The neurobiology and therapeutic potential of multi-targeting ß-secretase, glycogen synthase kinase 3ß and acetylcholinesterase in Alzheimer's disease.

Alzheimer's Disease (AD) is the most common form of dementia, affecting almost 50 million of people around the world, characterized by a complex and age-related progressive pathology with projections to duplicate its incidence by the end of 2050. AD pathology has two major hallmarks, the amyloid beta (Aß) peptides accumulation and tau hyperphosphorylation, alongside with several sub pathologies including neuroinflammation, oxidative stress, loss of neurogenesis and synaptic dysfunction. In recent years, extensive research pointed out several therapeutic targets which have shown promising effects on modifying the course of the disease in preclinical models of AD but with substantial failure when transposed to clinic trials, suggesting that modulating just an isolated feature of the pathology might not be sufficient to improve brain function and enhance cognition. In line with this, there is a growing consensus that an ideal disease modifying drug should address more than one feature of the pathology. Considering these evidence, ß-secretase (BACE1), Glycogen synthase kinase 3ß (GSK-3ß) and acetylcholinesterase (AChE) has emerged as interesting therapeutic targets. BACE1 is the rate-limiting step in the Aß production, GSK-3ß is considered the main kinase responsible for Tau hyperphosphorylation, and AChE play an important role in modulating memory formation and learning. However, the effects underlying the modulation of these enzymes are not limited by its primarily functions, showing interesting effects in a wide range of impaired events secondary to AD pathology. In this sense, this review will summarize the involvement of BACE1, GSK-3ß and AChE on synaptic function, neuroplasticity, neuroinflammation and oxidative stress. Additionally, we will present and discuss new perspectives on the modulation of these pathways on AD pathology and future directions on the development of drugs that concomitantly target these enzymes.

QTC-4-MeOBnE Ameliorated Depressive-Like Behavior and Memory Impairment in 3xTg Mice.

Growing evidence has associated major depressive disorder (MDD) as a risk factor or prodromal syndrome for the occurrence of Alzheimer's disease (AD). Although this dilemma remains open, it is widely shown that a lifetime history of MDD is correlated with faster progression of AD pathology. Therefore, antidepressant drugs with neuroprotective effects could be an interesting therapeutic conception to target this issue simultaneously. In this sense, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4- carboxamide (QTC-4-MeOBnE) was initially conceived as a multi-target ligand with affinity to ß-secretase (BACE), glycogen synthase kinase 3ß (GSK3ß), and acetylcholinesterase but has also shown secondary effects on pathways involved in neuroinflammation and neurogenesis in preclinical models of AD. Herein, we investigated the effect of QTC-4-MeOBnE (1 mg/kg) administration for 45 days on depressive-like behavior and memory impairment in 3xTg mice, before the pathology is completely established. The treatment with QTC-4-MeOBnE prevented memory impairment and depressive-like behavior assessed by the Y-Maze task and forced swimming test. This effect was associated with the modulation of plural pathways involved in the onset and progression of AD, in cerebral structures of the cortex and hippocampus. Among them, the reduction of amyloid beta (Aß) production mediated by changes in amyloid precursor protein metabolism and hippocampal tau phosphorylation through the inhibition of kinases. Additionally, QTC-4-MeOBnE also exerted beneficial effects on neuroinflammation and synaptic integrity. Overall, our studies suggest that QTC-4-MeOBnE has a moderate effect in a transgenic model of AD, indicating that perhaps studies regarding the neuropsychiatric effects as a neuroprotective molecule are more prone to be feasible.

"NO" Time in Fear Response: Possible Implication of Nitric-Oxide-Related Mechanisms in PTSD.

Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by persistent fear responses and altered neurotransmitter functioning due to traumatic experiences. Stress predominantly affects glutamate, a neurotransmitter crucial for synaptic plasticity and memory formation. Activation of the N-Methyl-D-Aspartate glutamate receptors (NMDAR) can trigger the formation of a complex comprising postsynaptic density protein-95 (PSD95), the neuronal nitric oxide synthase (nNOS), and its adaptor protein (NOS1AP). This complex is pivotal in activating nNOS and nitric oxide (NO) production, which, in turn, activates downstream pathways that modulate neuronal signaling, including synaptic plasticity/transmission, inflammation, and cell death. The involvement of nNOS and NOS1AP in the susceptibility of PTSD and its comorbidities has been widely shown. Therefore, understanding the interplay between stress, fear, and NO is essential for comprehending the maintenance and progression of PTSD, since NO is involved in fear acquisition and extinction processes. Moreover, NO induces post-translational modifications (PTMs), including S-nitrosylation and nitration, which alter protein function and structure for intracellular signaling. Although evidence suggests that NO influences synaptic plasticity and memory processing, the specific role of PTMs in the pathophysiology of PTSD remains unclear. This review highlights pathways modulated by NO that could be relevant to stress and PTSD.

1-(7-Chloroquinolin-4-yl)-N-(4-Methoxybenzyl)-5-Methyl-1H-1,2, 3-Triazole-4- carboxamide Reduces Aß Formation and Tau Phosphorylation in Cellular Models of Alzheimer's Disease.

1-(7-Chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4- carboxamide (QTC-4-MeOBnE) is a new multi-target directed ligand (MTDL) rationally designed to have affinity with ß-secretase (BACE), Glycogen Synthase Kinase 3ß (GSK3ß) and acetylcholinesterase, which are considered promising targets on the development of disease-modifying therapies against Alzheimer's Disease (AD). Previously, QTC-4-MeOBnE treatment showed beneficial effects in preclinical AD-like models by influencing in vivo neurogenesis, oxidative and inflammatory pathways. However, the biological effect and mechanism of action exerted by QTC-4-MeOBnE in AD cellular models have not been elucidated yet. Hereby we investigate the acute effect of QTC-4-MeOBnE on neuronal cells overexpressing Amyloid Protein Precursor (APP) or human tau protein, the two main features of the AD pathophysiology. When compared to the control group, QTC-4-MeOBnE treatment prevented amyloid beta (Aß) formation through the downregulation of APP and BACE levels in APPswe-expressing cells. Furthermore, in N2a cells overexpressing human tau, QTC-4-MeOBnE reduced the levels of phosphorylated forms of tau via the modulation of the GSK3ß pathway. Taken together, our findings provide new insights into the mechanism of action exerted by QTC-4-MeOBnE in AD cellular models, and further support its potential as an interesting therapeutic strategy against AD.

Beneficial effects of QTC-4-MeOBnE in an LPS-induced mouse model of depression and cognitive impairments: The role of blood-brain barrier permeability, NF-κB signaling, and microglial activation.

Clinical and preclinical investigations have suggested a possible biological link betweenmajor depressive disorder (MDD) and Alzheimer's disease (AD). Therefore, a pharmacologic approach to treating MDD could be envisioned as a preventative therapy for some AD cases. In line with this, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4 carboxamide (QTC-4-MeOBnE) is characterized as an inhibitor of ß-secretase, glycogen synthase kinase 3ß, and acetylcholinesterase and has also shown secondary effects underlying the modulation of neurogenesis and synaptic plasticity pathways. Therefore, we investigated the effects of QTC-4-MeOBnE treatment (0.1 or 1 mg/kg) on depressive-like behavior and cognitive impairments elicited by repeated injections of lipopolysaccharide (LPS; 250 µg/kg) in mice. Injections of LPS for seven days led to memory impairments and depressive-like behavior, as evidenced in the Y-maze/object recognition test and forced swimming/splash tests, respectively. However, these impairments were prevented in mice that, after the last LPS injection, were also treated with QTC-4-MeOBnE (1 mg/kg). This effect was associated with restoring blood-brain barrier permeability, reducing oxidative/nitrosative biomarkers, and decreasing neuroinflammation mediated NF-κB signaling in the hippocampus and cortex of the mice. To further investigate the involvement with NF-κB signaling, we evaluated the effects of QTC-4-MeOBnE on microglial cell activation through canonical and non-canonical pathways and the modulation of the involved components. Together, our findings highlight the pharmacological benefits of QTC-4-MeOBnE in a mouse model of sickness behavior and memory impairments, supporting the novel concept that since this molecule produces anti-depressant activity, it could also be beneficial for preventing AD onset and related dementias in subjects suffering from MDD through inflammatory pathway modulation.

