NMDA glutamate receptor antagonist MK-801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine.

Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to respective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain.

Cannabidiol modulates hippocampal genes involved in mitochondrial function, ribosome biogenesis, synapse organization, and chromatin modifications.

BACKGROUND: Cannabidiol (CBD) is one of the main cannabinoids present in Cannabis sativa female flowers. Previous investigation has already provided insights into the CBD molecular mechanism; however, there is no transcriptome data for CBD effects on hippocampal subfields. Here, we investigate transcriptomic changes in dorsal and ventral CA1 of adult mice hippocampus after 100 mg/kg of CBD administration (i.p.) for one or seven consecutive days. METHODS: C57BL/6JUnib mice were treated with either vehicle or CBD for 1 or 7 days. The collected brains were sectioned, and the hippocampal sub-regions were laser microdissected for RNA-Seq analysis. RESULTS: The transcriptome analysis following 7 days of CBD administration indicates the differential expression of 1559 genes in dCA1 and 2924 genes in vCA1. Furthermore, GO/KEGG analysis identified 88 significantly enriched biological process and 26 significantly enriched pathways for dCBD7, whereas vCBD7 revealed 128 enriched BPs and 24 pathways. CONCLUSION: This dataset indicates a widespread decrease of electron transport chain and ribosome biogenesis transcripts in CA1, while chromatin modifications and synapse organization transcripts were increased following CBD administration for 7 days.

Immunological imbalance in microcephalic children with congenital Zika virus syndrome.

Microcephalic children due congenital Zika virus syndrome (CZS) present neurological symptoms already well described. However, several other alterations can also be observed. Here, we aimed to evaluate the immune system of microcephaly CZS children. We showed that these patients have enlarged thymus, spleen and cervical lymph nodes, analysed by ultrasound and compared to the reference values for healthy children. In the periphery, they have an increase in eosinophil count and morphological alterations as hypersegmented neutrophils and atypical lymphocytes, even in the absence of urinary tract infections, parasitological infections or other current symptomatic infections. Microcephalic children due CZS also have high levels of IFN-γ, IL-2, IL-4, IL-5 and type I IFNs, compared to healthy controls. In addition, this population showed a deficient cellular immune memory as demonstrated by the low reactivity to the tuberculin skin test even though they had been vaccinated with BCG less than 2 years before the challenge with the PPD. Together, our data demonstrate for the first time that CZS can cause alterations in primary and secondary lymphoid organs and also alters the morphology and functionality of the immune system cells, which broadens the spectrum of CZS symptoms. This knowledge may assist the development of specific therapeutic and more efficient vaccination schemes for this population of patients.

Cannabinoids modulate proliferation, differentiation, and migration signaling pathways in oligodendrocytes.

Cannabinoid signaling, mainly via CB1 and CB2 receptors, plays an essential role in oligodendrocyte health and functions. However, the specific molecular signals associated with the activation or blockade of CB1 and CB2 receptors in this glial cell have yet to be elucidated. Mass spectrometry-based shotgun proteomics and in silico biology tools were used to determine which signaling pathways and molecular mechanisms are triggered in a human oligodendrocytic cell line (MO3.13) by several pharmacological stimuli: the phytocannabinoid cannabidiol (CBD); CB1 and CB2 agonists ACEA, HU308, and WIN55, 212-2; CB1 and CB2 antagonists AM251 and AM630; and endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The modulation of cannabinoid signaling in MO3.13 was found to affect pathways linked to cell proliferation, migration, and differentiation of oligodendrocyte progenitor cells. Additionally, we found that carbohydrate and lipid metabolism, as well as mitochondrial function, were modulated by these compounds. Comparing the proteome changes and upstream regulators among treatments, the highest overlap was between the CB1 and CB2 antagonists, followed by overlaps between AEA and 2-AG. Our study opens new windows of opportunities, suggesting that cannabinoid signaling in oligodendrocytes might be relevant in the context of demyelinating and neurodegenerative diseases. Proteomics data are available at ProteomeXchange (PXD031923).

