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).

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 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.

Alpha-lipoic acid in the treatment of psychiatric and neurological disorders: a systematic review.

Despite the existence of many preclinical studies, scientific evidence is lacking on the clinical use of alpha-lipoic acid (ALA) for central nervous system disorders. Therefore, we aimed at revising the literature concerning the use of ALA for the treatment of psychiatric and neurological conditions and to point out what is missing for the introduction of this antioxidant to this purpose. For this systematic review we performed a search using PubMed and SCOPUS databases with the following keywords: "alpha-Lipoic Acid AND central nervous system OR psychiatric disorders OR neurological disorders OR mood disorders OR anxiety OR psychosis OR Alzheimer OR Parkinson OR stroke". The total number of references found after automatically and manually excluding duplicates was 1061. After primary and secondary screening 32 articles were selected. Regarding psychiatric disorders, the studies of ALA in schizophrenia are advanced being ALA administration related to the improvement of schizophrenia symptoms and side effects of antipsychotic medication. In neurological disorders, ALA as a supplement was effective in the prevention of Alzheimer disease progression. For stroke, the use of the supplement ALAnerv® (containing 300 mg ALA) presented important results, since it was observed a reversal of clinical parameters and oxidative imbalance in these patients. For other neurological conditions, such as encephalopathy, multiple sclerosis, traumatic brain injury, mitochondrial disorders and migraine, the results are still preliminary. Overall, there is a need of well-designed clinical trials to enhance the clinical evidences of ALA effects for the treatment of neurological and psychiatric conditions.

The anxiolytic-like effect of 6-styryl-2-pyrone in mice involves GABAergic mechanism of action.

The present work aims to investigate the anxiolytic activity of 6-styryl-2-pyrone (STY), obtained from Aniba panurensis, in behavioral tests and amino acids dosage on male Swiss mice. The animals were treated with STY (1, 10 or 20 mg), diazepam (DZP 1 or 2 mg/kg) or imipramine (IMI 30 mg/kg). Some groups were administered with flumazenil, 30 min before administration of the STYor DZP. The behavioral tests performed were open field, rota rod, elevated plus maze (EPM), hole-board (HB) and tail suspension test (TST). After behavioral tests, these animals were sacrificed and had their prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) dissected for assaying amino acids (aspartate- ASP, glutamate- GLU, glycine- GLY, taurine- TAU and Gamma-aminobutyric acid- GABA). In EPM test, STY or DZP increased the number of entries and the time of permanence in the open arms, but these effects were reverted by flumazenil. In the HB test, STY increased the number of head dips however this effect was blocked by flumazenil. The effects of the STY on amino acid concentration in PFC showed increased GLU, GABA and TAU concentrations. In hippocampus, STY increased the concentrations of all amino acids studied. In striatum, STY administration at lowest dose reduced GLU concentrations, while the highest dosage caused the opposite effect. GLI, TAU and GABA concentrations increased with STY administration at highest doses. In conclusion, this study showed that STY presents an anxiolytic-like effect in behavioral tests that probably is related to GABAergic mechanism of action.

Central effects of lipoic acid associated with paroxetine in mice.

Antidepressants, including selective serotonin reuptake inhibitors, are commonly prescribed for the treatment of affective disorders such as anxiety and depression. The purpose of this study was to investigate the central effects of acute administration of paroxetine (PXT) combined with lipoic acid (LA) on various behavioral models in mice. Paroxetine (10 and 20 mg/kg), LA (100 mg/kg), or vehicle was administered, intraperitoneally, 30 minutes before the tests. The results showed that PXT (10 mg/kg) alone and in combination with LA increased locomotor activity. In the anxiety models studied, an anxiolytic effect was observed after the administration of LA and PXT. In the tail suspension test, PXT at both doses and in combination with LA caused a significant decrease in immobility time. These results indicate possible anxiolytic and antidepressant effects of LA associated with PXT. These data suggest that coadministration of LA and PXT may improve anxiolytic and antidepressant responses, and being more effective than each drug alone. However, further studies are necessary to investigate the mechanism by which antioxidants exert antidepressant or anxiolytic action.

