Cyclooxygenase-2 inhibitors alleviated depressive and anxious-like behaviors in mice exposed to lipopolysaccharide: Involvement of oxidative stress and neuroinflammation.

Depression and anxiety disorders have their pathophysiologies linked to inflammation and oxidative stress. In this context, celecoxib (CLX) and etoricoxib (ETR) inhibit cyclooxygenase 2 (COX-2), an enzyme expressed by cells involved in the inflammatory process and found in the brain. Studies have been using CLX as a possible drug in the treatment of depression, although its mechanisms at the central nervous system level are not fully elucidated. In this study, the effects of CLX and ETR on behavioral, oxidative, and inflammatory changes induced by systemic exposure to Escherichia coli lipopolysaccharide (LPS) were evaluated in adult male swiss mice. For ten days, the animals received intraperitoneal injections of LPS at 0.5 mg/kg. From the sixth to the tenth day, one hour after LPS exposure, they were treated orally with CLX (15 mg/kg), ETR (10 mg/kg), or fluoxetine (FLU) (20 mg/kg). Twenty-four hours after the last oral administration, the animals underwent evaluation of locomotor activity (open field test), predictive tests for depressive-like behavior (forced swim and tail suspension tests), and anxiolytic-like effect (elevated plus maze and hole board tests). Subsequently, the hippocampus, prefrontal cortex and striatum were dissected for the measurement of oxidative and nitrosative parameters (malondialdehyde, nitrite, and glutathione) and quantification of pro-inflammatory cytokines (IL-1ß and IL-6). LPS induced depressive and anxious-like behavior, and treatment with CLX or ETR was able to reverse most of the behavioral changes. It was evidenced that nitrosative stress and the degree of lipid peroxidation induced by LPS were reduced in different brain areas after treatment with the drugs, as well as the endogenous defense system against free radicals was strengthened. CLX and ETR also significantly reduced LPS-induced cytokine levels. These data are expected to expand information on the role of inflammation in depression and anxiety and provide insights into possible mechanisms of COX-2 inhibitors in psychiatric disorders with a neurobiological basis in inflammation and oxidative stress.

Cognitive dysfunction in systemic lupus erythematosus is associated with disease activity and oxidative stress: a comparative study with rheumatoid arthritis for identifying biomarkers.

BACKGROUND: The prevalence and pathophysiological mechanisms of cognitive deficits (CD) Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA) are very heterogeneous and poorly understood. We characterized CD in patients with SLE compared with RA patients and healthy controls. We compared the neuropsychological profile of SLE and RA with patients' oxidative/inflammatory biomarkers for CD. METHODS: We performed a cross-sectional study, including 50 SLE patients, 29 RA patients, and 32 healthy controls. SLEDAI and DAS28 assessed disease activity. SF-36 questionnaire and a battery of cognitive tests were applied to all participants. Blood samples were collected to determine IL-6, S100ß, myeloperoxidase (MPO), malondialdehyde and reduced glutathione (GSH) alterations. RESULTS: In the SLE group, higher GSH was associated with the absence of CD (With CD = 69 ± 49, Without CD = 112 ± 81, p = 0.030), while higher IL-6 was associated with the presence of CD in the RA group (With CD = 603 ± 173, Without CD = 431 ± 162, p = 0.032). Regarding specific cognitive domains, in SLE higher MPO was associated with poor performance in reasoning and abstraction (p = 0.039), higher IL-6 was associated with poor performance in inhibitory control and attention (p = 0.031), and higher GSH was associated with better performance in memory(p = 0.021). Higher SLEDAI was associated with poor performance in semantic fluency(p = 0.031), inhibitory control, and attention in the SLE group(p = 0.037). In the RA group, higher DAS-28 was associated with poor performance in executive functions(p = 0.016) and phonemic fluency (p = 0.003). CONCLUSION: SLE patients' disease activity, inflammatory state, and oxidative stress were associated with CD. In RA patients, CD was associated with disease activity and inflammatory state. These results encourage further studies with larger samples aiming to confirm oxidative stress parameters as biomarkers of CD in SLE patients.