Bis-triazolylchalcogenium-Functionalized Benzothiadiazole Derivatives as Light-up Sensors for DNA and BSA.

A range of bis-triazolylchalcogenium-BTD 3 was synthesized by a copper-catalyzed azide-alkyne cycloaddition of azido arylchalcogenides 1 and 4,7-diethynylbenzo[c][1,2,5]thiadiazole 2. Eight new compounds were obtained in moderate to good yields using 1 mol % of copper(II) acetate monohydrate under mild reaction conditions. In addition, the synthesized bis-triazolylchalcogenium-BTD 3a-3h were investigated regarding their photophysical, electrochemical, and biomolecule binding properties in solution. In general, compounds presented strong absorption bands at the 250-450 nm region and cyan to green emission properties. The redox process attributed to the chalcogen atom was observed by electrochemical analysis (CV techniques). In addition, spectroscopic studies by UV-vis, steady-state emission fluorescence, and molecular docking calculations evidenced the ability of each derivative to establish interactions with calf-thymus DNA (CT-DNA) and bovine serum albumin (BSA). The behavior presented for this new class of compounds makes them a promising tool as optical sensors for biomolecules.

Chrysin restores memory deficit in hypothyroidism mice: Behavioral, neurochemical and computational approaches involving the neurotrophinergic system.

Hypothyroidism is a condition that affects multiple systems, including the central nervous system, causing, for example, cognitive deficits closely related to Alzheimer's disease. The flavonoid chrysin is a natural compound associated with neuronal improvement in several experimental models. Here, we evaluated the effect of chrysin on cognitive impairment in hypothyroid female mice by exploring neuroplasticity. Hypothyroidism was induced by continuous exposure to 0.1% methimazole (MTZ) in drinking water for 31 days. On the 32nd day, the animals showed low plasma levels of thyroid hormones (hypothyroid mice) than the control group (euthyroid mice). Subsequently, mice were intragastrically administered with vehicle or chrysin (20 mg/kg) once a day for 28 consecutive days. At the end of the treatments, behavioral tests were performed: open-field test (OFT) and morris water maze (MWM). Then, the levels of neurotrophins (BDNF and NGF) in the hippocampus and prefrontal cortex were measured and tested the affinity of chrysin with neurotrophinergic receptors through molecular docking. Hypothyroid mice showed memory deficit in the MWM and reduced neurotrophins levels in the hippocampus and prefrontal cortex, meanwhile, the chrysin treatment was able to reversed the deficit of spatial memory function and increased the levels of BDNF in hipocamppus and NGF in both structures. Additionally, molecular docking analysis showed that chrysin potentially binds to the active site of the TrkA, TrkB, and p75NTR receptors. Together, these findings suggest that chrysin reversed behavioral and neurochemical alterations associated with memory deficit induced by hypothyroidism, possibly by modulating synaptic plasticity in the neurotrophinergic system.

Protective effects of octylseleno-xylofuranoside in a streptozotocin-induced mouse model of Alzheimer's disease.