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.

Effects of agomelatine on oxidative stress in the brain of mice after chemically induced seizures.

Agomelatine is a novel antidepressant drug with melatonin receptor agonist and 5-HT(2C) receptor antagonist properties. We analyzed whether agomelatine has antioxidant properties. Antioxidant activity of agomelatine (25, 50, or 75 mg/kg, i.p.) or melatonin (50 mg/kg) was investigated by measuring lipid peroxidation levels, nitrite content, and catalase activities in the prefrontal cortex, striatum, and hippocampus of Swiss mice pentylenetetrazole (PTZ) (85 mg/kg, i.p.), pilocarpine (400 mg/kg, i.p.), picrotoxin (PTX) (7 mg/kg, i.p.), or strychnine (75 mg/kg, i.p.) induced seizure models. In the pilocarpine-induced seizure model, all dosages of agomelatine or melatonin showed a significant decrease in TBARS levels and nitrite content in all brain areas when compared to controls. In the strychnine-induced seizure model, all dosages of agomelatine and melatonin decreased TBARS levels in all brain areas, and agomelatine at low doses (25 or 50 mg/kg) and melatonin decreased nitrite contents, but only agomelatine at 25 or 50 mg/kg showed a significant increase in catalase activity in three brain areas when compared to controls. Neither melatonin nor agomelatine at any dose have shown no antioxidant effects on parameters of oxidative stress produced by PTX- or PTZ-induced seizure models when compared to controls. Our results suggest that agomelatine has antioxidant activity as shown in strychnine- or pilocarpine-induced seizure models.

Prevention of haloperidol-induced alterations in brain acetylcholinesterase activity by vitamins B co-administration in a rodent model of tardive dyskinesia.

Tardive dyskinesia (TD) is an iatrogenic syndrome being a significant adverse outcome of typical and atypical antipsychotic therapy. Recently we demonstrated that vitamins B (B1, B6, B12 alone or in combination) were able to prevent haloperidol-induced orofacial dyskinesia (OD) possibly by their antioxidant activity in the striatum, using a well-established model of TD. Here, based on the fact that alterations in cholinergic neurotransmission are related to TD pathophysiology and that vitamins B seems to influence brain cholinergic neurotransmission, we decided to investigate the effects of vitamins B1, B6, B12 and their association, vitamin B cocktail in haloperidol-induced cholinergic alterations, evaluated by alterations in acetylcholinesterase (AChE) activity, in striatum, prefrontal cortex and hippocampus, as a way to determine the participation of cholinergic neurotransmission, in these vitamins antidyskinetic mechanism. Haloperidol 1 mg/kg i.p. daily administration during 21 days to Wistar rats caused OD while decreased AChE activity in all brain areas studied. Vitamins B administration (B1:B6:B12 at 60:60:0.6 mg/kg, s.c) alone and vitamin B cocktail co-administered with haloperidol prevented OD development and increased AChE activity in all brain areas studied, with the maximum activity increment observed in the hippocampus of the animals co-treated with vitamin B12 and vitamin B cocktail. The antidyskinetic drug, clozapine did not induce OD and increased AChE activity similarly to the groups coadministered with vitamin B and HAL. The present data suggest that vitamins B can prevent haloperidol-induced alterations in AChE activity what can be related to the mechanism underlying their antidyskinetic effect.

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.

Anticonvulsant effects of agomelatine in mice.

Agomelatine is a potent MT1 and MT2 melatonin receptor agonist and a 5-HT2C serotonin receptor antagonist. We analyzed whether agomelatine has anticonvulsant properties. The anticonvulsant activity of agomelatine (25, 50 or 75 mg/kg, i.p.) was evaluated in mouse models of pentylenetetrazole (PTZ-85 mg/kg, i.p.), pilocarpine (400mg/kg, i.p.), picrotoxin (7 mg/kg, i.p.), strychnine (75 mg/kg, i.p.) or electroshock-induced convulsions. In the PTZ-induced seizure model, agomelatine (at 25 or 50mg/kg) showed a significant increase in latency to convulsion, and agomelatine (at 50 or 75 mg/kg) also increased significantly time until death. In the pilocarpine-induced seizure model, only agomelatine in high doses (75 mg/kg) showed a significant increase in latency to convulsions and in time until death. In the strychnine-, electroshock- and picrotoxin-induced seizure models, agomelatine caused no significant alterations in latency to convulsions and in time until death when compared to controls. Our results suggest that agomelatine has anticonvulsant activity shown in PTZ- or pilocarpine-induced seizure models.

