α-Lipoic Acid as Adjunctive Treatment for Schizophrenia: A Randomized Double-Blind Study.

BACKGROUND/PURPOSE: There is evidence for low endogenous antioxidant levels and oxidative imbalance in patients with schizophrenia. A previous open-label study with α-lipoic acid (ALA), a potent antioxidant, improved patients' negative and cognitive symptoms and markers of lipid peroxidation. Here we report the results of a randomized double-blind, placebo-controlled study to verify the response of patients with schizophrenia to adjunctive treatment with ALA (100 mg/d) in a 4-month follow-up. METHODS: We conducted a 16-week, double-blind, placebo-controlled study of ALA at 100 mg/d dosages. We compared negative and positive symptoms, cognitive function, extrapyramidal symptoms, body mass index, and oxidative/inflammatory parameters between placebo and control groups. RESULTS: We found no significant improvement in body mass index, cognition, psychopathology, antipsychotic adverse effects, or oxidative stress and inflammation in the experimental group compared with placebo. The whole group of patients improved in several measures, indicating a strong placebo effect in this population. A surprising finding was a significant decrease in red blood cells, white blood cells, and platelets in the group treated with ALA. CONCLUSIONS: The decrease in red blood cells, white blood cells, and platelet counts requires further investigation and attention when prescribing ALA for patients with schizophrenia.

Decrease in cognitive performance and increase of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios with higher doses of antipsychotics in women with schizophrenia: a cross-sectional study.

BACKGROUND: We explored the relationship between symptoms, cognitive performance, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) (three markers of inflammation), and antipsychotic dose (in chlorpromazine units) in male and female patients with schizophrenia. METHODS: We conducted a cross-sectional analysis in patients with schizophrenia of the complete blood count and the results of neuropsychological testing, using the Welch t-test to compare groups and the Pearson test for correlations. RESULTS: We found that the NLR and the PLR are higher among women with schizophrenia when compared with men. In women, the NLR and the PLR correlate positively with antipsychotic drug dose and inversely with a working memory test (Direct Digit Span). Higher doses of antipsychotics are associated with worse working and semantic memory and mental flexibility in the women in our sample. CONCLUSION: Higher doses of antipsychotics were associated with worse working and semantic memory and mental flexibility in women with schizophrenia. No such correlations were present in men, suggesting that, in female patients, cognitive performance deteriorates as the antipsychotic dose is increased, a finding that could be mediated by inflammatory mechanisms, given the demonstrated relationship to biomarkers of inflammation - e.g., the NLR and the PLR. TRIAL REGISTRATION: NCT03788759 (ClinicalTrials.gov).

In vitro immunogenic profile of recombinant SARS-CoV2 S1-RBD peptide in murine macrophage and microglial cells.

BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can infect common mice inducing significant pathological lung lesions and inflammatory responses. This substantially mimics coronavirus disease 19 (COVID-19) infection and pathogenesis in humans. OBJECTIVES: To characterise the effects of recombinant SARS-CoV-2 S1 receptor-binding domain (RBD) peptide in murine macrophage and microglial cells' immune activation compared with classical PAMPs in vitro. METHODS: Murine RAW 264.7 macrophages and BV2 microglial cells were exposed to increasing concentrations of the RBD peptide (0.01, 0.05, and 0.1 µg/mL), Lipopolysaccharide (LPS) and Poly(I:C) and evaluated after two and 24 h for significant markers of macrophage activation. We determined the effects of RBD peptide on cell viability, cleaved caspase 3 expressions, and nuclear morphometry analysis. FINDINGS: In RAW cells, RBD peptide was cytotoxic, but not for BV2 cells. RAW cells presented increased arginase activity and IL-10 production; however, BV2 cells expressed iNOS and IL-6 after RBD peptide exposure. In addition, RAW cells increased cleaved-caspase-3, apoptosis, and mitotic catastrophe after RBD peptide stimulation but not BV2 cells. CONCLUSION: RBD peptide exposure has different effects depending on the cell line, exposure time, and concentration. This study brings new evidence about the immunogenic profile of RBD in macrophage and microglial cells, advancing the understanding of SARS-Cov2 immuno- and neuropathology.

Animal Model of Neonatal Immune Challenge by Lipopolysaccharide: A Study of Sex Influence in Behavioral and Immune/Neurotrophic Alterations in Juvenile Mice.