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.

Bothrops pauloensis snake venom-derived Asp-49 and Lys-49 phospholipases A2 mediates acute kidney injury by oxidative stress and release of inflammatory cytokines.

The envenomation caused by the Bothrops pauloensis snake leads to severe local and systemic effects including acute kidney injury. In this study, we investigated the renal effects by phospholipases A2 (PLA2s), divided into two main subgroups, Asp-49 and Lys-49, isolated from the Bothrops pauloensis snake venom (BpV) in isolated rat kidney system. Both PLA2s (3 µg/mL), added alone to the perfusion system and analyzed for 120 min, had significant effects on isolated rat kidney. Asp-49 reduced Glomerular Filtration Rate (GFR) at 60, 90 and 120 min, and the percentage of total tubular sodium transport (%TNa+) and potassium transport (%TK+) at 120 min. Lys-49 increased Perfusion Pressure (PP) at 120 min and reduced GFR, %TNa+ and the percentage of total tubular chloride transport (%TCl-) at 60, 90 and 120 min. Cytokine release in the kidney tissues were increased with Asp-49 PLA2 (IL-10) and Lys-49 PLA2 (TNF-α, IL-1ß, IL-10). Both increased MPO activity. Asp-49 PLA2 decreased Glutathione (GSH) and increased nitrite levels, while Lys-49 PLA2 increased Malondialdehyde (MDA), GSH and nitrite levels. Histological analysis of the perfused kidneys revealed the presence of glomerular degeneration and atrophy, deposit of proteinaceous material in Bowman's space and intratubular with both PLA2s. These findings indicated that both PLA2s modified the functional parameters in an isolated perfused kidney model with increased oxidative stress and cytokine release. PLA2s are one of the components at high concentration in BpV and our results provide important knowledge about their involvement with the nephrotoxic mechanism.

Involvement of monoaminergic targets in the antidepressant- and anxiolytic-like effects of the synthetic alkamide riparin IV: Elucidation of further mechanisms through pharmacological, neurochemistry and computational approaches.

Despite recent advances, current antidepressants have considerable limitations: late onset of action and the high profile of refractoriness. Biomedical research with natural products has gained growing interest in the last years, and had provide useful candidates for new antidepressants. Riparins are a group of natural alkamides obtained from Aniba riparia, which had marked neuroactive effects, mainly as antidepressant and antinociceptive agents. We made modifications of the basic structure of riparins, originating a synthetic alkamide, also known as riparin IV (RipIV). RipIV demonstrated a superior analgesic effect than its congeners and a marked antidepressant-like effect. However, the basic mechanism for the central effects of RipIV remains unknown. Here, we aimed to investigate the participation of monoaminergic neurotransmission targets in the antidepressant-like effects of RipIV. To do this, we applied a combined approach of experimental (classical pharmacology and neurochemistry) and computer-aided techniques. Our results demonstrated that RipIV presented antidepressant- and anxiolytic-like effects without modifying locomotion and motor coordination of mice. Also, RipIV increased brain monoamines and their metabolite levels. At the higher dose (100 mg/kg), RipIV increased serotonin concentrations in all studied brain areas, while at the lower one (50 mg/kg), it increased mainly dopamine and noradrenaline levels. When tested with selective receptor antagonists, RipIV antidepressant effect showed dependence of the activation of multiple targets, including D1 and D2 dopamine receptors, 5-HT2A/2, 5-HT3 receptors and α2 adrenergic receptors. Molecular docking demonstrated favorable binding conformation and affinity of RipIV to monoamine oxidase B (MAO-B), serotonin transporter (SERT), α1 receptor, D2 receptor, dopamine transporter (DAT) and at some extent GABA-A receptor. RipIV also presented a computationally predicted favorable pharmacokinetic profile. Therefore, this study demonstrated the involvement of monoaminergic targets in the mechanism of RipIV antidepressant-like action, and provide evidence of it as a promising new antidepressant.