Anticonvulsant action of Calotropis procera latex proteins.

Calotropis procera (Ait.) R.Br. is a laticiferous plant belonging to the Apocynaceae family. C. procera latex proteins were evaluated with respect to anticonvulsant and sedative activity in mouse models of pentylenetetrazol (PTZ)-, pilocarpine-, and strychnine-induced convulsions or turning behavior and pentobarbital-induced sleep. In the strychnine- and pilocarpine-induced seizure models, C. procera latex proteins caused no significant alterations in latencies to convulsions and death, as compared with controls. In the PTZ-induced seizure model, administration of C. procera latex proteins in high doses (50 or 100mg/kg) and diazepam caused significant increases in latencies to convulsions and death. C. procera latex proteins (50 or 100mg/kg) and 2mg/kg diazepam caused a decrease in sleep latency and an increase in sleep time compared with the control group and groups treated with 5 or 10mg/kg. Our results suggest that C. procera latex proteins have a central nervous system-depressant activity as reflected in their potentiation of pentobarbital-induced sleeping time and their anticonvulsant action in the PTZ-induced seizure model.

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.

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.

B vitamins attenuate haloperidol-induced orofacial dyskinesia in rats: possible involvement of antioxidant mechanisms.

Tardive dyskinesia (TD) is a serious motor disorder related to antipsychotic therapy, whose pathophysiology is associated to oxidative stress. Treatments that maintain antipsychotic efficacy while reducing TD risk are awaited. Haloperidol (HAL), a typical antipsychotic, is used as a putative murine model of TD. Here, we evaluated the protective role of vitamins B1, B6, and B12 alone or in combination (vitamin B cocktail) in preventing the HAL-induced orofacial dyskinesia (OD), based on their antioxidant properties. HAL (1 mg/kg) administered intraperitoneally to Wistar rats for 21 days caused OD and increased catalepsy time. The daily administration of B vitamins (B1 : B6 : B12 at 60 : 60 : 0.6 mg/kg) alone or the vitamin B cocktail, along with HAL, prevented the development of OD. Catalepsy time reduced in all groups treated with B vitamins, but to a lesser extent than OD. The participation of oxidative stress was assessed by the determination of reduced glutathione (GSH) levels and lipid peroxide formation in the striatum. HAL significantly decreased GSH levels and enhanced lipid peroxidation, whereas B1, B12, and vitamin B cocktail prevented the decrease in GSH levels. All groups treated with B vitamins presented a decrease in lipid peroxide formation. The data suggest a promising role for B vitamins in the prevention of OD.

The contributions of antioxidant activity of lipoic acid in reducing neurogenerative progression of Parkinson's disease: a review.

ABSTRACT This work reviews the evidence of the mechanism of neuronal degeneration in Parkinson's disease (PD) and the neuroprotective effect of lipoic acid and its use in the treatment of PD. PD is characterized by slow and progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta, leading to reduction of the striatal dopaminergic terminals. It is known that several factors influence neuronal damage. Among these factors, oxidative stress, immune system activity, microglial cells, and apoptotic mechanisms are of major importance. Currently, several antioxidants have been studied with the aim of reducing/slowing the progression of neurodegenerative processes. Lipoic acid is considered a universal antioxidant because it is an amphipathic substance. Lipoic acid and its reduced form, dihidrolipoic acid, act against reactive oxygen species, reducing oxidative stress. Therefore, this antioxidant has been used in the treatment of many diseases, including a new perspective for the treatment of Parkinson's disease.

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.