Polysaccharide-rich extract of Genipa americana leaves protects seizures and oxidative stress in the mice model of pentylenetetrazole-induced epilepsy.

Plant polysaccharides have biological activities in the brain and those obtained from Genipa americana leaves present antioxidant and anticonvulsant effects in the mice model of pentylenetetrazole (PTZ)-induced acute seizures. This study aimed to evaluate the polysaccharide-rich extract of Genipa americana leaves (PRE-Ga) in the models of acute seizures and chronic epilepsy (kindling) induced by PTZ. In the acute seizure model, male Swiss mice (25-35 g) received PRE-Ga (1 or 9 mg/kg; intraperitoneal- IP), alone or associated with diazepam (0.01 mg/kg), 30 min before induction of seizures with PTZ (70 mg/kg; IP). In the chronic epilepsy model, seizures were induced by PTZ (40 mg/kg) 30 min after treatment and in alternated days up to 30 days and evaluated by video. Brain areas (prefrontal cortex, hippocampus, striatum) were assessed for inflammatory and oxidative stress markers. Diazepam associated to PRE-Ga (9 mg/kg; i.p.) increased the latency of seizures in acute (222.4 ± 47.57 vs. saline: 62.00 ± 4.709 s) and chronic models (6.267 ± 0.502 vs. saline: 4.067 ± 0.407 s). In hippocampus, PRE-Ga (9 mg/kg) inhibited TNF-α (105.9 ± 5.38 vs. PTZ: 133.5 ± 7.62 pmol/g) and malondialdehyde (MDA) (473.6 ± 60.51) in the chronic model. PTZ increased glial fibrillar acid proteins (GFAP) and Iba-1 in hippocampus, which was reversed by PRE-Ga (GFAP: 1.9 ± 0.23 vs PTZ: 3.1 ± 1.3 and Iba-1: 2.2 ± 0.8 vs PTZ: 3.2 ± 1.4). PRE-Ga presents neuroprotector effect in the mice model of epilepsy induced by pentylenetetrazole reducing seizures, gliosis, inflammatory cytokines and oxidative stress.

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).

Epiisopiloturine, an Alkaloid from Pilocarpus microphyllus, Attenuates LPS-Induced Neuroinflammation by Interfering in the TLR4/NF-κB-MAPK Signaling Pathway in Microglial Cells.

Neuroinflammation is present in the pathophysiological mechanisms of several diseases that affect the central nervous system (CNS). Microglia have a prominent role in initiating and sustaining the inflammatory process. Epiisopiloturine (EPI) is an imidazole alkaloid obtained as a by-product of pilocarpine extracted from Pilocarpus microphyllus (jaborandi) and has shown promising anti-inflammatory and antinociceptive properties. In the present study, we investigated the effects of EPI on the inflammatory response in microglial cells (BV-2 cells) induced by lipopolysaccharide (LPS) and explored putative underlying molecular mechanisms. Cell viability was not affected by EPI (1-100 µg/mL) as assessed by both LDH activity and the MTT test. Pretreatment with EPI (25, 50, and 100 µg/mL) significantly reduced the proinflammatory response induced by LPS, as observed by a decrease in nitrite oxide production and iNOS protein expression. EPI (25 µg/mL) reduced IL-6 and TNF-α production, by 40% and 34%, respectively. However, no changes were observed in the anti-inflammatory IL-10 production. Mechanistically, EPI inhibited the TLR4 expression and phosphorylation of NF-κB p65 and MAPKs (JNK and ERK1/2) induced by LPS, but no changes were observed in TREM2 receptor expression in LPS-stimulated cells. In conclusion, our data demonstrated the potent anti-inflammatory properties of EPI in microglial cells. These effects are associated with the reduction of TLR4 expression and inhibition of intracellular signaling cascades, including NF-κB and MAPKs (JNK and ERK1/2).

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.

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.

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.

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.

Involvement of oxidative pathways and BDNF in the antidepressant effect of carvedilol in a depression model induced by chronic unpredictable stress.

RATIONALE: Depression is a severe psychiatric disorder with oxidative imbalance and neurotrophic deficits as underlying mechanisms. OBJECTIVES: Based on the antioxidant effects of carvedilol (CARV), here, we aimed to evaluate CARV's effects against depression induced by the chronic unpredictable stress (CUS) model. METHODS: Female Swiss mice were submitted to the CUS protocol for 21 days. Between days 15 and 22, the animals received CARV (5 or 10 mg/kg) or desvenlafaxine (DVS 10 mg/kg) orally. On the 22nd day, mice were subjected to behavioral tests to evaluate locomotion, depressive-like behavior (tail suspension test), motivation/self-care with the splash test (ST), social interaction, and working memory Y-maze test. The prefrontal cortex (PFC) and hippocampus were dissected to evaluate alterations of oxidative and brain-derived neurotrophic factor (BDNF). RESULTS: The CUS model reduced locomotion and increased grooming latency, while it reduced the number of groomings in the ST. Both doses of CARV and DVS reverted these alterations. In addition, DVS and CARV reversed CUS model-induced working memory and social interaction deficits. The CUS model decreased hippocampal reduced glutathione (GSH), while DVS and CARV increased GSH in the PFC (CARV5) and hippocampus (CARV5 and 10). The CUS model increased nitrite and malondialdehyde (MDA) concentrations in both areas. All treatments reversed nitrite alterations, while CARV10 changed MDA levels in PFC and all treatments in the hippocampus. The CUS model reduced BDNF levels. CARV10 increased BDNF in the PFC, while both doses of CARV increased hippocampal levels of this neurotrophin. CONCLUSIONS: CARV presents antidepressant-like effects comparable to those observed with DVS. In addition, it has an antioxidant effect and is capable of increasing BDNF brain concentrations. Further studies are needed to elucidate the mechanisms involved in the antidepressant effect of CARV.

Lipoic acid prevents mirtazapine-induced weight gain in mice without impairs its antidepressant-like action in a neuroendocrine model of depression.

Mirtazapine (MIRT) is a multi-target antidepressant used in treatment of severe depression with promising efficacy, but also with important side effects, mainly sedation and weight gain. Thus, the present study aimed to test the effects of the neuroprotective antioxidant lipoic acid (ALA) in the reversal of weight and metabolic changes induced by MIRT in corticosterone-induced depression model in mice, as well as proposed mechanisms for their association antidepressant and pro-cognitive effects. To do these male Swiss mice received Tween 80 (control), corticosterone (CORT 20 mg / kg), MIRT (3 mg / kg) and ALA (100 or 200 mg / kg), alone or associated for 21 days. After this, the animals were subjected to behavioral tests for affective and cognitive domains. Daily weight changes, blood cholesterol fractions and corticosterone were measured. Also, hippocampus (HC) protein expression of the serotonin transporter (SERT), synaptophysin, protein kinase B-Akt (total and phosphorylated) and the cytokines IL-4 and IL-6 were investigated. CORT induced a marked depression-like behavior, memory deficits, metabolic changes (total cholesterol and LDL) and increased serum corticosterone. Also, CORT increased SERT expression in the HC. MIRT alone or combined with ALA sustained its antidepressant-like effect, as well as reversed CORT-induced impairment in spatial recognition memory. Additionally, the association MIRT+ALA200 reversed the weight gain induced by the former antidepressant, as well as reduced serum corticosterone levels and SERT expression in the HC. ALA alone induced significant weight loss and reduced total cholesterol and HDL fraction. Our findings provide promising evidence about the ALA potential to prevent metabolic and weight changes associated to MIRT, without impair its antidepressant and pro-cognition actions. Therefore, ALA+MIRT combination could represent a new therapeutic strategy for treating depression with less side effects.

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.

Doxycycline at subantimicrobial dose combined with escitalopram reverses depressive-like behavior and neuroinflammatory hippocampal alterations in the lipopolysaccharide model of depression.

Doxycycline (DOXY) is a second-generation tetracycline with anti-inflammatory and neuroprotective effects. A proinflammatory profile seems to predict the severity of depressive symptoms. In the present study, we aimed at determining whether the anti-inflammatory action of subantimicrobial-dose doxycycline (SDD) (DOXY, 10mg/kg), alone or combined with the antidepressant escitalopram (ESC), could revert lipopolysaccharide-induced depressive-like alterations in mice. Male Swiss mice received saline or lipopolysaccharide (LPS) for ten consecutive days. From the 6th day of LPS exposure, they were treated with DOXY 10 mg/kg, ESC 4 mg/kg, DOXY 10 mg/kg plus ESC 4 mg/kg (DOXY+ESC), or saline. On the 10th day, we assessed behavioral despair (forced swimming test), anhedonia (sucrose preference test), brain oxidative stress markers, and inflammatory and protective pathways related to depression, such as NF-kB and phospho-CREB. Our results showed that DOXY alone or combined with ESC reduced hippocampal Iba-1 expression and interleukin (IL)-1ß levels. Only DOXY+ESC successfully reversed the LPS-induced increase in NF-kBp65 expression and TNFα levels. DOXY caused a marked increase in the hippocampal expression of phospho-CREB and GSH concentrations. DOXY and DOXY+ESC showed a tendency to modulate the functional status of mitogen-activated kinase p42-44 (Phospho-p44/42 MAPK) and of the phosphorylated form of glycogen synthase kinase 3 beta (GSK3ß), revealing a protective profile against inflammation. In conclusion, SDD, combined with ESC, seems to be a good strategy for reverting inflammatory changes and protecting against depression.

Low-dose candesartan prevents schizophrenia-like behavioral alterations in a neurodevelopmental two-hit model of schizophrenia.

Schizophrenia is a severe mental disorder with complex etiopathogenesis. Based on its neurodevelopmental features, an animal model induced by "two-hit" based on perinatal immune activation followed by peripubertal unpredictable stress was proposed. Sex influences the immune response, and concerning schizophrenia, it impacts the age of onset and symptoms severity. The neurobiological mechanisms underlying the influence of sex in schizophrenia is poorly understood. Our study aimed to evaluate sex influence on proinflammatory and oxidant alterations in male and female mice exposed to the two-hit model of schizophrenia, and its prevention by candesartan, an angiotensin II type 1 receptor (AT1R) blocker with neuroprotective properties. The two-hit model induced schizophrenia-like behavioral changes in animals of both sexes. Hippocampal microglial activation alongside the increased expression of NF-κB, and proinflammatory cytokines, namely interleukin (IL)-1ß and TNF-α, were observed in male animals. Conversely, females presented increased hippocampal and plasma levels of nitrite and plasma lipid peroxidation. Peripubertal administration of low-dose candesartan (0.3 mg/kg PO) prevented behavioral, hippocampal, and systemic changes in male and female mice. While these results indicate the influence of sex on inflammatory and oxidative changes induced by the two-hit model, candesartan was effective in both males and females. The present study advances the neurobiological mechanisms underlying sex influence in schizophrenia and opens new avenues to prevent this devasting mental disorder.

Is Riparin III a promising drug in the treatment for depression?

Stress is crucially related to the pathophysiology of mood disorders, including depression. Since the effectiveness and number of the current pharmacological options still presents significant limitations, research on new substances is paramount. In rodents, several findings have indicated that corticosterone administration induces the manifestation of behavioral and neurochemical aspects of depression. Recently, riparin III has shown antidepressant-like properties in trials performed on animal models. Thus, our goal was to investigate the effects of riparin III on behavioral tests, monoamines levels, oxidative stress and cytokines levels in chronic corticosterone-induced model of depression. To do this, female swiss mice were treated with subcutaneous administration of corticosterone for 22 days. In addition, for the last 10 days, riparin III or fluvoxamine were also administered per os in specific test groups. Control groups received subcutaneous saline injections or distilled water per os. At the end of the timeline, the animals were killed and their hippocampi, prefrontal cortex, and striatum dissected for neurochemical analysis. Brain changes following corticosterone administration were confirmed, and riparin III could reversed the most abnormal behavioral and neurochemical corticosterone-induced alterations. These results suggest the potential antioxidant, anti-inflammatory and antidepressant effects of riparin III after a chronic stress exposure.

Sex influences in the preventive effects of peripubertal supplementation with N-3 polyunsaturated fatty acids in mice exposed to the two-hit model of schizophrenia.

Schizophrenia is a devastating neurodevelopmental disorder. The animal model based on perinatal immune activation, as first-hit, combined with peripubertal stress, as a second hit, has gained evidence in recent years. Omega-3 polyunsaturated fatty acids (n3-PUFAs) is being a promise for schizophrenia prevention. Nevertheless, the influence of sex in schizophrenia neurobiology and prevention has been neglected. Thus, the present study evaluates the preventive effects of n3-PUFAs in both sexes' mice submitted to the two-hit model and the participation of oxidative changes in this mechanism. The two-hit consisted of polyI:C administration from postnatal days (PNs) 5-7, and unpredictable stress from PNs35-43. n3-PUFAs were administered from PNs30-60. Prepulse inhibition of the startle reflex (PPI), social interaction, and Y-maze tests were conducted between PNs70-72 to evaluate positive-, negative-, and cognitive-like schizophrenia symptoms. We assessed brain oxidative changes in brain areas and plasma. Both sexes' two-hit mice presented deficits in PPI, social interaction, and working memory that were prevented by n3-PUFAs. In two-hit females, n3-PUFAs prevented increments in nitrite levels in the prefrontal cortex (PFC), hippocampus, striatum, and plasma TBARS levels. In two-hit males, n3-PUFAs prevented the increase in TBARS in the PFC, hippocampus, and striatum. Notably, male mice that received only n3-PUFAs without hit exposure presented impairments in working memory and social interaction. These results add further preclinical evidence for n3-PUFAs as an accessible and effective alternative in preventing behavioral and oxidative changes related to schizophrenia but call attention to the need for precaution in this indication due to hit- and sex-sensitive issues.

Sex influences in the preventive effects of N-acetylcysteine in a two-hit animal model of schizophrenia.

BACKGROUND: Schizophrenia (SCZ) is a neurodevelopmental disorder influenced by patient sex. Mechanisms underlying sex differences in SCZ remain unknown. A two-hit model of SCZ combines the exposure to perinatal infection (first-hit) with peripubertal unpredictable stress (PUS, second-hit). N-acetylcysteine (NAC) has been tested in SCZ because of the involvement of glutathione mechanisms in its neurobiology. AIMS: We aim to investigate whether NAC administration to peripubertal rats of both sexes could prevent behavioral and neurochemical changes induced by the two-hit model. METHODS: Wistar rats were exposed to polyinosinic:polycytidylic acid (a viral mimetic) or saline on postnatal days (PND) 5-7. On PND30-59 they received saline or NAC 220 mg/kg and between PND40-48 were subjected to PUS or left undisturbed. On PND60 behavioral and oxidative alterations were evaluated in the prefrontal cortex (PFC) and striatum. Mechanisms of hippocampal memory regulation such as immune expression of G protein-coupled estrogen receptor 1 (GPER), α7-nAChR and parvalbumin were also evaluated. RESULTS: NAC prevented sensorimotor gating deficits only in females, while it prevented alterations in social interaction, working memory and locomotor activity in both sexes. Again, in rats of both sexes, NAC prevented the following neurochemical alterations: glutathione (GSH) and nitrite levels in the PFC and lipid peroxidation in the PFC and striatum. Striatal oxidative alterations in GSH and nitrite were observed in females and prevented by NAC. Two-hit induced hippocampal alterations in females, namely expression of GPER-1, α7-nAChR and parvalbumin, were prevented by NAC. CONCLUSION: Our results highlights the influences of sex in NAC preventive effects in rats exposed to a two-hit schizophrenia model.

Flavonoids: biological activities and therapeutic potential.

Flavonoids have aroused much interest in research, since they present a great diversity of biological activities observed in vitro, such as: antioxidant effect, modulation of the enzymatic activity and inhibition of cellular proliferation, exerting beneficial effects on the organism, as well as the use of its therapeutic potential. With wide distribution in the plant kingdom represent a class of phenolic compounds that differ in their chemical structure and particular characteristics. The objective of this review was to describe the relevant aspects of flavonoids, reporting the different known groups, the probable mechanisms by which they act, their pharmacological properties and to gain a better understanding of the reported beneficial health effects of these substances. This systematic review consisted of research using scientific databases such as Scopus, Science Direct, PubMed, SciVerse and SciELO, without time limitation. Some pharmacological properties of some flavonoids and their health benefits have been confirmed by previous studies.

Thymol reverses depression-like behaviour and upregulates hippocampal BDNF levels in chronic corticosterone-induced depression model in female mice.

OBJECTIVES: Based on this, the central therapeutic effects of thymol were verified in the neurotrophic pathway. METHODS: Female swiss mice were divided into four groups: control, corticosterone (Cort), thymol (Cort + thymol) and fluvoxamine (Cort + Flu). The administration of corticosterone was used to induce depressive symptoms for 23 days. After the treatment, the animals were exposed the behavioural tests, such as forced swimming test, tail suspension test, sucrose preference test, light/dark test, social interaction test, Y-maze test, plus-maze test and hole-board test. The hippocampus was also removed, and BDNF was measured by ELISA and Western blot. KEY FINDINGS: As a result, thymol and fluvoxamine were able to reverse the depressive symptoms, as well as to improve the anxious frame. The anhedonic and short-term memory was restored with the treatment. In the neurochemical tests, both thymol and fluvoxamine restored BDNF levels, improving the depressive condition. CONCLUSIONS: This work opens up new investigations aiming at the use of this molecule as a therapeutic alternative for treating depression disorders.

High Exploratory Phenotype Rats Exposed to Environmental Stressors Present Memory Deficits Accompanied by Immune-Inflammatory/Oxidative Alterations: Relevance to the Relationship Between Temperament and Mood Disorders.

Low-exploratory (LE) and high-exploratory (HE) rodents mimic human depressive and hyperthymic temperaments, respectively. Mood disorders (MD) may be developed by the exposure of these temperaments to environmental stress (ES). Psychiatric symptoms severity in MD patients is related to the magnitude of memory impairment. Thus, we aimed at studying the consequences of the exposure of LE and HE male Wistar rats, during periadolescence, to a combination of ES, namely, paradoxical sleep deprivation (PSD) and unpredictable stress (US), on anxiety-related behavior in the plus maze test, working (WM) and declarative memory (DM) performance. We also evaluated hippocampal immune-inflammatory/oxidative, as consequences of ES, and prevention of ES-induced alterations by the mood-stabilizing drugs, lithium and valproate. Medium exploratory (ME) control rats were used for comparisons with HE- and LE-control rats. We observed that HE-controls presented increased anxiolytic behavior that was significantly increased by ES exposure, whereas LE-controls presented increased anxiety-like behavior relative to ME-controls. Lithium and valproate prevented anxiolytic alterations in HE+ES rats. HE+ES- and LE+ES-rats presented WM and DM deficits. Valproate and lithium prevented WM deficits in LE-PSD+US rats. Lithium prevented DM impairment in HE+ES-rats. Hippocampal levels of reduced glutathione (GSH) increased four-fold in HE+ES-rats, being prevented by valproate and lithium. All groups of LE+ES-rats presented increased levels of GSH in relation to controls. Increments in lipid peroxidation in LE+ES- and HE+ES-rats were prevented by valproate in HE+ES-rats and by both drugs in LE+ES-rats. Nitrite levels were increased in HE+ES- and LE+ES-rats (five-fold increase), which was prevented by both drugs in LE+ES-rats. HE+ES-rats presented a two-fold increase in the inducible nitric oxide synthase (iNOS) expression that was prevented by lithium. HE+ES-rats showed increased hippocampal and plasma levels of interleukin (IL)-1ß and IL-4. Indoleamine 2, 3-dioxygenase 1 (IDO1) was increased in HE+ES- and LE+ES-rats, while tryptophan 2,3-dioxygenase (TDO2) was increased only in HE+ES-rats. Altogether, our results showed that LE- and HE-rats exposed to ES present distinct anxiety-related behavior and similar memory deficits. Furthermore, HE+ES-rats presented more brain and plasma inflammatory alterations that were partially prevented by the mood-stabilizing drugs. These alterations in HE+ES-rats may possibly be related to the development of mood symptoms.

Evidence for Host Epigenetic Signatures Arising From Arbovirus Infections: A Systematic Review.

Background: Arbovirus infections have steadily become a major pandemic threat. This study aimed at investigating the existence of host epigenetic markers arising from the principal arboviruses infections impacting on human health. We set to systematically review all published evidence describing any epigenetic modifications associated with infections from arboviruses, including, but not limited to, microRNAs, DNA methylation, and histone modifications. Methods: A comprehensive search was conducted using the electronic databases PubMed, Science Direct and Cochrane Library from inception to January 4th, 2018. We included reports describing original in vivo or in vitro studies investigating epigenetic changes related to arbovirus infections in either clinical subjects or human cell lines. Studies investigating epigenetic modifications related to the virus or the arthropod vector were excluded. A narrative synthesis of the findings was conducted, contextualizing comparative evidence from in vitro and in vivo studies. Results: A total of 853 unique references were identified and screened by two independent researchers. Thirty-two studies met the inclusion criteria and were reviewed. The evidence was centered mainly on microRNA and DNA methylation signatures implicated with secondary Dengue fever. Evidence for recent epidemic threats, such as the infections by Zika or Chikungunya viruses is still scant. Conclusions: Major epigenetic alterations found on arboviruses infections were miR-146, miR-30e and the Dicer complex. However, existing studies frequently tested distinct hypotheses resulting in a heterogeneity of methodological approaches. Whilst epigenetic signatures associated with arbovirus infections have been reported, existing studies have largely focused on a small number of diseases, particularly dengue. Validation of epigenetic signatures have an untapped potential, but concerted investigations are certainly required to deliver robust candidates of clinical utility for diagnosis, staging and prognosis of specific arboviral diseases.

Reversal effect of Riparin IV in depression and anxiety caused by corticosterone chronic administration in mice.

Mental disorders have a multifactorial etiology and stress presents as one of the causal factors. In depression, it is suggested that high cortisol concentration contributes directly to the pathology of this disease. Based on that, the study aims to evaluate the potential antidepressant effect of Riparin IV (Rip IV) in mice submitted to chronic stress model by repeated corticosterone administration. Female Swiss mice were selected into four groups: control (Ctrl), corticosterone (Cort), Riparin IV (Cort + Rip IV) and fluvoxamine (Cort + Flu). Three groups were administrated subcutaneously (SC) with corticosterone (20 mg/kg) during twenty-one days, while the control group received only vehicle. After the fourteenth day, groups were administrated tested drugs: Riparin IV, fluvoxamine or distilled water, by gavage, 1 h after subcutaneous injections. After the final treatment, animals were exposed to behavioral models such as forced swimming test (FST), tail suspension test (TST), open field test (OFT), elevated plus maze (EPM) and sucrose preference test (SPT). The hippocampus was also removed for the determination of BDNF levels. Corticosterone treatment altered all parameters in behavioral tests, leading to a depressive- and anxious-like behavior. Riparin IV and fluvoxamine exhibit antidepressant effect in FST, TST and SPT. In EPM and OFT, treatment displayed anxiolytic effect without alteration of locomotor activity. Corticosterone administration decreased BDNF levels and Riparin IV could reestablish them, indicating that its antidepressant effect may be related to ability to ameliorate hippocampal neurogenesis. These findings suggest that Riparin IV improves the depressive and anxious symptoms after chronic stress and could be a new alternative treatment for patients with depression.