Comparison of olanzapine-induced weight gain and metabolism abnormalities between topiramate and vitamin C in patients with schizophrenia: a preliminary study.

Background: Topiramate (TPM) may reduce olanzapine (OLZ)-related weight gain and metabolism abnormalities in patients with schizophrenia. However, differences in the efficacy of OLZ-related weight gain and metabolism abnormalities between TPM and vitamin C (VC) are not clear. This study aimed to investigate whether TPM is more effective than VC in reducing OLZ-induced weight gain and metabolic abnormalities in patients with schizophrenia and explore their patterns. Methods: This was a 12-week longitudinal comparison study in OLZ-treated patients with schizophrenia. Twenty-two patients who received OLZ monotherapy plus VC treatment (OLZ + VC group) was matched to 22 patients who received OLZ monotherapy plus TPM treatment (OLZ + TPM group). Body mass index (BMI) and metabolism indicators were measured at baseline and 12-weeks follow-up. Results: A significant difference in triglyceride (TG) levels at different time points (pre-treatment: F = 7.89, p = 0.008; 4-weeks treatment: F = 13.19, p = 0.001; 12-weeks treatment: F = 54.48, p < 0.001) was found. Latent profile analysis demonstrated that a 2-class model for OLZ + TPM group (high vs. low BMI in the first 4 weeks) and OLZ + VC group (high vs. low), respectively. Conclusion: Our findings suggested that TPM could better mitigates OLZ-induced increase in TG levels. The trajectories of change also differed in all metabolic indexes over time between the two groups.

Plasma complement C3 and C3a are increased in major depressive disorder independent of childhood trauma.

BACKGROUND: Dysregulated complement system is linked to pathophysiology of major depressive disorder (MDD). Childhood trauma has been associated with an increased incidence of adult depression via a putative mechanism of immune activation. This study aimed to measure and compare peripheral levels of complement C3, C3a, C1q and C-reactive protein (CRP) in MDD patients and healthy controls and explore the relationship between these molecule levels and childhood trauma history in the participants. METHODS: The participants were 49 medication-free MDD patients and 45 healthy controls. All participants were asked to finish the Childhood Trauma Questionnaire, followed by blood sampling for measurement of plasma complement C3, C3a, C1q and CRP by means of enzyme-linked immunosorbent assay. RESULTS: Peripheral plasma concentration of C3 and C3a in medication-free MDD group was significantly higher than that in the healthy controls; whereas the concentration of plasma C1q and CRP in depressed patients was comparable to that in healthy controls. All these inflammatory factors were not associated to childhood trauma experience in patients with MDD. CONCLUSION: Our data suggest that complement C3 and C3a may be implicated in the pathophysiology of MDD, although traumatic childhood experiences were not associated with the circulating levels of complement C3, C3a, C1q and CRP.

The effects of social defeat stress on hippocampal glial cells and interleukin-6 in adolescence and adulthood.

Adolescent social stress has been associated with the vulnerability to developing psychopathological disorders in adulthood that are accompanied by brain inflammatory processes. The purpose of this study is to investigate the dynamic changes of the hippocampal neuroinflammatory mediators, including microglia, astrocyte, and interleukin-6 (IL-6) levels in mice experiencing social defeat stress during adolescence. Adolescent mice were divided into the control group and stress group. Mice in the stress group were exposed to chronic intermittent social defeat for a total of 12 days, and control mice were reared in normal conditions. The hippocampal microglia, astrocyte, and IL-6 levels were measured 24 h and 3 weeks after the end of stress exposure. Microglia activation characterized by increased ionized calcium-binding adapter molecule 1 positive cell numbers or staining area in the CA1 and CA3 regions of the hippocampus were observed 24 h after the end of stress, which did not last into the adulthood. No short-term or long-term alterations of the number of hippocampal CA1 and CA3 glia fibrillary acidic protein astrocytes were found in mice experiencing adolescent social defeat, whereas IL-6 levels were only increased 3 weeks after the end of stress. These data suggested that exposure to chronic social defeat stress led to short-term and long-term neuroinflammatory changes in the hippocampus.