INTRODUCTION: The prenatal/perinatal exposure to infections may trigger neurodevelopmental alterations that lead to neuropsychiatric disorders such as autism spectrum disorder (ASD). Previous evidence points to long-term behavioral consequences, such as autistic-like behaviors in rodents induced by lipopolysaccharide (LPS) pre- and postnatal (PN) exposure during critical neurodevelopmental periods. Additionally, sex influences the prevalence and symptoms of ASD. Despite this, the mechanisms underlying this influence are poorly understood. We aim to study sex influences in behavioral and neurotrophic/inflammatory alterations triggered by LPS neonatal exposure in juvenile mice at an approximate age of ASD diagnosis in humans. METHODS: Swiss male and female mice on PN days 5 and 7 received a single daily injection of 500 µg/kg LPS from Escherichia coli or sterile saline (control group). We conducted behavioral determinations of locomotor activity, repetitive behavior, anxiety-like behavior, social interaction, and working memory in animals on PN25 (equivalent to 3-5 years old of the human). To determine BDNF levels in the prefrontal cortex and hippocampus, we used animals on PN8 (equivalent to a human term infant) and PN25. In addition, we evaluated iba-1 (microglia marker), TNFα, and parvalbumin expression on PN25. RESULTS: Male juvenile mice presented repetitive behavior, anxiety, and working memory deficits. Females showed social impairment and working memory deficits. In the neurochemical analysis, we detected lower BDNF levels in brain areas of female mice that were more evident in juvenile mice. Only LPS-challenged females presented a marked hippocampal expression of the microglial activation marker, iba-1, and increased TNFα levels, accompanied by a lower parvalbumin expression. DISCUSSION/CONCLUSION: Male and female mice presented distinct behavioral alterations. However, LPS-challenged juvenile females showed the most prominent neurobiological alterations related to autism, such as increased microglial activation and parvalbumin impairment. Since these sex-sensitive alterations seem to be age-dependent, a better understanding of changes induced by the exposure to specific risk factors throughout life represents essential targets for developing strategies for autism prevention and precision therapy.

What Can We Learn from Animal Models to Study Schizophrenia?

Schizophrenia is a complex and heterogeneous neurodevelopmental psychiatric disorder characterized by a variety of symptoms classically grouped into three main domains: positive (hallucinations, delusions, and thought disorder) and negative symptoms (social withdrawal, lack of affect) and cognitive dysfunction (attention, working and episodic memory functions, and processing speed). This disorder places an immense emotional and economic pressure on the individual and society-at-large. Although the etiology of schizophrenia is not completely known, it is proposed to involve abnormalities in neurodevelopmental processes and dysregulation in the signaling mediated by several neurotransmitters, such as dopamine, glutamate, and GABA. Preclinical research using animal models are essential in our understanding of disease development and pathology as well as the discovery and advance of novel treatment choices. Here we describe rodent models for studying schizophrenia, including those based on the effects of drugs (pharmacological models), neurodevelopmental disruption, demyelination, and genetic alterations. The advantages and limitations of such models are highlighted. We also discussed the great potential of proteomic technologies in unraveling the molecular mechanism of schizophrenia through animal models.

Tetracyclines, a promise for neuropsychiatric disorders: from adjunctive therapy to the discovery of new targets for rational drug design in psychiatry.

Major mental disorders, such as schizophrenia, bipolar disorder, and major depressive disorder, represent the leading cause of disability worldwide. Nevertheless, the current pharmacotherapy has several limitations, and a large portion of patients do not respond appropriately to it or remain with disabling symptoms overtime. Traditionally, pharmacological interventions for psychiatric disorders modulate dysfunctional neurotransmitter systems. In the last decades, compelling evidence has advocated for chronic inflammatory mechanisms underlying these disorders. Therefore, the repurposing of anti-inflammatory agents has emerged as an attractive therapeutic tool for mental disorders. Minocycline (MINO) and doxycycline (DOXY) are semisynthetic second-generation tetracyclines with neuroprotective and anti-inflammatory properties. More recently, the most promising results obtained in clinical trials using tetracyclines for major psychiatric disorders were for schizophrenia. In a reverse translational approach, tetracyclines inhibit microglial reactivity and toxic inflammation by mechanisms related to the inhibition of nuclear factor kappa B signaling, cyclooxygenase 2, and matrix metalloproteinases. However, the molecular mechanism underlying the effects of these tetracyclines is not fully understood. Therefore, the present review sought to summarize the latest findings of MINO and DOXY use for major psychiatric disorders and present the possible targets to their molecular and behavioral effects. In conclusion, tetracyclines hold great promise as (ready-to-use) agents for being used as adjunctive therapy for human neuropsychiatric disorders. Hence, the understanding of their molecular mechanisms may contribute to the discovery of new targets for the rational drug design of novel psychoactive agents.