Octylseleno-xylofuranoside (OSX) is an organic selenium compound which has previously shown antioxidant and antidepressant-like activities, trough the modulation of monoaminergic system and synaptic plasticity pathways. Since recent studies have suggested Major Depressive Disorder (MDD) as a potential risk factor or condition that precedes and correlates with Alzheimer's Disease (AD), this study aimed to evaluate the protective effects of OSX in an AD mouse model induced by intracerebroventricular injection of streptozotocin (STZ). To address this protective effect, mice were pre-treated with intragastrical OSX (0.1 mg/kg) or vehicle for 20 days. After the pre-treatment, mice were submitted to two alternated intracerebroventricular infusions of STZ (days 21 and 23) or saline. 15 days after the last STZ injection, cognitive and memory skills of the treated mice were evaluated on object recognition test, Y-maze, stepdown passive avoidance and social recognition paradigms. Added to that, measurements of oxidative stress markers and gene expression were evaluated in brain samples of the same mice groups. Mice pre-treatment with OSX protected mice from cognitive and memory decline elicited by STZ. This effect was attributed to the prevention of lipid peroxidation and modulation of acetylcholinesterase and monoamine oxidase activities in cerebral cortices and hippocampi by OSX treatment. Furthermore, OSX treatment demonstrated reduction of amyloidogenic pathway genes expression when compared to the control groups. Besides that, OSX treatment showed no hepatic and renal toxicity in the protocol used for treatment. Considering the antidepressant-like effect of OSX, together with the ability to prevent memory and cognitive impairment, this new compound may be an interesting strategy for targeting the comorbidity between MDD and AD, in a multitarget drug paradigm.

Effect of QTC-4-MeOBnE Treatment on Memory, Neurodegeneration, and Neurogenesis in a Streptozotocin-Induced Mouse Model of Alzheimer's Disease.

Growing evidence suggests that drugs targeting neurogenesis and myelinization could be novel therapeutic targets against Alzheimer's disease (AD). Intracerebroventricular (icv) injection of streptozotocin (STZ) induces neurodegeneration through multiple mechanisms ultimately resulting in reduced adult neurogenesis. Previously, the multitarget compound QTC-4-MeOBnE (1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide) demonstrated beneficial effects in preclinical models of AD. Here we investigated its pharmacokinetics profile and the effect on memory impairments and neurodegeneration induced by STZ. Two icv injections of STZ resulted in significant cognitive and memory impairments, assessed by novel object recognition, Y-maze, social recognition, and step-down passive avoidance paradigms. These deficits were reversed in STZ-injected mice treated with QTC-4-MeOBnE. This effect was associated with reversion of neuronal loss in hippocampal dentate gyrus, reduced oxidative stress, and amelioration of synaptic function trough Na+/K+ ATPase and acetylcholinesterase activities. Furthermore, brains from QTC-4-MeOBnE-treated mice had a significant increase in adult neurogenesis and remyelination through Prox1/NeuroD1 and Wnt/ß-catenin pathways. Overall, our findings support the potential anti-AD effect of QTC-4-MeOBnE through multiple pathways, all of which have been involved in the onset and progression of the disease.

The selenocompound 1-methyl-3-(phenylselanyl)-1H-indole attenuates depression-like behavior, oxidative stress, and neuroinflammation in streptozotocin-treated mice.

Major depressive disorder (MDD) is a chronic mental illness affecting a wide range of people worldwide. The pathophysiology of MDD is not completely elucidated, but it is believed that oxidative stress and neuroinflammation are involved. In light with this, the aim of the present study was to investigate whether a single administration of the antioxidant 1-methyl-3-(phenylselanyl)-1H-indole (MFSeI) was able to reverse the streptozotocin-induced depression-like behavior, oxidative stress, and neuroinflammation in mice. MFSeI (10 mg/kg) was administered intragastrically (i.g.) 24 h after the intracerebroventricular injection of STZ (0.2 mg/4 µL/per mouse). Thirty minutes after MFSeI administration, behavioral tests and neurochemical analyses were performed. Fluoxetine (10 mg/kg, i.g.) was used as a positive control. MFSeI and fluoxetine were able to reverse the STZ-induced depression-like behavior, as evidenced by decreased immobility time in the forced swimming test and increased grooming time in the splash test. Mechanistically, MFSeI reversed the increased levels of reactive species and lipid peroxidation in the prefrontal cortices and hippocampi of STZ-treated mice. Additionally, neuroinflammation (i.e. expression of NF-κB, IL-1ß, and TNF-α) and the reduced mRNA levels of BDNF in the and hippocampi of depressed mice were reversed by treatment with MFSeI. Fluoxetine did not improve the STZ-induced alterations at the levels of reactive species, NF-κB and BDNF in the prefrontal cortices neither the levels of TNF-α in both brain regions. Together, these data suggest that the MFSeI may be a promising compound with antidepressant-like action, reducing oxidative stress and modulating inflammatory pathways in the brain of depressed mice.