Rapid Eye Movement Sleep Deprivation Enhances Adenosine Receptor Activation and the CREB1/YAP1/c-Myc Axis to Alleviate Depressive-like Behaviors in Rats.

As neuromodulators, adenosine and its receptors are mediators of sleep-wake regulation. A putative correlation between CREB1 and depression has been predicted in our bioinformatics analyses, and its expression was also predicted to be upregulated in response to sleep deprivation. Therefore, this study aims to elaborate the A1 and A2A adenosine receptors and CREB1-associated mechanism underlying the antidepressant effect of rapid eye movement sleep deprivation (REMSD) in rats with chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors. The modeled rats were injected with adenosine A1 receptor antagonist DPCPX or adenosine A2A receptor antagonist ZM241385 to assess the role of adenosine receptors in depression. In addition, ectopic expression and depletion experiments of CREB1 and YAP1 were also conducted in vivo and in vitro. It was found that REMSD alleviated depressive-like behaviors in CUMS rats, as shown by increased spontaneous activity, sucrose consumption and percentage, and shortened escape latency and immobility duration. Meanwhile, A1 or A2A adenosine receptor antagonists negated the antidepressant effect of REMSD. REMSD enhanced adenosine receptor activation and promoted the phosphorylation of CREB1, thus increasing the expression of CREB1. In addition, the overexpression of CREB1 activated the YAP1/c-Myc axis and consequently alleviated depressive-like behaviors. Collectively, our results provide new mechanistic insights for an understanding of the antidepressant effect of REMSD, which is associated with the activation of adenosine receptors and the CREB1/YAP1/c-Myc axis.

Plasma complement component 4 alterations in patients with schizophrenia before and after antipsychotic treatment.

This study was performed to investigate the plasma C4 level and the influence of antipsychotic medication in schizophrenic patients. Thirty-six schizophrenic patients were followed-up for a mean of four weeks. The plasma level of C4 in schizophrenia was significantly higher than that in healthy controls at baseline, and was significantly decreased after antipsychotic treatment. CRP at both baseline and follow-up in patients were comparable to that in healthy controls. Our findings indicate that the plasma level of C4 is increased in schizophrenia patients at the acute stage of illness and can be decreased by antipsychotic medication.

Chronic social defeat stress caused region-specific oligodendrogenesis impairment in adolescent mice.

Introduction: Social stress in adolescents precipitates stress-related emotional disorders. In this study we aimed to investigate oligodendrogenesis in three stress-associated brain regions, medial prefrontal cortex (mPFC), habenula, and amygdala in adolescent mice exposed to social defeat stress. Methods: Four-week-old adolescent mice were subjected to social defeat for 10 days, followed by behavioral tests and evaluations of oligodendroglial proliferation and differentiation. Results: Stressed mice showed reduced social interaction, more stretched approach posture, lower sucrose preference, but no changes in the forced swimming test. EdU labeled proliferative cells, newly formed NG2+EdU + oligodendrocyte precursor cells (OPCs), and Olig2+EdU+ oligodendrocyte lineage cells (OLLs) were significantly decreased in the mPFC and the lateral habenula, but not in the amygdala and the medial habenula in socially defeated mice. APC+Edu+ newly-generated mature oligodendrocytes (OLs) were decreased in the mPFC in stressed mice. However, the total number of NG2+ OPCs, APC+ mature OLs, and Olig2+ OLLs were comparable in all the brain regions examined between stressed and control mice except for a decrease of APC+ mature OLs in the prelimbic cortex of stressed mice. Conclusion: Our findings indicate that adolescent social stress causes emotion-related behavioral changes and region-specific impairment of oligodendrogenesis.

