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The experimental autoimmune encephalomyelitis (EAE) is a model that mimics multiple sclerosis in rodents. Evidence has suggested that the activation of indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway (KP), plays a crucial role in inflammation-related diseases. The present study aimed to investigate the involvement of the inflammatory process and KP components in a model of EAE in mice. To identify the role of KP in EAE pathogenesis, mice received IDO inhibitor (INCB024360) at a dose of 200 mg/kg (per oral) for 25 days. We demonstrated that IDO inhibitor mitigated the clinical signs of EAE, in parallel with the reduction of cytokine levels (brain, spinal cord, spleen and lymph node) and ionized calcium-binding adaptor protein-1 (Iba-1) gene expression in the central nervous system of EAE mice. Besides, IDO inhibitor causes a significant decrease in the levels of tryptophan, kynurenine and neurotoxic metabolites of KP, such as 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) in the prefrontal cortex, hippocampus, spinal cord, spleen and lymph node of EAE mice. The mRNA expression and enzyme activity of IDO and kynurenine 3-monooxygenase (KMO) were also reduced by IDO inhibitor. These findings indicate that the inflammatory process concomitant with the activation of IDO/KP is involved in the pathogenic mechanisms of EAE. The modulation of KP is a promising target for novel pharmacological treatment of MS.

The aim of the present study was to assess the possible protective effect of γ-oryzanol (ORY) supplementation in a model of acute liver failure (ALF) induced by acetaminophen (APAP) in mice. Male Swiss strain mice were supplemented with ORY (10 and 50 mg/kg, per oral route) daily for 7 days. One hour after the last supplementation, animals received APAP (300 mg/kg, intraperitoneal). Twenty-four hours after APAP administration, mice were euthanized, and biochemical and histopathological determinations were performed. Histopathological analysis revealed that APAP caused vascular congestion, loss of cellular structure, and cellular infiltration in hepatocytes. Moreover, it caused oxidative damage (enzymatic and non-enzymatic analysis of oxidative stress), with loss of hepatic function leading to cell apoptosis (apoptotic parameters). ORY supplementation (ORY-10 and ORY-50) protected against all changes in ALF model. Thus, the protective effect of ORY supplementation was due to modulation of antioxidant defenses avoiding the apoptotic process.

Made available in DSpace on 2019-10-04T19:54:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-07-27 Fundacao de apoio a pesquisa do Estado do Rio Grande do Sul (FAPERGS) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Parkinson's disease (PD) is an age-related neurodegenerative disorder that severely affects quality of life of patients and their families. The flavonoid chrysin (5,7-dihydroxylflavone) is a naturally occurring flavone with several pharmacological activities, including anti-inflammatory and anti-oxidative. We investigated the effects of a 28-day chrysin treatment (10 mg/kg/day, i.g.) on a model of PD induced by 6-OHDA in aged (20-month old) mice. We found a protective effect of chrysin on behavioral and cognitive alterations (rotational behavior, passive avoidance and Barnes maze tests), nitric oxide synthesis (NOx), lipid peroxidation (HNE), glutathione levels (GSH), reactive species levels (RS), neuroinflammation (interleukin-1 beta - IL-1 beta and tumor necrosis factor alpha- TNF-alpha), Na+, K+-ATPase and nicotinamide adenine dinucleotide phosphate oxidase activity (NADPH oxidase) activities. In addition, chrysin protected against changes in striatal dopamine (DA), 3,4-di-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. In conclusion, chrysin improved several behavioral, cognitive and neurochemical parameters in a relevant preclinical model of PD in aged mice. Fed Univ Pampa, Lab Pharmacol & Toxicol Evaluat Appl Bioact Mol L, Campus Itaqui, BR-97650000 Itaqui, RS, Brazil Fed Univ Pampa Campus, Postgrad Program Pharmaceut Sci, Uruguaiana, RS, Brazil Univ Fed Rio Grande do Norte, Biosci Ctr, Lab Neuroanat, Dept Morphol, Natal, RN, Brazil Univ Sao Paulo, Coll Vet Med & Anim Sci, Dept Surg, Lab Stochast Stereol & Chem Anat, Sao Paulo, SP, Brazil Univ Sao Paulo, Bauru Dent Sch, Dept Biol Sci, Lab Histol, Sao Paulo, SP, Brazil Sao Paulo State Univ, Lab Optimizat Sports Performance Human LaBOEH, Sao Paulo, SP, Brazil Univ Fed Santa Maria, Lab Neurotox & Psychopharmacol LABNEURO, Santa Maria, RS, Brazil Univ Fed Santa Maria, Lab Pharmacol Mycotoxins & Toxicol LAFARMT, Santa Maria, RS, Brazil Sao Paulo State Univ, Lab Optimizat Sports Performance Human LaBOEH, Sao Paulo, SP, Brazil Fundacao de apoio a pesquisa do Estado do Rio Grande do Sul (FAPERGS): 16/2551-0000526-5 Fundacao de apoio a pesquisa do Estado do Rio Grande do Sul (FAPERGS): 16/2251-0000183-9 CAPES: 001

The mycotoxin zearalenone (ZEA) has strong estrogenic effects and elicits reproductive toxicity. Chrysin is a natural flavonoid found in many plant and has a broad range of pharmacological activities, including anticancer, antioxidant and anti-inflammatory. The present study aimed to investigate the potential protective effects of chrysin against ZEA toxicity. Mice received chrysin (5 or 20 mg/kg; i.g.) for ten days, and then received a single injection of ZEA (40 mg/kg). Two days thereafter, blood and testes were collected. ZEA decreased number and motility of sperm, plasma testosterone levels, enzymatic (glutathione peroxidase, glutathione reductase, glutathione-S-transferase) and non-enzimatic defenses (reduced glutathione). Moreover, ZEA increased 4-hydroxynonenal and 8-hydroxy-2′-deoxyguanosine levels, myeloperoxidase activity and levels of proinflammatory cytokines (interleukins-1β and 6, tumor necrosis factor alpha). ZEA also decreased levels of anti-inflammatory cytokine interleukin-10 and increased activity of caspases 3 and 9. Chrysin treatment increased the number and motility of sperm, testosterone levels, restored antioxidant defenses and reduced the inflammation and apoptosis process. In summary, chrysin attenuated the toxic effects caused by ZEA in blood and testes of mice, suggesting a potential preventive treatment against the deleterious effects of ZEA.

The lipopolysaccharide (LPS) and d -galactosamine (D-GalN)-induced hepatotoxicity is a classical model to elucidate the mechanisms and explore potential therapeutic drugs for fulminant hepatic failure (FHF). γ-Oryzanol (γ-ORY) has been showed to possess both antioxidant and anti-inflammatory properties in several pathological models. However, it remains unclear whether γ-ORY could protect against LPS/D-GalN-induced hepatotoxicity. Thus, the aim of the current study was to evaluate the effects of γ-ORY supplementation (for 7 consecutive days) in LPS/D-GalN-induced FHF in mice. One hour after the last supplementation with γ-ORY, the animals received LPS/D-GalN (50 and 500 mg/kg, respectively; i.p.). Twenty-four hours after LPS/D-GalN administration, biochemical assays were performed. LPS/D-GalN administration caused severe histological damage in the liver, such as vascular congestion and megalocytosis, as well as elicited hepatic failure. LPS/D-GalN treatment also caused alterations in liver function, increased levels of oxidative stress and inflammatory markers. In contrast, γ-ORY supplementation protected against histological, oxidative and inflammatory alterations induced by LPS/D-GalN exposure. Collectively, our data supports the notion that both oxidative stress and inflammatory responses are two key pathogenic factors that contribute to LPS/D-GaIN-mediated FHF. Due to its antioxidant and anti-inflammatory actions, our study indicates γ-ORY as a putative pharmacological option to prevent LPS/D-GalN-induced hepatotoxicity.