Neutrophils from patients with the cardiac clinical form of Chagas disease release less NETs than neutrophils from healthy individuals.

INTRODUCTION: Chagas disease (CD) is a global health concern with approximately 12 000 deaths per year worldwide. In the chronic phase, about 30% of patients develop the cardiac clinical form, which presents symptoms associated with the presence of inflammatory cells in the cardiac tissue. Neutrophils are inflammatory cells able to modulate the chronic immune response against pathogens. These cells are capable of interacting with Trypanosoma cruzi, the aetiological agent of CD, and perform several effector functions, such as NET release. However, few studies have been carried out to investigate the role of these cells in the disease. AIMS: To investigate the release of NETs by neutrophils from CD patients by measuring the amount of DNA and elastase released. METHODS AND RESULTS: Measurement of DNA release by neutrophils from chronic CD patients presenting the indeterminate (IND group; n = 18) and cardiac (CARD group; n = 15) clinical forms and nonchagasic subjects (n = 18) stimulated with soluble antigen of T. cruzi was quantified using the Quant-iT™ PicoGreen® dsDNA assay kit. Patients from CARD group release less DNA (117.3 ± 21.85 ng/mL; *P = .0131) than neutrophils from control (177.7 ± 58.41 ng/mL). Elastase enzyme degranulation was measured using the substrate N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide (SAAVNA). Absorbance values of elastase degranulation activity showed that only cells from healthy individuals presented a high release profile of elastase. Also, we found a negative correlation between DNA released concentration and risk of death (r = -.6574; *P = .0173); the lower the neutrophil DNA release from chagasic patients with cardiac event, the higher the risk of death. CONCLUSION: These preliminary data show that patients with the cardiac form of CD release less NETs than nonchagasic individuals, raising the possibility that lower release of NETs enhances risk of death in CD patients with cardiac events.

Proteomics for Target Identification in Psychiatric and Neurodegenerative Disorders.

Psychiatric and neurodegenerative disorders such as schizophrenia (SCZ), Parkinson's disease (PD), and Alzheimer's disease (AD) continue to grow around the world with a high impact on health, social, and economic outcomes for the patient and society. Despite efforts, the etiology and pathophysiology of these disorders remain unclear. Omics technologies have contributed to the understanding of the molecular mechanisms that underlie these complex disorders and have suggested novel potential targets for treatment and diagnostics. Here, we have highlighted the unique and common pathways shared between SCZ, PD, and AD and highlight the main proteomic findings over the last 5 years using in vitro models, postmortem brain samples, and cerebrospinal fluid (CSF) or blood of patients. These studies have identified possible therapeutic targets and disease biomarkers. Further studies including target validation, the use of large sample sizes, and the integration of omics findings with bioinformatics tools are required to provide a better comprehension of pharmacological targets.

Proteomic Markers for Depression.

Major depressive disorder is a multifactorial disease, with molecular mechanisms not fully understood. A breakthrough could be reached with a panel of diagnostic biomarkers, which could be helpful to stratify patients and guide physicians to a better therapeutic choice, reducing the time between diagnostic and remission. This review brings the most recent works in proteomic biomarkers and highlights several potential proteins that could compose a panel of biomarkers to diagnostic and response to medication. These proteins are related to immune, inflammatory, and coagulatory systems and may also be linked to energy metabolism, oxidative stress, cell communication, and oligodendrogenesis.

Proteomics and Lipidomics in the Elucidation of Endocannabinoid Signaling in Healthy and Schizophrenia Brains.