Involvement of anti-inflammatory, antioxidant, and BDNF up-regulating properties in the antipsychotic-like effect of the essential oil of Alpinia zerumbet in mice: a comparative study with olanzapine.

The current drug therapy for schizophrenia effectively treats acute psychosis and its recurrence; however, this mental disorder's cognitive and negative symptoms are still poorly controlled. Antipsychotics present important side effects, such as weight gain and extrapyramidal effects. The essential oil of Alpinia zerumbet (EOAZ) leaves presents potential antipsychotic properties that need further preclinical investigation. Here, we determined EAOZ effects in preventing and reversing schizophrenia-like symptoms (positive, negative, and cognitive) induced by ketamine (KET) repeated administration in mice and putative neurobiological mechanisms related to this effect. We conducted the behavioral evaluations of prepulse inhibition of the startle reflex (PPI), social interaction, and working memory (Y-maze task), and verified antioxidant (GSH, nitrite levels), anti-inflammatory [interleukin (IL)-6], and neurotrophic [brain-derived neurotrophic factor (BDNF)] effects of this oil in hippocampal tissue. The atypical antipsychotic olanzapine (OLZ) was used as standard drug therapy. EOAZ, similarly to OLZ, prevented and reversed most KET-induced schizophrenia-like behavioral alterations, i.e., sensorimotor gating deficits and social impairment. EOAZ had a modest effect on the prevention of KET-associated working memory deficit. Compared to OLZ, EOAZ showed a more favorable side effects profile, inducing less cataleptic and weight gain changes. EOAZ efficiently protected the hippocampus against KET-induced oxidative imbalance, IL-6 increments, and BDNF impairment. In conclusion, our data add more mechanistic evidence for the anti-schizophrenia effects of EOAZ, based on its antioxidant, anti-inflammatory, and BDNF up-regulating actions. The absence of significant side effects observed in current antipsychotic drug therapy seems to be an essential benefit of the oil.

Tryptophan catabolites along the indoleamine 2,3-dioxygenase pathway as a biological link between depression and cancer.

Both depression and cancer are related to a dysregulation of inflammatory and immune pathways. Indeed, depression is associated with increased expression of interferon-γ, interleukin-1ß, and tumor necrosis factor α (TNF-α). In contrast, reductions of the activity of major histocompatibility complex protein molecules - class I and class II and natural killer cells are also observed. Similarly, cancers present elevated levels of TNF-α, reduced major histocompatibility complex class I and II, and natural killer cells. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of the tryptophan catabolite (TRYCAT) pathway, is induced by interferon-γ, interleukin-6, TNF-α, and oxidative stress. IDO catabolizes tryptophan, the amino acid precursor of serotonin and melatonin, to the metabolites collectively called TRYCATs. TRYCAT pathway activation is accompanied by downregulation of immune cell proliferation, function, and survival. The increase in IDO activity in tumor microenvironments is related to tumor cell escape from immune surveillance. Despite the evidence of inflammatory mechanisms underlying cancer and depression, it is important to emphasize that both diseases are heterogeneous and, as such, inflammatory mechanisms may not be relevant to all patients. Thus, the purpose of this review is to examine whether detrimental TRYCATs - synthesis of which increases in depression and cancer - are a pathophysiological link between the two diseases, and whether IDO is a potential pharmacological target for the treatment of the comorbid depression and cancer.

Minocycline protects against oxidative damage and alters energy metabolism parameters in the brain of rats subjected to chronic mild stress.

Studies have been suggested that minocycline can be a potential new agent for the treatment of depression. In addition, both oxidative stress and energy metabolism present an important role in pathophysiology of depression. So, the present study was aimed to evaluate the effects of minocycline on stress oxidative parameters and energy metabolism in the brain of adult rats submitted to the chronic mild stress protocol (CMS). After CMS Wistar, both stressed animals as controls received twice ICV injection of minocycline (160 µg) or vehicle. The oxidative stress and energy metabolism parameters were assessed in the prefrontal cortex (PF), hippocampus (HIP), amygdala (AMY) and nucleus accumbens (Nac). Our findings showed that stress induced an increase on protein carbonyl in the PF, AMY and NAc, and mynocicline injection reversed this alteration. The TBARS was increased by stress in the PF, HIP and NAc, however, minocycline reversed the alteration in the PF and HIP. The Complex I was incrased in AMY by stress, and minocycline reversed this effect, however reduced Complex I activity in the NAc; Complex II reduced in PF and AMY by stress or minocycline; the Complex II-III increased in the HIP in stress plus minocycline treatment and in the NAc with minocycline; in the PF and HIP there were a reduced in Complex IV with stress and minocycline. The creatine kinase was reduced in AMY and NAc with stress and minocycline. In conclusion, minocycline presented neuroprotector effects by reducing oxidative damage and regulating energy metabolism in specific brain areas.

Targeting the Renin-Angiotensin System (RAS) for Neuropsychiatric Disorders.

BACKGROUND: Neuropsychiatric disorders, such as mood disorders, schizophrenia, and Alzheimer's disease (AD) and related dementias, are associated to significant morbidity and mortality worldwide. The pathophysiological mechanisms of neuropsychiatric disorders remain to be fully elucidated, which has hampered the development of effective therapies. The Renin Angiotensin System (RAS) is classically viewed as a key regulator of cardiovascular and renal homeostasis. The discovery that RAS components are expressed in the brain pointed out a potential role for this system in central nervous system (CNS) pathologies. The understanding of RAS involvement in the pathogenesis of neuropsychiatric disorders may contribute to identifying novel therapeutic targets. AIMS: We aim to report current experimental and clinical evidence on the role of RAS in physiology and pathophysiology of mood disorders, schizophrenia, AD and related dementias. We also aim to discuss bottlenecks and future perspectives that can foster the development of new related therapeutic strategies. CONCLUSION: The available evidence supports positive therapeutic effects for neuropsychiatric disorders with the inhibition/antagonism of the ACE/Ang II/AT1 receptor axis or the activation of the ACE2/Ang-(1-7)/Mas receptor axis. Most of this evidence comes from pre-clinical studies and clinical studies lag much behind, hampering a potential translation into clinical practice.

Effectiveness of pharmacological interventions for managing ADHD symptoms in individuals with autism spectrum disorder: A systematic review and meta-analysis.

OBJECTIVES: This systematic review sought to provide evidence for the effectiveness of common pharmacological interventions used for treating attention deficit hyperactivity disorder (ADHD) symptoms in the autism spectrum disorder (ASD) population, considering studies attempting to find safe and effective drugs. METHODS: We searched for randomized controlled trials describing the effectiveness and/or safety profile of pharmacological interventions for treating ASD and ADHD or ASD with ADHD symptoms using three bibliographic databases: PubMed, Cochrane Library, and Embase. We have chosen ADHD symptoms measured by any clinical scale as the primary outcome. As additional outcomes, we have used other symptoms of aberrant behavior measured by the aberrant behavior checklist, satisfaction with treatment, and peer satisfaction. RESULTS: Twenty-two publications met the inclusion criteria for the systematic review and eight for the meta-analysis. In our investigation, we found a few articles using clonidine, modafinil, and bupropion as interventions when compared to methylphenidate (MPH). Our meta-analysis showed that MPH had positive changes compared to placebo in symptoms such as hyperactivity, irritability, or inattention. However, no effect was found in stereotyped symptoms, and our data's quantitative analysis revealed a large effect of MPH-induced adverse effects on the dropout rate. On the other hand, atomoxetine initiation had positive effects when compared to placebo on symptoms of hyperactivity and inattention. We have found no effect of atomoxetine on stereotypes or irritability. Furthermore, atomoxetine did not influence side effects that caused dropouts from studies. CONCLUSION: Our results indicated that atomoxetine has a modest effect on hyperactivity and inattention symptoms, with a relatively benign profile of side effects. MPH appears to be effective in handling hyperactivity, inattention, and irritability symptoms. However, our results on atomoxetine revealed increased dropouts due to adverse effects when compared to MPH or placebo. Evidence for other substances such as guanfacine, clonidine, bupropion, or modafinil is either preliminary or nonexistent.

Long-term Environmental Enrichment Normalizes Schizophrenia-like Abnormalities and Promotes Hippocampal Slc6a4 Promoter Demethylation in Mice Submitted to a Two-hit Model.

Here, we explored the impact of prolonged environmental enrichment (EE) on behavioral, neurochemical, and epigenetic changes in the serotonin transporter gene in mice subjected to a two-hit schizophrenia model. The methodology involved administering the viral mimetic PolyI:C to neonatal Swiss mice as a first hit during postnatal days (PND) 5-7, or a sterile saline solution as a control. At PND21, mice were randomly assigned either to standard environment (SE) or EE housing conditions. Between PND35-44, the PolyI:C-treated group was submitted to various unpredictable stressors, constituting the second hit. Behavioral assessments were conducted on PND70, immediately after the final EE exposure. Following the completion of behavioral assessments, we evaluated the expression of proteins in the hippocampus that are indicative of microglial activation, such as Iba-1, as well as related to neurogenesis, including doublecortin (Dcx). We also performed methylation analysis on the serotonin transporter gene (Slc6a4) to investigate alterations in serotonin signaling. The findings revealed that EE for 50 days mitigated sensorimotor gating deficits and working memory impairments in two-hit mice and enhanced their locomotor and exploratory behaviors. EE also normalized the overexpression of hippocampal Iba-1 and increased the expression of hippocampal Dcx. Additionally, we observed hippocampal demethylation of the Slc6a4 gene in the EE-exposed two-hit group, indicating epigenetic reprogramming. These results contribute to the growing body of evidence supporting the protective effects of long-term EE in counteracting behavioral disruptions caused by the two-hit schizophrenia model, pointing to enhanced neurogenesis, diminished microglial activation, and epigenetic modifications of serotonergic pathways as underlying mechanisms.

Doxycycline reversal of amphetamine-induced mania-like behavior is related to adjusting brain monoamine abnormalities and antioxidant effects in primary hippocampal neurons.

Mania is associated with disturbed dopaminergic transmission in frontotemporal regions. D-amphetamine (AMPH) causes increased extracellular DA levels, considered an acknowledged mania model in rodents. Doxycycline (DOXY) is a second-generation tetracycline with promising neuroprotective properties. Here, we tested the hypothesis that DOXY alone or combined with Lithium (Li) could reverse AMPH-induced mania-like behavioral alterations in mice by the modulation of monoamine levels in brain areas related to mood regulation, as well as cytoprotective and antioxidant effects in hippocampal neurons. Male Swiss mice received AMPH or saline intraperitoneal (IP) injections for 14 days. Between days 8-14, mice receive further IP doses of DOXY, Li, or their combination. For in vitro studies, we exposed hippocampal neurons to DOXY in the presence or absence of AMPH. DOXY alone or combined with Li reversed AMPH-induced risk-taking behavior and hyperlocomotion. DOXY also reversed AMPH-induced hippocampal and striatal hyperdopaminergia. In AMPH-exposed hippocampal neurons, DOXY alone and combined with Li presented cytoprotective and antioxidant effects, while DOXY+Li also increased the expression of phospho-Ser133-CREB. Our results add novel evidence for DOXY's ability to reverse mania-like features while revealing that antidopaminergic activity in some brain areas, such as the hippocampus and striatum, as well as hippocampal cytoprotective effects may account for this drug's antimanic action. This study provides additional rationale for designing clinical trials investigating its potential as a mood stabilizer agent.

The psychological defensive profile of hemodialysis patients and its relationship to health-related quality of life.

Preliminary data suggest that defensive profile of hemodialysis (HD) patients might influence adaptation to the disease. However, the association of defense mechanisms with health-related quality of life (HRQoL) of HD patients remains unknown. In this cross-sectional investigation, 170 HD patients and 170 age- and sex-matched healthy participants had their psychological profile assessed with the Defense Style Questionnaire-40 and the Hospital Anxiety and Depression Scale. Furthermore, the HD patients had their HRQoL measured with the World Health Organization Quality of Life instrument-abbreviated version. The HD patients had a more neurotic and immature defensive profile. Splitting, projection, reaction formation, and denial were significantly associated with impaired HRQoL, independent of psychological distress. Somatization was an independent correlate of worse overall and physical HRQoL. These findings suggest that, apart from the treatment of psychological distress symptoms, clinicians should also consider the defensive profile of HD patients because it is independently associated with HRQoL and may be amenable to treatment.

Immunoinflammatory and oxidative alterations in subjects with schizophrenia under clozapine: A meta-analysis.

Clozapine presents immunoregulatory properties not well understood. To address this issue, we performed this systematic review to evaluate the immune alterations induced by clozapine and its relationship with the drug's clinical response and compare it with other antipsychotics. Our systematic review has selected nineteen studies meeting the inclusion criteria, from which eleven were included in the meta-analysis, totalizing 689 subjects distributed over three different comparisons. The results revealed that clozapine treatment activates the compensatory immune-regulatory system (CIRS) (Hedges's g = +1.049; CI +0.62 - +1.47, p < 0.001) but has no effects on the immune-Inflammatory Response System (IRS) (Hedges's g= -0.27; CI -1.76 - +1.22, p = 0.71), M1 macrophage (Hedges's g= -0.32; CI -1.78 - +1.14, p = 0.65) and Th1 (Hedge's g = 0.86; CI -0.93 - +1.814, p = 0.07) profiles. Comparing clozapine-treated patients with other anti-psychotics-treated, plasma levels of interleukin (IL)-6 were greater in the clozapine group (Hedge's g = 0.75; CI 0.35 - 1.15, p<0.001). In addition, higher IL-6 plasma levels after four weeks of clozapine treatment were related to the development of clozapine-induced fever; however, IL-6 levels recovered to baseline in 6-10 weeks due to an unexplained compensatory mechanism. In conclusion, our results show that clozapine treatment causes a time-dependent mixed immune profile characterized by increased IL-6 levels and CIRS activation, which may contribute to this drug mechanism of action and adverse effects. Future studies must be designed to investigate the relationship between clozapine-induced immune alterations and symptom remission, treatment resistance, and adverse effects, given the importance of this drug for treating resistant schizophrenia.

Sex and the Estrous-Cycle Phase Influence the Expression of G Protein-Coupled Estrogen Receptor 1 (GPER) in Schizophrenia: Translational Evidence for a New Target.

Schizophrenia is a mental disorder with sex bias in disease onset and symptom severity. Recently, it was observed that females present more severe symptoms in the perimenstrual phase of the menstrual cycle. The administration of estrogen also alleviates schizophrenia symptoms. Despite this, little is known about symptom fluctuation over the menstrual cycle and the underlying mechanisms. To address this issue, we worked with the two-hit schizophrenia animal model induced by neonatal exposure to a virus-like particle, Poly I:C, associated with peripubertal unpredictable stress exposure. Prepulse inhibition of the startle reflex (PPI) in male and female mice was considered analogous to human schizophrenia-like behavior. Female mice were studied in the proestrus (high-estrogen estrous cycle phase) and diestrus (low-estrogen phase). Additionally, we evaluated the hippocampal mRNA expression of estrogen synthesis proteins; TSPO and aromatase; and estrogen receptors ERα, ERß, and GPER. We also collected peripheral blood mononuclear cells (PBMCs) from male and female patients with schizophrenia and converted them to induced microglia-like cells (iMGs) to evaluate the expression of GPER. We observed raised hippocampal expression of GPER in two-hit female mice at the proestrus phase without PPI deficits and higher levels of proteins related to estrogen synthesis, TSPO, and aromatase. In contrast, two-hit adult males with PPI deficits presented lower hippocampal mRNA expression of TSPO, aromatase, and GPER. iMGs from male and female patients with schizophrenia showed lower mRNA expression of GPER than controls. Therefore, our results suggest that GPER alterations constitute an underlying mechanism for sex influence in schizophrenia.

Effects of alpha-lipoic acid in an animal model of mania induced by D-amphetamine.