QTC-4-MeOBnE Rescues Scopolamine-Induced Memory Deficits in Mice by Targeting Oxidative Stress, Neuronal Plasticity, and Apoptosis.

Cognitive decline and memory impairment induced by disruption of cholinergic neurons and oxidative brain damage are among the earliest pathological hallmark signatures of Alzheimer's disease. Scopolamine is a postsynaptic muscarinic receptor blocker which causes impairment of cholinergic transmission resulting in cognitive deficits. Herein we investigated the effect of QTC-4-MeOBnE (1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide) on memory impairments in mice chronically treated with scopolamine and the molecular mechanisms involved. Administration of scopolamine (1 mg/kg) for 15 days resulted in significant impairments in working and short-term memory in mice, as assessed by the novel object recognition and the Y-maze paradigms. However, both deficits were prevented if mice receiving the scopolamine were also treated with QTC-4-MeOBnE. This effect was associated with an increase in antioxidant enzymes (superoxide dismutase and catalase), a reduction in lipid peroxidation, and an increase in Nrf2 expression. Moreover, brains from QTC-4-MeOBnE treated mice had a significant decrease in acetylcholinesterase activity and glycogen synthase kinase-3ß levels but an increase in brain-derived neurotrophic factor and Bcl-2 expression levels. Taken together our findings demonstrate that the beneficial effect of QTC-4-MeOBnE in a mouse model of scopolamine-induced memory impairment is mediated via the involvement of different molecular pathways including oxidative stress, neuroplasticity, neuronal vulnerability, and apoptosis. Our study provides further evidence on the promising therapeutic potential of QTC-4-MeOBnE as a multifactorial disease modifying drug in AD and related dementing disorders.

Synthesis, Molecular Docking, and Preliminary Evaluation of 2-(1,2,3-Triazoyl)benzaldehydes As Multifunctional Agents for the Treatment of Alzheimer's Disease.

We described here our results on the use of thiourea as a ligand in the copper catalysed azide-alkyne cycloaddition (CuAAC) of 2-azidobenzaldehyde with alkynes. Reactions were performed reacting 2-azidobenzaldehyde with a range of terminal alkynes using 10 mol % of copper iodide as a catalyst, 20 mol % of thiourea as a ligand, triethylamine as base, DMSO as solvent at 100 °C under nitrogen atmosphere. The corresponding 2-(1H-1,2,3-triazoyl)-benzaldehydes (2-TBH) were obtained in moderated to excellent yields and according our experiments, the use of thiourea decreases the formation of side products. The obtained compounds were screened for their binding affinity with multiple therapeutic targets of AD by molecular docking: ß-secretase (BACE), glycogen synthase kinase (GSK-3ß) and acetylcholinesterase (AChE). The three compounds with highest affinity, 5 a (2-(4-phenyl-1H-1,2,3-triazol-1-yl)benzaldehyde), 5 b (2-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl)benzaldehyde), and 5 d (2-(4-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-1-yl)benzaldehyde) were selected and evaluated on its antioxidant effect, in view of select the most promising one to perform the in vivo validation. Due the antioxidant potential ally to the affinity with BACE, GSK-3ß and AChE, compound 5 b was evaluated in a mouse model of AD induced by intracerebroventricular injection of streptozotocin (STZ). Our results indicate that 5 b (1 mg/kg) treatment during 20 days is able to reverse the cognitive and memory impairment induced by STZ trough the modulation of AChE activity, amyloid cascade and GSK-3ß expression.