Interest in the modulation of endocannabinoid signaling has increased since the discovery of receptors for compounds of Cannabis sativa. Endocannabinoids are crucial neuromodulators of many brain functions and changes in the ligands and their receptors have been associated with psychiatric disorders, such as schizophrenia. Genetic, neuroimaging, and behavioral studies have reinforced the role of endocannabinoids in the pathobiology of schizophrenia. However, molecular pathways and biological processes involved in cannabinoid effects are not totally understood. Additionally, the endocannabinoid signaling network with other non-cannabinoid targets, and the effects of phytocannabinoids increase the complexity to understand their role in schizophrenia and homeostasis conditions. Thus, proteomic studies can provide evidence about the involvement of cannabinoid receptors, as well as the metabolic and synthetic enzymes of the endocannabinoids in these disorders. Additionally, quantification of endocannabinoids in the blood serum or cerebrospinal fluid can be a useful approach to identify new biomarkers in schizophrenia, and lipidomic techniques can be used to quantify these compounds. Herein, the authors review proteomic and lipidomic studies that have been used for analysis of the endocannabinoid system in healthy and schizophrenia function. The findings may contribute to understand the involvement of endocannabinoids in the brain and in the neurobiological basis of schizophrenia.

Involvement of neutrophils in Chagas disease pathology.

Chagas disease (CD) is a public health problem in Latin America. The acute phase presents nonspecific symptoms and most patients recover from acute parasitemia and undergo a prolonged asymptomatic phase. Several years later, about 30% of infected individuals develop chronic cardiopathy with progressive cardiomegaly, arrhythmia, thromboembolic events and heart failure. These symptoms suggest a persistent association with the presence of inflammatory infiltrate and tissue, and cellular destruction in the heart muscle. Nevertheless, few research studies have attempted to understand the role of inflammatory cells, such as neutrophils, in establishing the pathology and progression of CD. Only recently have some studies been performed with this intention. Despite this effort, the role of neutrophils in CD is still considered controversial. This review discusses the morphological and functional characteristics of neutrophils that describes their participation in the establishment and progression of Trypanosoma cruzi infection, through the development of its effector functions, such as release of lithic components, production of oxidative agents and release of inflammatory mediators capable of modulating the host immune response.

Cannabinoids and glial cells: possible mechanism to understand schizophrenia.

Clinical and neurobiological findings have reported the involvement of endocannabinoid signaling in the pathophysiology of schizophrenia. This system modulates dopaminergic and glutamatergic neurotransmission that is associated with positive, negative, and cognitive symptoms of schizophrenia. Despite neurotransmitter impairments, increasing evidence points to a role of glial cells in schizophrenia pathobiology. Glial cells encompass three main groups: oligodendrocytes, microglia, and astrocytes. These cells promote several neurobiological functions, such as myelination of axons, metabolic and structural support, and immune response in the central nervous system. Impairments in glial cells lead to disruptions in communication and in the homeostasis of neurons that play role in pathobiology of disorders such as schizophrenia. Therefore, data suggest that glial cells may be a potential pharmacological tool to treat schizophrenia and other brain disorders. In this regard, glial cells express cannabinoid receptors and synthesize endocannabinoids, and cannabinoid drugs affect some functions of these cells that can be implicated in schizophrenia pathobiology. Thus, the aim of this review is to provide data about the glial changes observed in schizophrenia, and how cannabinoids could modulate these alterations.

Dimethyl Sulfoxide (DMSO) Decreases Cell Proliferation and TNF-α, IFN-γ, and IL-2 Cytokines Production in Cultures of Peripheral Blood Lymphocytes.

Dimethylsulfoxide (DMSO) is an amphipathic molecule composed of a polar domain characterized by the sulfinyl and two nonpolar methyl groups, for this reason it is able to solubilize polar and nonpolar substances and transpose hydrophobic barriers. DMSO is widely used to solubilize drugs of therapeutic applications and studies indicated that 10% v/v concentration did not modify culture viability when used to treat human peripheral blood mononuclear cells (PBMC). However, some DMSO concentrations could influence lymphocyte activation and present anti-inflammatory effects. Therefore, the objective of this study was to evaluate the effect of DMSO on lymphocyte activation parameters. Cell viability analysis, proliferation, and cytokine production were performed on PBMC from six healthy subjects by flow cytometry. The results indicated that 2.5% v/v DMSO concentrations did not modify lymphocytes viability. DMSO at 1% and 2% v/v concentrations reduced the relative proliferation index of lymphocytes and at 5% and 10% v/v concentrations reduced the percentage of total lymphocytes, cluster of differentiation 4⁺ (CD4⁺) T lymphocytes and CD8⁺ T lymphocytes interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) producers. Thus, it was concluded that DMSO has an in vitro anti-inflammatory effect by reducing lymphocyte activation demonstrated with proliferation reduction and the decrease of cytokine production.