Deep rTMS Mitigates Behavioral and Neuropathologic Anomalies in Cuprizone-Exposed Mice Through Reducing Microglial Proinflammatory Cytokines.

In comparison to conventional repetitive transcranial magnetic stimulation (rTMS), theta burst stimulation is stronger and more effective as a brain stimulation approach within short periods. Although this deep rTMS technique is being applied in treating neuropsychiatric disorders, few animal studies have attempted to clarify the neurobiological mechanisms underlying its beneficial effects. This animal study examined the effects of deep rTMS on the cuprizone-induced neuropathologic and behavioral anomalies and explored the underlying mechanism. Adolescent male C57BL/6 mice were fed a rodent chow without or with cuprizone (CPZ; 0.2% w/w) for 5 weeks. Another two groups of mice were subjected to deep rTMS or sham rTMS once a day during weeks 2-5 of the CPZ-feeding period. The behaviors of all mice were assessed after the withdrawal of CPZ before neuropathological and immunological analyses. Compared to the CNT group, mice in CPZ and CPZ + Sham groups showed deficits in social recognition and spatial working memory as well as anxiety-like behavior, in addition to myelin breakdown and OL loss in the corpus callosum (CC), caudate putamen, cerebral cortex, and hippocampus of the brain. Deep rTMS effectively reduced behavioral anomalies and blocked myelin breakdown and OL loss in CPZ-fed mice. Besides, it also dampened microglia activation at lesion sites and rectified cytokines levels (IL-1ß, IL-6, and IL-10) in CPZ-affected regions. The most significant effect was seen in the cerebral cortex where alleviated neuropathology co-existed with less microglia activation and higher IL-10 level. These data provided experimental evidence for the beneficial effects of deep rTMS in CPZ-fed mice and revealed a neurobiological mechanism of the modality.

Mapping the Alterations of Glutamate Using Glu-Weighted CEST MRI in a Rat Model of Fatigue.

Objective: Glutamate dysregulation may play an important role in the pathophysiology of fatigue. Glutamate weighted chemical exchange saturation transfer (Glu-weighted CEST) MRI is a recently developed technology which enables measuring glutamate in vivo with high sensitivity and spatial resolution. The purpose of this study is to map the alternations of brain glutamate in a rat model of fatigue. Methods: Rats were subjected to 10 days fatigue loading procedure (fatigue group) or reared without any fatigue loading (control group). Spontaneous activities of rats in the fatigue group were recorded from 3 days before fatigue loading to 4 days after the end of fatigue loading. Glu-weighted CEST were performed following 10-day fatigue loading. Results: Rats in the fatigue group exhibited significant reduced spontaneous activities after 10-day fatigue loading. The glutamate level in the whole brain increased significantly in the fatigue group compared to that in the control group. Further analysis of glutamate in the sub-regions of brain including the prefrontal cortex, hippocampus, and striatum revealed a trend of increment, although statistical significance was not reached. Significance: The increase of glutamate level in the brain may be a crucial process involved in the pathophysiology of fatigue.

The Long-Term Effects of Adolescent Social Defeat Stress on Oligodendrocyte Lineage Cells and Neuroinflammatory Mediators in Mice.

OBJECTIVE: Adverse childhood and adolescent experiences are associated with the emergences of psychopathology later in life and have negative consequences on white matter integrity. However, this adversity-induced white matter impairment remains not fully investigated. METHODS: Adolescent Balb/c mice were subjected to intermittent social defeat stress once a day during postnatal days 25 to 40. Then, the subjects were allowed to recover for three weeks before sacrifice. At the end, oligodendrocyte (OL) lineage cells, cell proliferation, and microglia activation, as well as myelin basic protein (MBP) levels in frontal cortex and hippocampus were evaluated. The levels of interleukin (IL)-1ß and IL-6 in the brain regions were assessed. RESULTS: MBP protein level in frontal cortex, but not in the hippocampus of defeated mice, decreased significantly compared to controls. The numeral densities of mature OLs, oligodendrocyte progenitor cells, and proliferating cells in medial prefrontal cortex were comparable between the defeated mice and controls. The defeated mice, however, showed significantly higher IL-1ß level, although IL-6 level and numeral density of microglia in frontal cortex did not change relative to controls. CONCLUSION: These results indicate that effects of intermittent social defeat stress on the white matter integrity and OL lineage cells in mouse brain are region- and developmental stage-specific. Upregulated IL-1ß may contribute to this negative consequence though the underlying mechanism remains to be investigated.