Chrysin is a natural flavonoid which is found in bee propolis, honey and various plants, and neuroprotective effect of chrysin in mice was previously demonstrated by our group. Neuroinflammation, neurotrophic factors and neuronal recovery factors associated with the neuroprotective effect of this flavonoid require further investigations. Thus, now we investigated the possible involvement of inflammatory cytokines, neurotrophic factors and neuronal recovery in the effect of chrysin in 6-hydroxidopamine (6-OHDA), a well-established model of Parkinson's disease, in striatum of mice. The 6-OHDA microinjection induced behavioral alterations on the rotarod test and apomorphine-induced circling behavior in mice. 6-OHDA administration elevated levels of tumour necrosis factor-α, interferon-gamma, interleukin-1β, interleukin-2, interleukin-6 and nuclear factor-kappa B and decreased the interleukin-10 levels, total reactive antioxidant potential and total antioxidant reactivity in striatum, as well as, modified the calcium-binding protein B (S100B), brain-derived neurotrophic factor, nerve growth factor and glial cell line-derived neurotrophic factor levels. The intrastriatal injection of 6-OHDA also induced an decrease of dopamine, 3,4-dihydroxyphenylacetic acid, homovanylic acid levels and tyrosine hydroxylase content. Oral treatment with chrysin (10 mg/kg, 28 days), culminated with the prevention of these alterations occasioned by 6-OHDA. These results corroborated with the neuroprotective effect of chrysin in the treatment of Parkinson's disease and, indicated the mechanism involved throught the inflammatory cytokines, neurotrophic factors and recovery of dopaminergic neurons in striatum.

The aim of this study was to investigate whether (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD) protects against hepatotoxicity induced by thioacetamide (TAA). On the first day of treatment, male adult Wistar rats received BPD (10 or 50 mg·kg–1). On the second day, the rats received a single intraperitoneal injection of TAA (400 mg·kg–1). Twenty-four hours after TAA administration, biochemical determinations and liver histological analysis were carried out. BPD (50 mg·kg–1) reduced plasma aspartate and alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities increased by TAA exposure. Treatment with BPD was effective against increased lipid peroxidation levels and attenuated a decrease in hepatic reduced glutathione and ascorbic acid levels as well as an inhibition of glutathione peroxidase activity caused by TAA exposure. The higher dose of BPD protected against the inhibition of hepatic δ-aminolevulinic dehydratase activity induced by TAA. Finally, histopathological examination of the liver showed that BPD markedly ameliorated TAA-induced hepatic injury. In conclusion, BPD protected against hepatotoxicity and oxidative stress caused by TAA exposure in rats.

The aim of the present study was to investigate the effects of SCH58261, a selective adenosine A2A receptor antagonist, on striatal toxicity induced by 3-nitropropionic acid (3-NP) in rats. The experimental protocol consisted of 10 administrations (once a day) of SCH58261 (0.01 or 0.05 mg/kg/day, intraperitoneal, i.p.). From 7th to 10th day, 3-NP (20 mg/kg/day, i.p.) was injected 1 h after SCH58261 administration. Twenty-four hours after the last 3-NP injection, the body weight gain, locomotor activity (open-field test), motor coordination (rotarod test), striatal succinate dehydrogenase (SDH) activity and parameters linked to striatal oxidative status were evaluated in rats. The marked body weight loss resulting from 3-NP injections in rats was partially protected by SCH 58261 at both doses. SCH 58261 at the highest dose was effective against impairments on motor coordination and locomotor activity induced by 3-NP. SCH 58261 was unable to restore the inhibition of SDH activity caused by 3-NP. In addition, the increase in striatal reactive species (RS) levels, depletion of reduced glutathione (GSH) content and stimulation of glutathione reductase (GR) activity provoked by 3-NP injections were alleviated by both doses of SCH 58261. The highest dose of SCH 58261 was also effective in attenuating the increase of protein carbonyl levels as well as the inhibition of glutathione peroxidase (GPx) activity in rats exposed to 3-NP. Our results revealed that reduction of oxidative stress in rat striatum by adenosine A2A receptor antagonism contributes for alleviating 3-NP-induced toxicity.