Rational design, cognition and neuropathology evaluation of QTC-4-MeOBnE in a streptozotocin-induced mouse model of sporadic Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial pathology characterized by amyloid deposits, neurofibrillary formation, oxidative stress and cholinergic system dysfunction. In this sense, here we report the rational design of a multi-target directed ligand (MTDL) for AD based on virtual screening and bioinformatic analyses, exploring the molecular targets ß-secretase (BACE-1), glycogen synthase kinase-3ß (GSK-3ß) and acetylcholinesterase (AChE). After this screening, the compound with higher molecular docking affinity was selected, the 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4 carboxamide(QTC-4-MeOBnE). To further our studies, the protective effect of QTC-4-MeOBnE (0.1 and 1 mg/kg for 20 days) on STZ-induced sporadic AD mice was determined. QTC-4-MeOBnE pretreatment attenuated cognitive and memory deficit induced by STZ in an object recognition test, Y-maze, social recognition test and step-down passive avoidance. The mechanisms underlying this action might be attributed to the reduction of lipid peroxidation and reactive species formation in the prefrontal cortex and hippocampus of mice submitted to STZ. In addition, QTC-4-MeOBnE pretreatment abolished the up-regulation of AChE activity and the overexpression of GSK 3ß and genes involved in amyloid cascade such as BACE-1, protein precursor amyloid, у-secretase, induced by STZ. Moreover, toxicological parameters were not modified by QTC-4-MeOBnE chronic treatment. This evidence suggests that QTC-4-MeOBnE exerts its therapeutic effect through multiple pathways involved in AD.

Lipopolysaccharide-induced depressive-like, anxiogenic-like and hyperalgesic behavior is attenuated by acute administration of α-(phenylselanyl) acetophenone in mice.

The lipopolysaccharide (LPS) is an endotoxin derived from gram-negative bacteria, which induces inflammation. The aims of this study were to evaluate the possible α-(phenylselanyl) acetophenone (PSAP) activity in reducing comorbid hyperalgesia, depressive-like and anxiogenic-like symptoms induced by LPS in mice. In additional, investigated physical chemical properties of PSAP through in silico analysis by ADMET predictor software. The LPS (100 µg/kg, intraperitoneally) or saline were administered and after 4 h the treatment with PSAP (0.001-10 mg/kg, intragastric route [i.g.]) or FLX (10 mg/kg, i.g.) was performed, and after 30 min, the behavioral tests were carried out. LPS reduced the latency time for the first episode of immobility and increased the immobility time in the FST as well as decreased the grooming time in the splash test. PSAP reversed these alterations demonstrating an antidepressive-like effect. LPS also enhances the anxiogenic behavior in the elevated plus maze test (EPM). PSAP reversed these parameters, showing anxiolytic-like effect. LPS also decreased the latency time (s) on the hot plate and the treatment with PSAP at all doses significantly reversed the hyperalgesic effect of LPS. LPS increased the activation of p38MAPK and p-p65NF-κB pathways as well as the COX-2 levels in the cerebral cortex, which are indicative of an inflammatory response. Besides, it also reduced the levels of mBDNF, involved in neuroplasticity. Treatment with PSAP restored all these neurochemical alterations induced by LPS. The results demonstrated that PSAP presents antidepressive-like, anxiolytic-like and anti-hyperalgesic effects related to reduction in neuroinflammation.

α- (phenylselanyl) acetophenone mitigates reserpine-induced pain-depression dyad: Behavioral, biochemical and molecular docking evidences.