Evaluation of neuron-glia integrity by in vivo proton magnetic resonance spectroscopy: Implications for psychiatric disorders.

Proton magnetic resonance spectroscopy (1H-MRS) has been widely applied in human studies. There is now a large literature describing findings of brain MRS studies with mental disorder patients including schizophrenia, bipolar disorder, major depressive disorder, and anxiety disorders. However, the findings are mixed and cannot be reconciled by any of the existing interpretations. Here we proposed the new theory of neuron-glia integrity to explain the findings of brain 1H-MRS stuies. It proposed the neurochemical correlates of neuron-astrocyte integrity and axon-myelin integrity on the basis of update of neurobiological knowledge about neuron-glia communication and of experimental MRS evidence for impairments in neuron-glia integrity from the authors and the other investigators. Following the neuron-glia integrity theories, this review collected evidence showing that glutamate/glutamine change is a good marker for impaired neuron-astrocyte integrity and that changes in N-acetylaspartate and lipid precursors reflect impaired myelination. Moreover, this new theory enables us to explain the differences between MRS findings in neuropsychiatric and neurodegenerative disorders.

A Potential Magnetic Resonance Imaging Technique Based on Chemical Exchange Saturation Transfer for In Vivo γ-Aminobutyric Acid Imaging.

PURPOSE: We developed a novel magnetic resonance imaging (MRI) technique based on chemical exchange saturation transfer (CEST) for GABA imaging and investigated the concentration-dependent CEST effect ofGABA in a rat model of brain tumor with blood-brain barrier (BBB) disruption. MATERIALS AND METHODS: All MRI studies were performed using a 7.0-T Agilent MRI scanner. Z-spectra for GABA were acquired at 7.0 T, 37°C, and a pH of 7.0 using varying B1 amplitudes. CEST images of phantoms with different concentrations of GABA solutions (pH, 7.0) and other metabolites (glutamine, myoinositol, creatinine, and choline) were collected to investigate the concentration-dependent CEST effect of GABA and the potential contribution from other brain metabolites. CEST maps for GABA in rat brains with tumors were collected at baseline and 50 min, 1.5 h, and 2.0 h after the injection of GABA solution. RESULTS: The CEST effect of GABA was observed at approximately 2.75 parts per million(ppm) downfield from bulk water, and this effect increased with an increase in the B1 amplitude and remained steady after the B1 amplitude reached 6.0 µT (255 Hz). The CEST effect of GABA was proportional to the GABA concentration in vitro. CEST imaging of GABA in a rat brain with a tumor and compromised BBB showed a gradual increase in the CEST effect after GABA injection. CONCLUSION: The findings of this study demonstrate the feasibility and potential of CEST MRI with the optimal B1 amplitude, which exhibits excellent spatial and temporal resolutions, to map changes in GABA.

The recovery trajectory of adolescent social defeat stress-induced behavioral, (1)H-MRS metabolites and myelin changes in Balb/c mice.

Adolescent exposure to social stress precipitates emotion-related disorders and affects the development and function of medial prefrontal cortex (mPFC). However, this adversity-induced behavioral and neurological changes remain not fully explored. Adolescent Balb/c mice were subjected to intermittent social defeat stress during postnatal days 28 to 42. Proton magnetic resonance spectroscopy ((1)H-MRS) measurements, behavioral tests and immunohistochemistry were performed one day or 3 weeks after the last stress episode. Defeated mice exhibited hypoactivity and social avoidance with the latter lasting into the early adulthood, while the anxiety level was unchanged. Social defeat experience lead to temporary decreases in the levels of total creatines (Cr + pCr) and Glx (Glu + Gln), but a delayed increase of N- acetylaspartate (NAA) levels. These alternations were accompanied with a persistent reduction of myelin basic protein expression although the number of mature oligodendrocyte did not change. These findings provide evidence that adolescent adverse social experience permanently impairs the emotion-related behavioral performance and induces biochemical and molecular changes in the brain which at least lasts into early adulthood, thus enhancing our understanding of the neurobiology of social defeat stress. Our finding also implicates that NAA signals on MRS may reflect myelin status.

Cortical and subcortical gray matter shrinkage in alcohol-use disorders: a voxel-based meta-analysis.

Although gray matter (GM) damages caused by long term and excessive alcohol consumption have long been reported, the structural neuroimaging findings on alcohol-use disorders (AUD) are inconsistent. The aim of this study was to conduct a meta-analysis, using a novel voxel-based meta-analytic method effect-size signed differential mapping (ES-SDM), to characterize GM changes in AUD patients. Twelve studies including 433 AUD patients and 498 healthy controls (HCs) were retrieved. The AUD group demonstrated significant GM reductions in the corticostriatal-limbic circuits, including bilateral insula, superior temporal gyrus, striatum, dorsal lateral prefrontal cortex (DLPFC), precentral gyrus, anterior cingulate cortex (ACC), left thalamus and right hippocampus compared to HCs. GM reduction in the right striatum is significantly negatively related to duration of alcohol dependence, while GM shrinkage of the left superior, middle frontal gyrus, and left thalamus is related to lifetime alcohol consumption. The findings demonstrate that the GM abnormalities caused by AUD are in corticostriatal-limbic circuits whose dysfunctions may involve in craving and observed functional deficits.

Changes in proinflammatory cytokines and white matter in chronically stressed rats.

Although the pathogenesis of depression, an incapacitating psychiatric ailment, remains largely unknown, previous human and animal studies have suggested that both proinflammatory cytokines and altered oligodendrocytes play important roles in the condition. This study examined these two factors in the brains of rats following unpredictable chronic mild stress for 4 weeks, with the hypothesis that chronic stress may affect oligodendrocytes and elevate proinflammatory cytokines in the brain. After suffering unpredictable stressors for 4 weeks, the rats showed depression-like behaviors, including decreased locomotion in the open field, increased immobility time in the forced swim test, and decreased sucrose consumption and less sucrose preference when compared with controls. Immunohistochemical staining of brain sections showed higher immunoreactivity of proinflammatory cytokines in certain brain regions of stressed rats compared with controls; lower immunoreactivity of myelin basic protein and fewer mature oligodendrocytes were seen in the prefrontal cortex, but no demyelination was detected. These results are interpreted and discussed in the context of recent findings from human and animal studies.

Role of CT perfusion imaging in patients with variously differentiated gastric adenocarcinoma.