Prevalence of urologic sequelae and bladder and bowel dysfunctions in patients with congenital Zika syndrome: A multicenter evaluation of the Zika virus bladder and bowel sequelae assistance network.

INTRODUCTION: Neurogenic bladder was first confirmed as a urological sequela of Congenital Zika Syndrome (CZS) in 2018. Further clinical-epidemiological evidence also confirmed neurogenic bowel dysfunction and cryptorchidism. To strengthen the care for these children, the Congenital Zika Virus Bladder and Bowel Sequelae Network (RASZ in Brazilian) was created, including six integrated centers in Brazil. This article represents the initial outcome of the efforts by RASZ. OBJECTIVE: To evaluate the prevalence of bladder and bowel dysfunction, cryptorchidism and other urological sequelae related to CZS in cohorts attended in six Brazilian states. STUDY DESIGN: Observational, prospective, multicenter study including children with CZS assisted in one of six RASZ collaborative centers between June 2016 and February 2023. Data were collected from patient's first assessment using the same protocols for urological and bowel evaluation. Categorical variables were analyzed by frequency of occurrence and numerical variables by mean, median, and standard deviation. The study was approved by the Research Ethics Committees of each center, all parents/caregivers provided written informed consent. RESULTS: The study included 414 children aged 2 months to 7 years (mean 2.77 years, SD 1.73), 227 (54.8 %) were male and 140 (33,8 %) referred urological and bowel symptoms on arrival. Prevalence of both urological and bowel sequelae was 66.7 %, 51 % of children aged 4 years and older had urinary incontinence (UI). UTI was confirmed in 23.4 % (two presented toxemia) and among males, 18.1 % had cryptorchidism. Renal ultrasonography, performed in 186 children, was abnormal in 25 (13.4 %), 7 had hydronephrosis. Among the 287 children who performed urodynamics, 283 (98.6 %) were altered: 232 had a lower bladder capacity, 144 a maximum bladder pressure of ≥40 cm H2O, and 127 did not satisfactorily empty their bladder. DISCUSSION: A higher prevalence of NLUTD, neurogenic bowel and cryptorchidism was confirmed in children with CZS. Early diagnosis and appropriate treatment, including a multidisciplinary approach, may reduce the risk of UTIs, UI and kidney damage. A limitation of the study was the inability of children to complete the protocol, specifically urodynamic evaluation, and ultrasonography. In both exams, the percentage of abnormal cases was higher than that expected in the normal population. CONCLUSION: A 66,7 % prevalence of combined urological sequelae and bladder-bowel dysfunction related to CZS was confirmed in patients evaluated in six Brazilian cohorts. The most frequent changes were related to NLUTD, neurogenic bowel, and cryptorchidism. Prevalence may be underestimated due to access restrictions to diagnostic tests.

Trajectory of Systemic Blood Pressure in Early Life: A Cohort Study.

Objective. To track the BP (blood pressure) trajectory of healthy infants during the first year of life of healthy infants born in Northeast Brazil. Methods. In this cohort study, BP was assessed by oscillometry at the first 24 hours of life and 12 months of age. Results. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) increased with age (P < .001) and were not influenced by gender (SBP: P = .178 and DBP: P = .623) or type of delivery (SBP: P = .827 and DBP: P = .106), when compared between the first 24 hours of life and 12 months of age. Conclusion. The data from the present study increased knowledge about the trajectory of BP during the first year of life. The increase in BP between the first month and the first year of life was not influenced by gender or type of delivery.