Chronic pain and depressive disorders have been estimated to co-occur in up to 80% of patients and traditional antidepressants and analgesics have shown limited clinical efficacy. α- (phenylselanyl) acetophenone (PSAP) is an organic selenium compound which has already demonstrated antioxidant, antidepressant and antinociceptive activities in animal models, without showing acute toxicity. In view of develop more effective treatments to comorbid pain and depression, the purpose of this study was to evaluate the behavioral and biochemical effects of PSAP on reserpine induced pain-depression dyad model in mice as well to analyze the interaction of PSAP with specific targets by molecular docking analysis. Reserpine (0.5 mg/kg daily, for 3 days, i.p.) decreased the latency for the first episode of immobility and the swimming time, as well as increased the immobility time of mice in the modified forced swimming test (mFST). Reserpine also led to a significant decrease in nociceptive threshold in thermal hyperalgesia in the hot plate test. PSAP or imipramine (10 mg/kg daily, for 2 days, i.g.) reversed these alterations in both mFST and hot plate test. Additionaly, PSAP reduced nitrite and malondialdehyde (MDA) levels and catalase (CAT) activity in the cerebral cortex and hippocampus of reserpinised mice. PSAP also normalized monoamine oxidase (MAO-A and MAO-T) activity increased in reserpinised mice. According to the molecular docking analysis, PSAP has affinity to MAO-A, suggesting an inhibition of this enzyme. The data presented here show that PSAP had reversed effects in the pain-depression dyad induced by reserpine, possibly by its antioxidant property and MAO-A inhibition.

Correction: Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice.

[This corrects the article DOI: 10.1371/journal.pone.0187445.].

Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice.

A series of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles with different substituents were screened for their binding affinity with serotonin transporter (SERT) and dopamine transporter (DAT) by docking molecular. 5-(4methoxyphenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (SeTACN) exhibited the best conformation with SERT even higher than fluoxetine and serotonin, suggesting a competitive inhibition. SeTACN demonstrated additional affinity to other serotonergic receptors involved in antidepressant effects: 5HT1a, 5HT2a and 5HT3. In another set of experiments, SeTACN led to significant reductions in the immobility time of mice submitted to forced swimming test (FST) in the dose range of 0.1- 20mg/kg, suggesting an antidepressant-like effect. The possible mechanism of action was investigated using serotonergic and dopaminergic antagonists. The antidepressant-like effect of SeTACN (0.1mg/kg i.g.) was prevented by the pretreatment with WAY100635 (a selective 5HT1a antagonist), ketanserin (a 5HT2a/c antagonist) and ondansetron (a selective 5ht3 antagonist), PCPA (an inhibitor of serotonin synthesis) but not with SCH23390 (dopaminergic D1 antagonist) and sulpiride (D2 antagonist). Sub-effective dose of fluoxetine was able to potentiate the effects of a sub-effective dose of SeTACN in FST. None of the treatments affected locomotor activity in open field test (OFT). These results together, suggest that the SeTACN antidepressant-like effect is mediate, at least in parts, by serotonergic system.

Ultrasound-promoted copper-catalyzed synthesis of bis-arylselanyl chrysin derivatives with boosted antioxidant and anticancer activities.

Herein we report the use of ultrasonic irradiation (US) in the synthesis of six new semi-synthetic selenium-containing chrysin derivatives by a simple and effective methodology utilizing CuI as catalyst, in good to excellent yields (60-89%). It was observed that US accelerates the reaction compared to conventional heating with excellent selectivity for diselenylated products. Compounds were tested for their antioxidant and anticancer activities in vitro and it was observed that the presence of selenium in the A-ring of chrysin enhanced both antioxidant and anticancer properties. Semi-synthetic 6,8-bis(o-tolylselanyl)-chrysin 3b has the best radical scavenging activity of DPPH (Imax: 39.79µM) and ABTS+ (IC50: 6.5µM) radicals. Similarly, in the Reactive Species (RS) assay, 3b showed high antioxidant activity in mice cortex (IC50: 5.67µM), whereas 6,8-bis(p-anisoylselanyl)-chrysin 3c was the more active in the hippocampus (IC50: 5.63µM). The Se-chrysins were effective in prevention of lipid peroxidation, highlighting 6,8-bis(p-fluorophenylselanyl)-chrysin 3d in cortex (IC50: 0.54µM) and 3b in hippocampus (IC50: 0.27µM). In addition, 3d was effective in inhibiting human lung adenocarcinoma (A549) cells growth, with a IC50 of 19.9µM after 72h of treatment, while 6,8-bis(p-anisoylselanyl)-chrysin 3c presented the higher antiproliferative activity after 48h of treatment (IC50 of 41.4µM).