This study aims to investigate the protective effect of p-chloro-phenyl-selenoesterol [PCS; 0,2 mg/kg; 10 ml/kg i.g.) in colitis induced by 2,4,6-trinitrobenzene sulfonic acid [TNBS; 2 mg/100 µl 50% ethanol; intrarectally) in mice. Several parameters including weight, length, histological analyses determination, thiobarbituric acid reactive species, reactive species levels, superoxide dismutase, catalase, and myeloperoxidase (MPO) activity of colon were evaluated. The serum levels of tumor necrosis factor alpha [TNF-α) and interleukin 6 [IL-6) were also assessed. Treatment with PCS reduced the clinical and histopathologic severity of TNBS-induced colitis, characterized by colon length reduction and increased colon weight and microscopic intestinal inflammation. The therapeutic effects of PCS in this model were associated with significant decrease in proinflammatory cytokines TNF-α and IL-6 and decrease in MPO activity. Furthermore, combined with improvements in inflammatory parameters, treatment with the PCS was able to decrease oxidative stress and to prevent the decrease in antioxidant defenses in animals with TNBS-induced colitis. This finding suggests that PCS can improve experimental colitis in mice and it could be a potential therapeutic agent for the treatment of patients with IBD. J. Cell. Biochem. 118: 709-717, 2017. © 2016 Wiley Periodicals, Inc.

Chrysin is a flavonoid which is found in bee propolis, honey and various plants. Antidepressant-like effect of chrysin in chronically stressed mice was previously demonstrated by our group. Conversely, neurochemical factors associated with this effect require further investigations. Thus, we investigated the possible involvement of pro-inflammatory cytokines, kynurenine pathway (KP), 5-hydroxytryptamine (5-HT) metabolism and caspases activities in the effect of chrysin in mice exposed to unpredictable chronic stress (UCS). UCS applied for 28 days induced a depressive-like behavior, characterized by decrease in the time of grooming in the splash test and by increase in the immobility time in the tail suspension test. Oral treatment with chrysin (5 or 20mg/kg, 28 days), similarly to fluoxetine (10mg/kg, positive control), culminated in the prevention of these alterations. UCS elevated plasma levels of corticotropin-releasing hormone and adrenocorticotropic hormone, as well the tumor necrosis factor-α, interleukin-1β, interleukin-6 and kynurenine levels in the prefrontal cortex (PFC) and hippocampus (HP). UCS induced the decrease in the 5-HT levels in the HP and the increase in the indoleamine-2,3-dioxygenase, caspase 3 and 9 activities in the PFC and HP. Treatment with chrysin, similarly to fluoxetine, promoted the attenuation of these alterations occasioned by UCS. These results corroborated with the antidepressant potential of chrysin in the treatment of psychiatric diseases. Furthermore, this work indicated the association of pro-inflammatory cytokines synthesis, KP, 5-HT metabolism and caspases activities with the action exercised by chrysin in mice exposed to UCS.

Some studies have showed that intake of blackberry juice (BBJ) can prevent urinary tract infections. However, there is a lack of studies that evaluate the mechanisms by which BBJ has protective effect. Thus, the aim of current study was to evaluate the effects of BBJ supplementation on cisplatin-induced renal pathophysiology in mice. Mice were supplemented with BBJ (10 mL/kg) for seven days. One hour after the last supplementation with BBJ, mice received cisplatin (10 mg/kg, i.p.). Seventy-two hours after cisplatin administration, blood was collected and biochemical analysis were performed (urea and creatinine), kidney was dissected and utilized in histological and oxidative evaluations. Cisplatin caused severe injury in renal tissue, in markers of renal damage (urea and creatinine) generated increased of plasmatic levels. Besides that, the cisplatin induced decreased of enzymes activities in renal tissue (superoxide dismutase, glutathione S-transferase and catalase). In contrast, BBJ supplementation protected against histopathological alterations through decreased in urea and creatinine levels and modulation of catalase enzyme activity. Thus, BBJ supplementation protected the renal system of mice from deleterious effects. We suggest that high concentrations of Cyanidin 3-O-glucoside and Cyanidin 3-O-rutinoside are responsible for antioxidant role of BBJ supplementation in renal pathophysiology induced by cisplatin exposure. Also, these results reinforcing the importance of including BBJ in the human diet aimed at preventing renal diseases.

Background Multiple sclerosis (MS) is a chronic autoimmune disease which causing demyelination, resulting in several damages to central nervous system. NonCoding microRNAs (miRNAs) are post transcriptional gene expression regulators that have been associated with MS-pathophysiology. In this context, chrysin is a bioactive compound that has several pharmacological, nutraceutical and neuroprotective effects. Thus, the aim of study was to investigate the effect of chrysin supplementation in alterations caused by experimental autoimmune encephalomyelitis (EAE) model in mice, analyzing histological parameters and changes in expression levels of MIR21, MIR155 and MIR326 (miRNAs-21, 155 and 326). Methods For induction of EAE was used myelin oligodendrocyte glycoprotein (35–55) peptide in C57BL/6 mice. EAE model caused increase of inflammatory infiltrate in SC and upregulated expression levels of miRNAs analyzed. Results Supplementation with chrysin was able to decrease of miRNAs-21 and 155 expression levels altered in EAE. Chrysin supplementation did not modulate miRNA-326 expression levels. Conclusions The findings suggest that chrysin attenuated inflammatory process presented in histological analysis, probably due to its indirect modulatory effect on miRNAs-21 and 155. Therefore, chrysin supplementation may represent an advance for MS therapeutic, however, further studies are needed to understand the role of miRNAs-21 and 155 in your modulatory response.

Nandrolone decanoate (ND) belongs to the class II of anabolic–androgenic steroids (AAS), which is composed of 19-nor-testosterone-derivatives. AAS represent a group of synthetic testosterone that is used in clinical treatment. However, these drugs are widely abused among individuals as a means of promoting muscle growth or enhancing athletic performance. AAS in general and ND in particular have been associated with several behavioral disturbances, such as anxiety, aggressiveness and depression. A factor that contributes to the development of depression is the brain activation of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of kynurenine pathway (KP). In the present study, we examined the involvement of KP in depressive phenotype induced by a ND treatment (10 mg/kg/day/s.c., for 28 days) that mimics human abuse system (e.g. supraphysiological doses) in C57B/6J mice. Our results showed that ND caused depressive like-behavior in the tail suspension test and anhedonic-like state measured in the sucrose preference test. ND administration decreased the levels of brain-derived neurotrophic factor and neurotrophin-3 and reduced Na+,K+-ATPase activity in the hippocampus, striatum and prefrontal cortex. We also found that ND elicited KP activation, as reflected by the increase of IDO activity and kynurenine levels in these brain regions. Moreover, ND decreased serotonin levels and increased 5-hydroxyindoleacetic acid levels in the brain. Treatment with IDO inhibitor 1-methyl- dl -trypthophan (1 mg/kg/i.p.) reversed the behavioral and neurochemical alterations induced by ND. These results indicate for the first time that KP plays a key role in depressive-like behavior and neurotoxicity induced by supraphysiological doses of ND in mice.

The γ-orizanol present in rice bran oil contains a mix of steryl triterpenyl esters of ferulic acid, which is believed to be linked to its antioxidant potential. In this study we investigated the neuroprotective actions of γ-orizanol (ORY) against the toxicity induced by rotenone (ROT) in Drosophila melanogaster. The flies (both genders) aged between 1 and 5 days old were divided into four groups of 50 flies each: (1) control, (2) ORY 25 μM, (3) ROT 500 μM, (4) ORY 25 μM+ROT 500 μM. Flies were concomitantly exposed to a diet containing ROT and ORY for 7 days according to their respective groups. Survival and behavior analyses were carried out in vivo, and ex vivo analyses involved acetylcholinesterase activity (AChE), determination of dopaminergic levels, cellular viability and mitochondrial viability, activities of superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), reactive species levels (RS), lipid peroxidation (TBARS) and contents of total thiols and non-proteic thiols (NPSH). Our results show for the first time that ORY not only acts as an endogenous activator of the cellular antioxidant defenses, but it also ameliorates rotenone induced mortality, oxidative stress and mitochondrial dysfunction. Our salient findings regarded the restoration of cholinergic deficits, dopamine levels and improved motor function provided by ORY. These results demonstrate the neuroprotective potential of ORY and that this effect can be potentially due to its antioxidant action. In conclusion, the present results show that ORY is effective in reducing the ROT induced toxicity in D. melanogaster, which showed a neuroprotective action, possibly due to the presence of the antioxidant constituents such as the ferulic acid.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a clinically and progressive loss of cognitive function, neuropsychiatric and behavioral disorders. Some studies showed that chrysin has antioxidant and anti-inflammatory properties. However, your bioavailability is relatively low. Therefore, the present study was designed to investigate the effects of chrysin loaded lipid-core nanocapsules (LNCs) on neurochemical and behavioral changes in a model of AD induced by β-amyloid1-42 (Aβ1-42) peptide in aged female mice. For this purpose, aged female mice received free chrysin (FC) (5 mg/kg, per oral, p.o.) or chrysin loaded LNCs (C1-LNC and C5-LNC) (1 or 5 mg/kg, p.o.) for 14 days after Aβ1-42 administration (400 pmol, i.c.v.). Aβ1-42 induced significant impairments on memory and learning (morris water maze task, object recognition and step-down-type passive avoidance), also caused oxidative stress, reduced the levels of brain-derived neurotrophic factor (BDNF), increased neuroinflammation in prefrontal cortex and hippocampus of aged animals. Thus, C1-LNC and C5-LNC displayed significant effect against Aβ₁-₄2, via attenuation of oxidative stress and neuroinflammation, modulation of neurochemical and behavioral changes in a model of AD. These results point to chrysin loaded LNCs (mainly C5-LNC) can be a promising biomedical tool and a new therapeutic approach for treatment and prevention of AD.

Carbon tetrachloride (CCl4) is a hepatotoxin used to induce the model of hepatic fibrosis in mice. The mechanism by which ccl4 causes hepatic fibrosis is via imbalance in antioxidant system, increase of inflammatory and apoptotic processes. In this sense, gamma Oryzanol (γ-ORY) is a bioactive compound derived from rice oil, which has shown antioxidant and anti-inflammatory activities. However, the effects of γ-ORY in therapy against hepatic fibrosis has not yet been studied. Thus, purpose of present study was to evaluate the possible hepatoprotective effect of γ-ORY supplementation in a model of hepatic fibrosis CCl4-induced in mice. Male Swiss mice were supplemented with γ-ORY (50 mg/kg, per oral) daily for seven days. 1 h after the last supplementation, CCl4 (1 mg/kg, intraperitoneal) was injected. 24 h after the administration of CCl4, biochemical and histological analysis were performed. CCl4 administration occasioned hepatic fibrosis trough histological alterations and increase of hepatic enzymes. Also, via oxidative, inflammatory (increase of TNF-α, IL-1β, IL-6, TGF- β1, MCP-1 and IFN-γ levels) and apoptotic (increase of caspase 3 and 9 activities) alterations. This study revealed that γ-ORY supplementation prevented all alterations CCl4-induced. Thus, the protective effect of γ-ORY supplementation in hepatic fibrosis was trough antioxidant, anti-inflammatory and antiapoptotic activities.

This study investigated the effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) at a dose of 1 mg/kg in memory impairment and anxiety in an Alzheimer's disease (AD) model induced by amyloid β-peptide (Aβ) (fragment 25-35) in mice. The involvement of acetylcholinesterase (AChE) activity and lipid peroxidation in hippocampus and cerebral cortex was evaluated. Male Swiss mice were pretreated with 4-PSQ (1 mg/kg, intragastrically (i.g.), daily) for fourteen days. Thirty minutes after the first treatment with 4-PSQ, the animals received a single injection of Aβ (3 nmol/3 μl/per site, intracerebroventricular (i.c.v.)). Mice were submitted to the behavioral tasks (open-field, elevated plus maze, Barnes maze, object recognition and location, and step-down inhibitory avoidance tests) from the fifth day onwards. On the fifteenth day, blood was removed for analysis of biochemical markers (glucose, triglycerides, urea, aspartate (AST) and alanine (ALT) aminotrasferases), and cerebral cortex and hippocampus for determination of AChE activity and thiobarbituric acid reactive species (TBARS) levels. Aβ caused memory impairment, anxiogenic behavior, increased AChE activity in the cerebral structures and TBARS levels in the cerebral cortex. 4-PSQ was effective to protect against behavioral changes, AChE activity and TBARS levels. In conclusion, 4-PSQ protected against learning and memory impairment and anxiety in a mouse model of AD induced by Aβ, and anticholinesterase and antioxidant actions are involved in the pharmacological effect of the compound.