The multimodal Munich Clinical Deep Phenotyping study to bridge the translational gap in severe mental illness treatment research.

Introduction: Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. Methods: In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Results: Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. Discussion: The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat.

Changes in renal function increase the need for advanced ventilatory support and increase the risk of mortality in critically ill patients with COVID-19.

In addition to respiratory failure, another important outcome presented by patients hospitalized with coronavirus disease 2019 (COVID-19) is renal failure, which is related to increased severity of infection and a greater risk of mortality. Severity is often represented by the need for respiratory and/or life support, which can range from oxygen therapy to invasive mechanical ventilation. This study aimed to determine the association between the degree of renal and inflammatory impairment in patients with the need for advanced respiratory support and mortality. Included in the present study were 79 critically ill patients with COVID-19 on different days, who required a nasal cannula and/or orotracheal intubation. Data from laboratory tests, arterial blood gases and information on their clinical evolution were collected. The results obtained showed that the biochemical markers of renal function, as well as the inflammatory markers and the partial pressure of carbon dioxide, were significantly increased in patients who succumbed to the infection. Similarly, these markers were higher amongst patients who required increased respiratory assistance.

Factors Associated with Behavioral Disorders in Children with Congenital Zika Syndrome and Their Families-A Cross-Sectional Study.

The Zika virus was responsible for an outbreak between 2015 and 2016 in Brazil: an alarming public health problem of international relevance. The Congenital Zika Syndrome (CZS) is often associated with manifestations that are responsible for cognitive and motor development delays and behavioral disorders. Thus, we aimed to characterize the clinical-epidemiological and familial context of those children and to identify factors associated with the risk of behavioral disorders using the Survey of Well-Being of Young Children questionnaire (SWYC). In total, 52 children diagnosed with CZS were evaluated. Logistic regressions were employed to assess predictive variables for behavioral alteration. Eighteen (35%) of the children presented a risk of behavioral alteration. Children born normocephalic were 36-fold more likely to present behavioral alteration (95% CI: 3.82 to 337.92, p = 0.002). Children with hearing and visual impairments showed reduced risks. In total, 35% percent of families reported food insecurity and 21% were at risk for maternal depression. Our findings suggest better social interactions and conditions to externalize reactions for children with CZS born normocephalic. The continuous assessment of these children and families may identify conditions associated with behavioral alteration and psychosocial vulnerabilities that help in decision-making, therefore optimizing patient-family interactions.

Plasma proteomic signature of major depressive episode in the elderly.

Depression is a complex and multifactorial disease, affecting about 6.5% of the elderly population in what is referred to as late-life depression (LLD). Despite its public health relevance, there is still limited information about the molecular mechanisms of LLD. We analyzed the blood plasma of 50 older adults, 19 with LLD and 31 controls, through untargeted mass spectrometry, and used systems biology tools to identify biochemical pathways and biological processes dysregulated in the disease. We found 96 differentially expressed proteins between LLD patients and control individuals. Using elastic-net regression, we generated a panel of 75 proteins that comprises a potential model for determining the molecular signature of LLD. We also showed that biological pathways related to vesicle-mediated transport and voltage-dependent calcium channels may be dysregulated in LLD. These data can help to build an understanding of the molecular basis of LLD, offering an integrated view of the biomolecular alterations that occur in this disorder. SIGNIFICANCE: Major depressive disorder in the elderly, called late-life depression (LLD), is a common and disabling disorder, with recent prevalence estimates of 6.5% in the general population. Despite the public health relevance, there is still limited information about the molecular mechanisms of LLD. The findings in this paper shed light on LLD heterogeneous biological mechanisms. We uncovered a potential novel biomolecular signature for LLD and biological pathways related to this condition which can be targets for the development of novel interventions for prevention, early diagnosis, and treatment of LLD.

Spirometric values associated with clinical form and risk of death and stroke in chagasic patients.