Modulation of PKA, PKC, CAMKII, ERK 1/2 pathways is involved in the acute antidepressant-like effect of (octylseleno)-xylofuranoside (OSX) in mice.

RATIONALE: (Octylseleno)-xylofuranoside (OSX) is an organoselenium compound from the class of alkylseleno carbohydrates possessing a C8 alkyl chain. Members of this class of organoselenium compounds have promising pharmacological activities, among them are antioxidant and acute antidepressant-like activities with the involvement of monoaminergic system, as previously presented by our research group. OBJECTIVE: The objective of the study was to investigate the possible involvement of cellular signalling pathways in the antidepressant-like effect caused by OSX (0.01 mg/kg, oral route (p.o.) by gavage) in the tail suspension test (TST) in mice. METHODS: Mice were treated by intracerebroventricular (i.c.v.) injection either with vehicle or with H-89 (1 µg/site i.c.v., an inhibitor of protein kinase A-PKA), KN-62 (1 µg/site i.c.v., an inhibitor of Ca2+/calmodulin-dependent protein kinase II-CAMKII), chelerythrine (1 µg/site i.c.v., an inhibitor of protein kinase C-PKC) or PD098059 (5 µg/site i.c.v., an inhibitor of extracellular-regulated protein kinase 1/2-ERK1/2). Fifteen minutes after, vehicle or OSX was injected, and 30 min later, the TST and open field tests (OFT) were carried out. RESULTS: The antidepressant-like effect of orally administered OSX was blocked by treatment of the mice with H-89, KN-62, chelerythrine and PD098059; all inhibitors of signalling proteins involved with neurotrophic signalling pathways. The number of crossings in the OFT was not altered by treatment with OSX and/or signalling antagonists. CONCLUSIONS: The results demonstrated that OSX showed an antidepressant-like effect in the TST in mice through the activation of protein kinases PKA, PKC, CAMKII and ERK1/2 that are involved in intracellular signalling pathways.

Involvement of monoaminergic system in the antidepressant-like effect of (octylseleno)-xylofuranoside in the mouse tail suspension test.

Depression is one of the most commonly diagnosed neuropsychiatric disorders and several studies have demonstrated a role for selenium in mood disorders. For this reason, the present study investigated the role of the monoaminergic system in the antidepressant-like action of (octylseleno)-xylofuranoside (OSX), an organoselenium compound, in the tail suspension test (TST) in mice. For this purpose, OSX (0.001­10 mg/kg) was administered orally (p.o.) 30 min prior to testing, and all of the tested doses reduced the immobility time in the TST without changing the locomotor activity measured in the open field test (OFT). Furthermore, the antidepressant-like effect of OSX (0.01 mg/kg, p.o.) in the TSTwas prevented by pre-treatment in mice with ketanserin (1 mg/kg, intraperitoneal route (i.p.); a 5-HT2A/2C receptor antagonist),WAY100635 (0.1mg/kg, subcutaneous (s.c.); a selective 5-HT1A receptor antagonist), p-chlorophenylalaninemethyl ester-PCPA (100mg/kg, i.p.; a selective inhibitor of tryptophan hydroxylase), prazosin (1 mg/kg, i.p.; an α1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p.; an α2-adrenoceptor antagonist), SCH233390 (0.05 mg/kg, s.c., a dopaminergic D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopaminergic D2 receptor antagonist), but not with ondansetron (1 mg/kg, i.p.; a selective 5-HT3 receptor antagonist). Taken together, these data demonstrate that OSX has a potent antidepressant like effect in TST at lower doses (0.001­10 mg/kg), which is dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems.