Atorvastatin ameliorates cerebral vasospasm and early brain injury after subarachnoid hemorrhage and inhibits caspase-dependent apoptosis pathway

<p>Abstract</p> <p>Backgroud</p> <p>Cerebral vasospasm (CVS) and early brain injury remain major causes of morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH). Hydroxymethylglutaryl coenzyme A reductase inhibitors, also known as statins, has the neuroprotective effects and ameliorating CVS after SAH. This study was designed to explore apoptosis inhibiting effects of atorvastatin and its potential apoptotic signal pathway after SAH.</p> <p>Results</p> <p>Preserving blood-brain-barrier permeability, decreasing brain edema, increasing neurological scores and ameliorating cerebral vasospasm were obtained after prophylactic use of atorvastatin. TUNEL-positive cells were reduced markedly both in basilar artery and in brain cortex by atorvastatin. Apoptosis-related proteins P53, AIF and Cytochrome C were up-regulated after SAH, while they were not affected by atorvastatin. In addition, up-regulation of caspase-3 and caspase-8 after SAH was decreased by atorvastatin treatment both in mRNA and in protein levels.</p> <p>Conclusion</p> <p>The neuroprotective effects of atorvastatin after SAH may be related to its inhibition of caspase-dependent proapoptotic pathway based on the present results.</p

Glucocorticoid Receptor 1B and 1C mRNA Transcript Alterations in Schizophrenia and Bipolar Disorder, and Their Possible Regulation by GR Gene Variants

Abnormal patterns of HPA axis activation, under basal conditions and in response to stress, are found in individuals with schizophrenia and bipolar disorder. Altered glucocorticoid receptor (GR) mRNA and protein expression in the dorsolateral prefrontal cortex (DLPFC) in psychiatric illness have also been reported, but the cause of these abnormalities is not known. We quantified expression of GR mRNA transcript variants which employ different 5′ promoters, in 35 schizophrenia cases, 31 bipolar disorder cases and 34 controls. We also explored whether sequence variation within the NR3C1 (GR) gene is related to GR mRNA variant expression. Total GR mRNA was decreased in the DLPFC in schizophrenia cases relative to controls (15.1%, p<0.0005) and also relative to bipolar disorder cases (8.9%, p<0.05). GR-1B mRNA was decreased in schizophrenia cases relative to controls (20.2%, p<0.05), while GR-1C mRNA was decreased in both schizophrenia and bipolar disorder cases relative to controls (16.1% and 17.2% respectively, both p<0.005). A dose-dependent effect of rs10052957 genotype on GR-1B mRNA expression was observed, where CC homozygotes displayed 18.4% lower expression than TC heterozygotes (p<0.05), and 31.8% lower expression than TT homozygotes (p<0.005). Similarly, a relationship between rs6190 (R23K) genotype and GR-1C expression was seen, with 24.8% lower expression in GG homozygotes than GA heterozygotes (p<0.01). We also observed an effect of rs41423247 (Bcl1) SNP on expression of 67 kDa GRα isoform, the most abundant GRα isoform in the DLPFC. These findings suggest possible roles for the GR-1B and GR-1C promoter regions in mediating GR gene expression changes in psychotic illness, and highlight the potential importance of sequence variation within the NR3C1 gene in modulating GR mRNA expression in the DLPFC

Evolution of complexity in the zebrafish synapse proteome

The proteome of human brain synapses is highly complex and mutated in over 130 diseases. This complexity arose from two whole genome duplications early in the vertebrate lineage. Zebrafish are used in modelling human diseases, however its synapse proteome is uncharacterised and whether the teleost-specific genome duplication (TSGD) influenced complexity is unknown. We report the characterisation of the proteomes and ultrastructure of central synapses in zebrafish and analyse the importance of the TSGD. While the TSGD increases overall synapse proteome complexity, the Post Synaptic Density (PSD) proteome of zebrafish has lower complexity than mammals. A highly conserved set of ~1000 proteins is shared across vertebrates. PSD ultrastructural features are also conserved. Lineage-specific proteome differences indicate vertebrate species evolved distinct synapse types and functions. The datasets are a resource for a wide range of studies and have important implications for the use of zebrafish in modelling human synaptic diseases

Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability

Abstract The scaffold protein DLGAP1 is localized at the post-synaptic density (PSD) of glutamatergic neurons and is a component of supramolecular protein complexes organized by PSD95. Gain-of-function variants of DLGAP1 have been associated with obsessive-compulsive disorder (OCD), while haploinsufficient variants have been linked to autism spectrum disorder (ASD) and schizophrenia in human genetic studies. We tested male and female Dlgap1 wild type (WT), heterozygous (HT), and knockout (KO) mice in a battery of behavioral tests: open field, dig, splash, prepulse inhibition, forced swim, nest building, social approach, and sucrose preference. We also used biochemical approaches to examine the role of DLGAP1 in the organization of PSD protein complexes. Dlgap1 KO mice were most notable for disruption of protein interactions in the PSD, and deficits in sociability. Other behavioral measures were largely unaffected. Our data suggest that Dlgap1 knockout leads to PSD disruption and reduced sociability, consistent with reports of DLGAP1 haploinsufficient variants in schizophrenia and ASD

A proteomic investigation of similarities between conventional and herbal antidepressant treatments

Increasing clinical evidence for the effectiveness of herbal antidepressants has led to investigations at the molecular level. Using two-dimensional gel electrophoresis, this study investigated similarities in protein expression between clomipramine, St John’s wort and a Chinese herbal formula, xiaoyao-san, often used in mood disorder treatment. HT22 cells, derived from a mouse hippocampal cell line, were treated for 24 h, and protein expression was compared with that of the untreated cells (n = 4/group). Forty-three protein spots were found to be significantly differentially expressed (P < 0.05) in more than one of the treatment groups. Twentynine of these were identified using mass spectrometry. The most affected proteins were those involved in the cytoskeleton and energy metabolism, and an up-regulation of vimentin by all three treatments was confirmed by Western blotting. This study provides preliminary evidence for multiple common molecular targets between conventional and alternative antidepressants, which appear to collectively affect neuronal plasticity

Complement proteins are elevated in blood serum but not CSF in clinical high-risk and antipsychotic-naïve first-episode psychosis

Alterations in the complement system have been reported in some people with psychotic disorder, including in pre-psychotic individuals, suggesting that complement pathway dysregulation may be a feature of the early psychosis phenotype. Measurement of complement protein expression in psychosis has been largely restricted to the blood from patients with established illness who were taking antipsychotic medication. The present study examined a range of complement proteins in blood and cerebrospinal fluid (CSF) derived from individuals at clinical high-risk for psychosis (CHR), antipsychotic-naïve first-episode psychosis (FEP) and healthy controls.  A panel of complement proteins (C1q, C3, C3b/iC3b, C4, factor B and factor H) were quantified in serum and matched CSF in 72 participants [n = 23 individuals at CHR, n = 24 antipsychotic-naïve FEP, n = 25 healthy controls] using a multiplex immunoassay. Analysis of covariance was used to assess between-group differences in complement protein levels in serum and CSF. Pearson's correlation was used to assess the relationship between serum and CSF proteins, and between complement proteins and symptom severity.  In serum, all proteins, except for C3, were significantly higher in FEP and CHR. While a trend was observed, protein levels in CSF did not statistically differ between groups and appeared to be impacted by BMI and sample storage time. Across the whole sample, serum and CSF protein levels were not correlated. In FEP, higher levels of serum classical and alternative grouped pathway components were correlated with symptom severity.  Our exploratory study provides evidence for increased activity of the peripheral complement system in the psychosis spectrum, with such elevations varying with clinical severity. Further study of complement in CSF is warranted. Longitudinal investigations are required to elucidate whether complement proteins change peripherally and/or centrally with progression of psychotic illness. </p

Development of Proteomic Prediction Models for Transition to Psychotic Disorder in the Clinical High-Risk State and Psychotic Experiences in Adolescence

Importance: Biomarkers that are predictive of outcomes in individuals at risk of psychosis would facilitate individualized prognosis and stratification strategies. Objective: To investigate whether proteomic biomarkers may aid prediction of transition to psychotic disorder in the clinical high-risk (CHR) state and adolescent psychotic experiences (PEs) in the general population. Design, Setting, and Participants: This diagnostic study comprised 2 case-control studies nested within the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) and the Avon Longitudinal Study of Parents and Children (ALSPAC). EU-GEI is an international multisite prospective study of participants at CHR referred from local mental health services. ALSPAC is a United Kingdom-based general population birth cohort. Included were EU-GEI participants who met CHR criteria at baseline and ALSPAC participants who did not report PEs at age 12 years. Data were analyzed from September 2018 to April 2020. Main Outcomes and Measures: In EU-GEI, transition status was assessed by the Comprehensive Assessment of At-Risk Mental States or contact with clinical services. In ALSPAC, PEs at age 18 years were assessed using the Psychosis-Like Symptoms Interview. Proteomic data were obtained from mass spectrometry of baseline plasma samples in EU-GEI and plasma samples at age 12 years in ALSPAC. Support vector machine learning algorithms were used to develop predictive models. Results: The EU-GEI subsample (133 participants at CHR (mean [SD] age, 22.6 [4.5] years; 68 [51.1%] male) comprised 49 (36.8%) who developed psychosis and 84 (63.2%) who did not. A model based on baseline clinical and proteomic data demonstrated excellent performance for prediction of transition outcome (area under the receiver operating characteristic curve [AUC], 0.95; positive predictive value [PPV], 75.0%; and negative predictive value [NPV], 98.6%). Functional analysis of differentially expressed proteins implicated the complement and coagulation cascade. A model based on the 10 most predictive proteins accurately predicted transition status in training (AUC, 0.99; PPV, 76.9%; and NPV, 100%) and test (AUC, 0.92; PPV, 81.8%; and NPV, 96.8%) data. The ALSPAC subsample (121 participants from the general population with plasma samples available at age 12 years (61 [50.4%] male) comprised 55 participants (45.5%) with PEs at age 18 years and 61 (50.4%) without PEs at age 18 years. A model using proteomic data at age 12 years predicted PEs at age 18 years, with an AUC of 0.74 (PPV, 67.8%; and NPV, 75.8%). Conclusions and Relevance: In individuals at risk of psychosis, proteomic biomarkers may contribute to individualized prognosis and stratification strategies. These findings implicate early dysregulation of the complement and coagulation cascade in the development of psychosis outcomes