The aim of the present study was to compare pulmonary function among patients with different clinical forms and scores for risk of death and stroke. Patients were recruited from the Chagas Disease Ambulatory Service at the University of Rio Grande do Norte State (Mossoró, Brazil). The evaluation of pulmonary function was performed through spirometry techniques using a digital spirometer, and information about the clinical forms (cardiac, cardiodigestive, digestive and undetermined) and scores for risk of death (Rassi's risk-of-death score) and stroke was subsequently collected. Upon completion of the evaluation, comparisons of the values obtained between the groups for different clinical forms, risk stratification of stroke and Rassi's risk-of-death were made. The study cohort consisted of 72 patients. Individuals with a low risk of death had significantly higher values in the Tiffeneau index and individuals with a low risk of stroke presented with higher percentage values for forced vital capacity and forced expiratory volume in 1 sec. In addition, individuals with heart disease had worse percentage values for FVC and FEV1. In conclusion, the results showed that spirometry was an effective analytical technique and was associated with clinical forms, and death and stroke risk scores, in patients with Chagas disease, adding an important prognostic tool to those currently available.

Molecular Mechanisms Associated with Antidepressant Treatment on Major Depression.

Major depressive disorder (MDD) is a complex and multifactorial psychiatric disorder that causes serious health, social, and economic concerns worldwide. The main treatment of the symptoms is through antidepressant (AD) drugs. However, not all patients respond properly to these drugs. Omic sciences are widely used to analyze not only biomarkers for the AD response but also their molecular mechanism. In this review, we aimed to focus on omics data to better understand the molecular mechanisms involving AD effects on MDD. We consistently found, from preclinical to clinical data, that glutamatergic transmission, immune/inflammatory processes, energy metabolism, oxidative stress, and lipid metabolism were associated with traditional and potential new ADs. Despite efforts of studies investigating biomarkers of response to ADs, which could contribute to personalized treatment, there is no biomarker panel available for clinical application. From clinical genomic studies, we found that the main findings contribute to the development of pharmacogenomic tests for AD efficacy for each patient. Several studies pointed at DRD2, PXDNL, CACNA1E, and CACNA2D1 genes as potential targets for MDD treatment and the efficacy and rapid-antidepressant effect of ketamine. Finally, more in-depth studies of the molecular targets pointed here are needed to determine the clinical relevance and provide further evidence for precision MDD treatment.

Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13.

Cannabidiol, a compound of Cannabis sativa, has been proposed as an alternative treatment of schizophrenia. Preclinical and clinical data have suggested that cannabidiol shares more similarity with atypical antipsychotics than typical, both of which are customarily used to manage schizophrenia symptoms. While oligodendrocytes are known to be relevant targets of antipsychotics, the biochemical knowledge in this regard is still limited. Here we evaluated the molecular pathways modulated by cannabidiol compared to the antipsychotics clozapine (atypical) and haloperidol (typical), additionally evaluating the effects of benztropine, a muscarinic receptor antagonist that displays a protective effect in oligodendrocytes and myelination. For this purpose, we employed nano-chromatography coupled with mass spectrometry to investigate the proteomic response to these drugs both in healthy oligodendrocytic cells and in a cuprizone-based toxicity model, using the human oligodendrocyte precursor cell line MO3.13. Cannabidiol shares similarities of biochemical pathways with clozapine and benztropine, in agreement with other studies that indicated an atypical antipsychotic profile. All drugs tested affected metabolic and gene expression pathways and cannabidiol, benztropine, and clozapine modulated cell proliferation and apoptosis when administered after cuprizone-induced toxicity. These general pathways are associated with cuprizone-induced cytotoxicity in MO3.13 cells, indicating a possible proteomic approach when acting against the toxic effects of cuprizone. In conclusion, although modeling oligodendrocytic cytotoxicity with cuprizone does not represent the entirety of the pathophysiology of oligodendrocyte impairments, these results provide insight into the mechanisms associated with the effects of cannabidiol and antipsychotics against cuprizone toxicity, offering new directions of study for myelin-related processes and deficits.