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.

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.

Impact of the Chronic Omega-3 Fatty Acids Supplementation in Hemiparkinsonism Model Induced by 6-Hydroxydopamine in Rats.

Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra. The neuronal degeneration may result from the convergence of a number of different pathogenic factors, including apoptosis, excitotoxicity and oxidative stress. Many studies emphasize the importance of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in vital processes such as maintenance of the properties of cell membranes and the participation in signal transduction and biodynamic activity of neuronal membranes. In this study, the protective effect of ω-3 PUFA administration on the 6-hydroxydopamine (6-OHDA) model of PD in rats was investigated. ω-3 PUFA (1.5 and 3.0 g/kg) was orally administered by gavage during 28 consecutive days to male Wistar rats. On the 4th day, hemiparkinsonism was induced through intrastriatal injection of 6-OHDA. On the 25th day, the animals were submitted to behavioural analysis. On the 28th day, after euthanasia, the brain areas were collected for neurochemical evaluation. ω-3 PUFAs (1.5 and 3.0 g/kg) restored monoamine and amino acid levels on the striatum from hemiparkinsonian rats, followed by reduction in the number of apomorphine-induced rotations and promotion of a partial locomotor recovery. In addition, ω-3 PUFAs (1.5 and 3.0 g/kg) decreased the lipid peroxidation levels and nitrite levels in the brain areas from hemiparkinsonian rats. Thus, this study suggests that supplementation with ω-3 PUFAs prevents behavioural and neurochemical disturbances induced by 6-OHDA, presenting a potential neuroprotective action.

Involvement of monoaminergic system in the antidepressant-like effect of riparin I from Aniba riparia (Nees) Mez (Lauraceae) in mice.

In past studies conducted by our group, riparin I (rip I) isolated from the green fruit of Aniba riparia presented antianxiety effects in mice, while its analogs rip II and III showed anxiolytic and antidepressant-like actions. This time around, we investigated a possible antidepressant activity of rip I using the forced swimming test (FST) and tail suspension test (TST) as predictive tests for antidepressant activity in rodents. In addition, the involvement of the monoaminergic system in this effect was also assessed. rip I was acutely administered by intraperitoneal (i.p.) and oral (p.o) routes to male mice at doses of 25 and 50 mg/kg. Results showed that rip I at both tested doses and administration routes produced a significant decrease in immobility time in FST and TST. The pretreatment of mice with prazosin (1 mg/kg, i.p., an α1 -adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α2 -adrenoceptor antagonist), SCH23390 (15 µg/kg, i.p., a dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist), p-chlorophenylalanine (100 mg/kg, an inhibitor of serotonin synthesis) or ritanserin (4 mg/kg, a serotonin 5-HT2(A)/2(C) receptor antagonist) blocked the anti-immobility effects elicited by rip I (50 mg/kg, p.o.) in the FST. Taken together, results indicate that rip I produces significant antidepressant-like activity in the FST and TST, and this effect seems to be dependent on its interaction with noradrenergic, dopaminergic and serotonergic systems.

Effects of doxycycline on depressive-like behavior in mice after lipopolysaccharide (LPS) administration.