OBJECTIVES: Oxidative stress and neurotrophic factors are involved in the pathophysiology of bipolar disorder (BD). Alpha-lipoic acid (ALA) is a naturally occurring compound with strong antioxidant properties. The present study investigated ALA effects in an amphetamine-induced model of mania. METHODS: In the reversal protocol, adult mice were first given d-amphetamine (AMPH) 2 mg/kg, intraperitoneally (i.p.) or saline for 14 days. Between days 8 and 14, the animals received ALA 50 or 100 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention paradigm, mice were pretreated with ALA, Li, or saline prior to AMPH. Locomotor activity was assessed in the open-field task. Superoxide dismutase (SOD) activity, reduced glutathione (GSH), and thiobarbituric acid-reactive substance (TBARS) levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC), and striatum (ST). Brain-derived neurotrophic factor (BDNF) levels were measured in the HC. RESULTS: ALA and Li prevented and reversed the AMPH-induced increase in locomotor activity. PREVENTION MODEL: ALA and Li co-administration with AMPH prevented the decrease in SOD activity induced by AMPH in the HC and ST, respectively; ALA and Li prevented GSH alteration in the HC and TBARS formation in all brain areas studied. REVERSAL MODEL: ALA reversed the decrease in SOD activity in the ST. TBARS formation was reversed by ALA and Li in all brain areas. Furthermore, ALA reversed AMPH-induced decreases in BDNF and GSH in the HC. CONCLUSIONS: Our findings showed that ALA, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations, providing a rationale for the design of clinical trials investigating ALA's possible antimanic effect.

The tetrapartite synapse in neuropsychiatric disorders: Matrix metalloproteinases (MMPs) as promising targets for treatment and rational drug design.

Inflammation and an exacerbated immune response are widely accepted contributing mechanisms to the genesis and progression of major neuropsychiatric disorders. However, despite the impressive advances in understanding the neurobiology of these disorders, there is still no approved drug directly linked to the regulation of inflammation or brain immune responses. Importantly, matrix metalloproteinases (MMPs) comprise a group of structurally related endopeptidases primarily involved in remodeling extracellular matrix (ECM). In the central nervous system (CNS), these proteases control synaptic plasticity and strength, patency of the blood-brain barrier, and glia-neuron interactions through cleaved and non-cleaved mediators. Several pieces of evidence have pointed to a complex scenario of MMPs dysregulation triggered by neuroinflammation. Furthermore, major psychiatric disorders' affective symptoms and neurocognitive abnormalities are related to MMPs-mediated ECM changes and neuroglia activation. In the past decade, research efforts have been directed to broad-spectrum MMPs inhibitors with frustrating clinical results. However, in the light of recent advances in combinatorial chemistry and drug design technologies, specific and CNS-oriented MMPs modulators have been proposed as a new frontier of therapy for regulating ECM properties in the CNS. Therefore, here we aim to discuss the state of the art of MMPs and ECM abnormalities in major neuropsychiatric disorders, namely depression, bipolar disorder, and schizophrenia, the possible neuro-immune interactions involved in this complex scenario of MMPs dysregulation and propose these endopeptidases as promising targets for rational drug design.

Anxiolytic Effect of Carvedilol in Chronic Unpredictable Stress Model.

Anxiety disorders are the most prevalent psychiatric disorders being also a comorbid state of other diseases. We aimed to evaluate the anxiolytic-like effects of carvedilol (CVD), a drug used to treat high blood pressure and heart failure with potent antioxidant effects, in animals exposed to chronic unpredictable stress (CUS). To do this, female Swiss mice were exposed to different stressors for 21 days. Between days 15 and 21, the animals received oral CVD (5 or 10 mg/kg) or the antidepressant desvenlafaxine (DVS 10 mg/kg). On the 22nd day, behavioral tests were conducted to evaluate locomotor activity (open field) and anxiety-like alterations (elevated plus-maze-EPM and hole board-HB tests). After behavioral determinations, the animals were euthanized, and the adrenal gland, blood and brain areas, prefrontal cortex (PFC), and hippocampus were removed for biochemical analysis. CUS reduced the crossings while increased rearing and grooming, an effect reversed by both doses of CVD and DVS. CUS decreased the number of entries and permanence time in the open arms of the EPM, while all treatments reversed this effect. CUS reduced the number of head dips in the HB, an effect reversed by CVD. The CUS reduced weight gain, while only CVD5 reversed this effect. A reduction in the cortical layer size of the adrenal gland was observed in stressed animals, which CVD reversed. Increased myeloperoxidase activity (MPO) and interferon-γ (IFN-γ), as well as reduction of interleukin-4 (IL-4) induced by CUS, were reversed by CVD. DVS and CVD increased IL-6 in both brain areas. In the hippocampus, DVS caused an increase in IFN-γ. Our data show that CVD presents an anxiolytic effect partially associated with immune-inflammatory mechanism regulation.