIV-1 transactivator of transcription (Tat) has also shown the potent capability to induce neuronal death and impaired brain function. The present study aims to study the synergistic effect of MA and Tat on cytokine synthesis in substantia nigra, striatal dopamine content, and behavioral performance in the rats. Although increased expression of cytokines (interleukin-1ß and tumor necrosis factor-α) was observed in the substantia nigra in the rats receiving either MA or Tat alone, a combination of MA and Tat induced a larger and more sustained upregulation of cytokines. In the rats receiving either MA or Tat alone, significant loss in striatal dopamine content was found, which was further exacerbated in the rats receiving both MA and Tat. In the rats receiving either MA or Tat alone, significantly lower performance in the rotarod test and open-field test was observed, whereas the rats receiving both MA and Tat showed more sustained behavioral impairments. These results suggested that Tat protein synergized with MA to induce central neuroinflammation and impair the dopaminergic transmission, thus leading to sustained Parkinson's-like behavior.

Paliperidone protects prefrontal cortical neurons from damages caused by MK-801 via Akt1/GSK3ß signaling pathway.

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 GSK3ß (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/GSK3ß signaling pathway.