Current evidences support inflammation, oxidative and nitrogen stress, as well as brain-derived neurotrophic factor (BDNF) signaling mechanisms as important in depression pathophysiology. Tetracycline antibiotics have anti-inflammatory and antioxidant properties. Preliminary evidence indicates that minocycline has antidepressant properties. Doxycycline (DOXY) has favorable pharmacokinetic and safety profiles when compared to other tetracycline congeners. The antidepressant activity of DOXY has not been adequately investigated. This study evaluated the effects of DOXY (25 and 50 mg/kg, i.p.) on LPS-induced (0.5 mg/kg, i.p.) depressive-like behavior. Doxycycline was administered 30 min before LPS (pre-LPS) or 1.5 and 23.5 h following LPS (post-LPS) administration in mice. LPS-treated animals presented an increase in immobility time in the forced swimming test (FST) when compared to controls 24 h after endotoxin administration. Similarly to imipramine (IMI-10 mg/kg, i.p.), DOXY at both doses prevented and reversed LPS-induced alterations in the FST. IL-1ß content was increased 24 h after LPS administration in striatum, hippocampus and prefrontal cortex. IMI and DOXY prevented and reversed LPS-induced increase in IL-1ß. IMI and DOXY also prevented and reversed LPS-induced alterations in nitrite content and oxidative stress parameters (lipid peroxidation and reduced glutathione levels). Both DOXY and IMI prevented LPS-induced decrease in hippocampal BDNF levels. Taken together, our results demonstrate that DOXY is comparable to IMI in effectively ameliorate LPS-induced depressive-like behavior, providing a rationale for testing DOXY's antidepressant efficacy in humans.

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.

Antidepressant effect of aminophylline after ethanol exposure.

This work investigated the association of acute ethanol and aminophylline administration on behavioral models of depression and prefrontal monoamine levels (i.e. norepinephrine and dopamine) in mice. The animals received a single dose of ethanol (2 g/kg) or aminophylline (5 or 10 mg/kg) alone or in association. Thirty minutes after the last drug administration, the animals were assessed in behavioral models by the forced swimming and tail suspension tests. After these tests, the animals were sacrificed and the prefrontal cortices dissected to measure monoamine content. Results showed that ethanol presented depression-like activity in the forced swimming and tail suspension tests. These effects were reversed by the association with aminophylline in all tests. Norepinephrine and dopamine levels decreased, while an increase in the dopamine metabolite, (4-hydroxy-3-methoxyphenyl)acetic acid (DOPAC), after ethanol administration was observed. On the contrary, the association of ethanol and aminophylline increased the norepinephrine and dopamine content, while it decreased DOPAC when compared to the ethanol group, confirming the alterations observed in the behavioral tests. These data reinforce the involvement of the adenosinergic system on ethanol effects, highlighting the importance of the norepinephrine and dopamine pathways in the prefrontal cortex to the effects of ethanol.

Time course of the effects of lipopolysaccharide on prepulse inhibition and brain nitrite content in mice.

The systemic administration of lipopolysaccharide (LPS) induces time-dependent behavioral alterations, which are related to sickness behavior and depression. The time-course effects of LPS on prepulse inhibition (PPI) remain unknown. Furthermore, the time-dependent effects of LPS on central nitrite content had not been investigated. Therefore, we studied alterations induced by single LPS (0.5mg/kg, i.p.) administration to mice on parameters, such as PPI, depressive- and anxiety-like behaviors, working memory, locomotor activity and motor coordination, 1.5 and 24h post-LPS administration. IL-1ß and TNFα in the blood and brain as well as brain nitrite levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST). An overall hypolocomotion was observed 1.5h post-LPS, along with depressive-like behaviors and deficits in working memory. Increments in IL-1ß content in plasma and PFC, TNFα in plasma and decreases in nitrite levels in the ST and PFC were also verified. Twenty-four hours post-LPS treatment, depressive-like behaviors and working memory deficits persisted, while PPI levels significantly reduced along with increases in IL-1ß content in the PFC and a decrease in nitrite levels in the HC, ST and PFC. Our data demonstrate that a delayed increase (i.e., 24h post-LPS) in PPI levels ensue, which may be useful behavioral parameter for LPS-induced depression. A decrease in nitrergic neurotransmission was associated with these behavioral findings.

Augmentation therapy with alpha-lipoic acid and desvenlafaxine: a future target for treatment of depression?