PURPOSE: To explore the characteristics of variously differentiated gastric cancers on computed tomography (CT) perfusion imaging, including specific perfusion parameter values, and potential clinical applications in the prognosis assessment of gastric cancer. MATERIALS AND METHODS: Fifty patients with gastric cancer confirmed by gastroscope pathology were studied prospectively using CT perfusion imaging examinations on a 64-slice spiral CT scanner. The acquired volume data were used for calculations, mapping, and analysis by using an abdominal tumor perfusion protocol (deconvolution method) in the CT perfusion software package to measure 4 parameters: blood flow (BF), blood volume (BV), mean transit time (MTT), and the permeability surface (PS) area product. The different differentiated Gastric cancers with CT perfusion values were divided into 3 groups: well-differentiated, moderately differentiated and poorly differentiated gastric adenocarcinoma, and compared statistically with one another by statistical software. RESULTS: The mean perfusion values of 10 patients with well-differentiated gastric adenocarcinoma were as follows: BF, 75.28 ± 6.81 mL/100 g/min; BV, 9.01 ± 0.94 mL/100 g; MTT, 9.89 ± 1.65 s; and PS, 10.05 ± 0.71 mL/100 g/min. The mean perfusion values of 24 patients with moderately differentiated gastric adenocarcinoma were as follows: BF, 110.01 ± 31.90 mL/100 g/min; BV, 18.18 ± 5.62 mL/100 g; MTT, 9.81 ± 3.69 s; and PS, 40.08 ± 15.82 mL/100 g/min. The mean perfusion values of 16 patients with poorly differentiated gastric adenocarcinoma were as follows: BF, 138.59 ± 38.09 mL/100 g/min; BV, 21.08 ± 4.11 mL/100 g; MTT, 9.47 ± 1.80 s; and PS, 57.50 ± 13.28 mL/100 g/min. Comparing the 3 groups, differences between the well-differentiated group and the moderate differentiation group were all statistically significant for BF, BV, and PS (p < 0.05, respectively), differences between the well-differentiated group and the poor differentiation group were all statistically significant for BF, BV, and PS (p < 0.05,respectively) as well; While MTT value showed no statistical difference among the 3 groups (p > 0.05). CONCLUSION: Stomach CT perfusion imaging is a functional imaging technology from the perspective of hemodynamics with potential clinical applications. The BF, BV and PS values could serve as indicators of the degree of malignancy and aid in prognostic assessment of gastric cancer.

Fluoxetine improves behavioral performance by suppressing the production of soluble ß-amyloid in APP/PS1 mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder of the central nervous system. Current approaches for AD treatment only ameliorate symptoms. Therapeutic strategies that target the pathological processes of the disease remain elusive. Fluoxetine (FLX) is one of the most widely used antidepressants for the treatment of depression and anxiety associated with AD, however, it is unknown if the drug affects the pathogenesis of the disease. We showed that FLX improved spatial memory, learning and emotional behaviors of APP/PS1 mice, a well characterized model of AD. In the same mice, FLX effectively prevented the protein loss of synaptophysin (SYP) and microtubuleassociated protein 2 (MAP2). FLX was unable to prevent plaque formation, but significantly lowered high levels of soluble ß-amyloid (Aß) in brain tissue, cerebrospinal fluid (CSF) and blood sera. FLX also effectively inhibited the phosphorylation of amyloid precursor protein (APP) at T668, which may be a possible mechanism of the reduced Aß production in APP/PS1 mouse after treatment.

Desvenlafaxine prevents white matter injury and improves the decreased phosphorylation of the rate-limiting enzyme of cholesterol synthesis in a chronic mouse model of depression.

Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes 2-3 weeks for the mood-enhancing effects, which indicate other mechanisms may underlie their treatment effects. Here, we investigated the role of white matter in treatment and pathogenesis of depression using an unpredictable chronic mild stress (UCMS) mouse model. Desvenlafaxine (DVS) was orally administrated to UCMS mice at the dose of 10 mg/kg/day 1 week before they went through a 7-week stress procedure and lasted for over 8 weeks before the mice were killed. No significant changes were found for protein markers of neurons and astrocytes in UCMS mice. However, myelin and oligodendrocyte-related proteins were significantly reduced in UCMS mice. DVS prevented the stress-induced injury to white matter and the decrease of phosphorylated 5'-AMP-activated protein kinase and 3-hydroxy-3-methyl-glutaryl-CoA reductase protein expression. DVS increased open arm entries in an elevated plus-maze test, sucrose consumption in the sucrose preference test and decreased immobility in tail suspension and forced swimming tests. These findings suggest that stress induces depression-like behaviors and white matter deficits in UCMS mice. DVS may ameliorate the oligodendrocyte dysfunction by affecting cholesterol synthesis, alleviating the depression-like phenotypes in these mice. We examined the possible role of oligodendrocyte and myelin in the pathological changes of depression with an unpredictable chronic mild stress (UCMS) mouse model. Oligodendrocyte-related proteins in the mouse brain were specifically changed during the stress period. The depressive-like behaviors and oligodendrocyte deficits could be prevented by the administration of desvenlafaxine. Oligodendrocyte and myelin may be an essential target of desvenlafaxine for the treatment of depression.