This study was designed to investigate the possible antidepressant effects of the antioxidant alpha-lipoic acid (ALA) as a stand-alone treatment or in association with desvenlafaxine (DVS) in the chronic corticosterone (CORT)-induced depression model. The depression model was induced by repeated administrations of CORT (20 mg/kg, subcutaneous) in mice over a period of 14 days. Between days 15 and 21, a randomized group of mice received DVS (10 or 20 mg/kg, per os [PO]), ALA (100 or 200 mg/kg, PO), or a combination of DVS (10 or 20 mg/kg, PO) and ALA (100 or 200 mg/kg, PO) along with the CORT injections for the remaining 7 days. Other groups of mice received DVS (10 or 20 mg/kg, PO) or ALA (100 or 200 mg/kg, PO) alone. Open field test, elevated plus maze (EPM) test, tail suspension test (TST), and forced swimming test (FST) were carried out 1 h after the last injection of CORT. Repeated CORT injections induced anxiety-like and depressive-like behaviors as observed by decreased open arms entries in the EPM test and increased immobility time in the TST and FST. The administration of DVS and ALA alone was able to reverse the increases in the immobility time. The combination of ALA and DVS potentiated the observed effects of DVS. These results suggest that augmentation therapy with the addition of antioxidant drugs may be an important pharmacological approach for the treatment of depression.

Synergistic effects of amiodarone and fluconazole on Candida tropicalis resistant to fluconazole.

There have recently been significant increases in the prevalence of systemic invasive fungal infections. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of cross-resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapies have become one of the most widely used and effective strategies to alleviate this problem. Amiodarone (AMD) is classically used for the treatment of atrial fibrillation and is the drug of choice for patients with arrhythmia. Recent studies have shown broad antifungal activity of the drug when administered in combination with fluconazole (FLC). In the present study, we induced resistance to fluconazole in six strains of Candida tropicalis and evaluated potential synergism between fluconazole and amiodarone. The evaluation of drug interaction was determined by calculating the fractional inhibitory concentration and by performing flow cytometry. We conclude that amiodarone, when administered in combination with fluconazole, exhibits activity against strains of C. tropicalis that are resistant to fluconazole, which most likely occurs via changes in the integrity of the yeast cell membrane and the generation of oxidative stress, mitochondrial dysfunction, and DNA damage that could lead to cell death by apoptosis.

Antidepressant-like effect of bis-eugenol in the mice forced swimming test: evidence for the involvement of the monoaminergic system.

Dehydrodieugenol, known as bis-eugenol, is a eugenol ortho dimer, and both compounds were able to exhibit anti-inflammatory and antioxidant activities in previous studies. Furthermore, eugenol showed antidepressant-like effect; however, the biological actions of bis-eugenol on experimental models for screening antidepressant activity are still unknown. The present study investigated a possible antidepressant-like activity of bis-eugenol in the forced swimming test (FST) and tail suspension test (TST) in mice and the involvement in the monoaminergic system in this effect. In addition, a neurochemical analysis on brain monoamines of mice acutely treated with bis-eugenol was also conducted. Bis-eugenol decreased the immobility time in the FST and TST without accompanying changes in ambulation in the open field test at 10 mg/kg, i.p.. Nevertheless, it induced ambulation at 25 and 50 mg/kg doses. The anti-immobility effect of bis-eugenol (10 and 50 mg/kg, i.p.) was prevented by pretreatment of mice with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), yohimbine (1 mg/kg, i.p., an α2-adrenoceptor antagonist), SCH23390 (15 µg/kg, s.c., a dopamine D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist). Monoamines analysis using high-performance liquid chromatograph revealed significant increase in the 5-HT, NE and DA levels in brain striatum. The present study indicates that bis-eugenol possesses antidepressant-like activity in FST and TST by altering dopaminergic, serotonergic and noradrenergic systems function.

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.