Astrocyte-dependent protective effect of quetiapine on GABAergic neuron is associated with the prevention of anxiety-like behaviors in aging mice after long-term treatment.

Previous studies have demonstrated that quetiapine (QTP) may have neuroprotective properties; however, the underlying mechanisms have not been fully elucidated. In this study, we identified a novel mechanism by which QTP increased the synthesis of ATP in astrocytes and protected GABAergic neurons from aging-induced death. In 12-month-old mice, QTP significantly improved cell number of GABAegic neurons in the cortex and ameliorated anxiety-like behaviors compared to control group. Complimentary in vitro studies showed that QTP had no direct effect on the survival of aging GABAergic neurons in culture. Astrocyte-conditioned medium (ACM) pretreated with QTP (ACMQTP) for 24 h effectively protected GABAergic neurons against aging-induced spontaneous cell death. It was also found that QTP boosted the synthesis of ATP from cultured astrocytes after 24 h of treatment, which might be responsible for the protective effects on neurons. Consistent with the above findings, a Rhodamine 123 test showed that ACMQTP, not QTP itself, was able to prevent the decrease in mitochondrial membrane potential in the aging neurons. For the first time, our study has provided evidence that astrocytes may be the conduit through which QTP is able to exert its neuroprotective effects on GABAergic neurons. The neuroprotective properties of quetiapine (QTP) have not been fully understood. Here, we identify a novel mechanism by which QTP increases the synthesis of ATP in astrocytes and protects GABAergic neurons from aging-induced death in a primary cell culture model. In 12-month-old mice, QTP significantly improves cell number of GABAegic neurons and ameliorates anxiety-like behaviors. Our study indicates that astrocytes may be the conduit through which QTP exerts its neuroprotective effects on GABAergic neurons.

Olanzapine ameliorates neuropathological changes and increases IGF-1 expression in frontal cortex of C57BL/6 mice exposed to cuprizone.

Cuprizone (CPZ) induced demyelinating mouse has been used as an animal model to examine the assumed roles of altered oligodendrocytes in the pathophysiology and treatment of schizophrenia. The objectives of this study were to examine the effect of olanzapine, an atypical antipsychotic, on cuprizone-induced neuropathological changes in the frontal cortex of C57BL/6 mice, and to explore the underlying mechanism for the possible protective effects. The effects of six-week olanzapine (10 mg/kg/day) treatments on neuropathological changes were examined by immunohistochemistry and Western-blot analyses. Olanzapine treatment for six weeks effectively decreased the breakdown of myelin and oligodendrocytes loss of cuprizone-fed mice. Reactive cellular changes, including astrocyte gliosis, microglia accumulation and increased activation of oligodendrocyte progenitor cells, were also attenuated by olanzapine. However, the cortical expression level of insulin-like growth factor 1 (IGF-1) was significantly increased by olanzapine treatment in cuprizone-fed mice as measured by the quantitative real-time polymerase chain reaction (PCR) method. Olanzapine treatment in control mice consuming normal food had no effect on all above measures. These results provide the first in vivo evidence for the protective effects of olanzapine on cuprizone-induced neuropathological changes and suggest that up-regulated insulin-like growth factor 1 may contribute to the protective effects of this antipsychotic.