Objective Parkinson's disease (PD) may be caused by the interaction of a number of factors, including genetics, toxins, oxidative stress, mitochondrial abnormalities, and aging. Studies have shown that consumption of an antioxidant-rich diet may reduce the incidence of neurodegenerative diseases. The aim of this study was to evaluate the role of the flavonoid hesperidin in an animal model of PD induced by 6-hidroxidopamine (6-OHDA). Methods: Aged mice were treated with hesperidin (50 mg/kg) during 28 d after an intracerebroventricular injection of 6-OHDA. The enzymatic activities of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and glutathione S-transferase, the levels of glutathione, reactive oxygen species, total reactive antioxidant potential, dopamine and its levels of metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid, was analyzed in the striatum. The behavioral parameters (depressive-like, memory, and locomotor) were measured. Results This study demonstrated that hesperidin (50 mg/kg) treatment was effective in preventing memory impairment in the Morris water maze test, as well as, depressive-like behavior in the tail suspension test. Hesperidin attenuated the 6-OHDA-induced reduction in glutathione peroxidase and catalase activity, total reactive antioxidant potential and the dopamine and its metabolite levels in the striatum of aged mice. 6-OHDA increased reactive oxygen species levels and glutathione reductase activity in the striatum, and these alterations were mitigated by chronic administration of hesperidin. Conclusion This study demonstrated a protective effect of hesperidin on the neurotoxicity induced by 6-OHDA in aged mice, indicating that it could be useful as a therapy for the treatment of PD.

Hypothyroidism is often associated with psychiatric disorders such as depression. In this study, we evaluated the effect of chrysin on depressive-like behavior and monoamine levels in hypothyroid female mice. Hypothyroidism was induced by continuous exposure to 0.1% methimazole (MTZ) in drinking water for 31 days. Exposure to MTZ was associated with low plasma levels of thyroid hormones T3 and T4 compared with the control group. Subsequently, euthyroid and MTZ-induced hypothyroid mice were intragastrically administered vehicle or chrysin (20mg/kg) once a day for 28 consecutive days. After treatments, the following behavioral assessments were performed: Open-Field Test (OFT), Tail suspension test (TST), and Forced Swimming Test (FST). Additionally, T3 and T4 levels were measured again, and serotonin (5HT), dopamine, and noradrenaline levels were analyzed in the prefrontal cortex and the hippocampus. Chrysin treatment could not reverse T3 and T4 levels. Hypothyroid mice showed an increased immobility time in TST and FST; chrysin treatment reversed these effects. Reduced levels of 5HT and dopamine in the prefrontal cortex and the hippocampus were observed in the hypothyroid mice than in the euthyroid mice. Chrysin treatment recovered 5HT content in both structures and dopamine content only in the hippocampus. Noradrenaline content was not altered by treatments. Together, our results have demonstrated that chrysin treatment reverses depressive-like behaviors in hypothyroid female mice and suggests the involvement of 5HT and dopamine in these effects.

The protective effect of ebselen was investigated against 3-nitropropionic acid (3-NP)-induced behavioral and biochemical toxicities in rats. Ebselen (10 or 25 mg/kg, intragastrically) was administered to rats 30 min before 3-NP (20 mg/kg, intraperitoneally) once a day for a period of 4 days. Locomotor activity, motor coordination, and body weight gain were determined. The striatal content of reactive oxygen species (ROS), reduced glutathione (GSH), ascorbic acid (AA), and protein carbonyl as well as catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) activities was determined 24 h after the last dose of 3-NP. Na(+)/ K(+)-ATPase, succinate dehydrogenase (SDH), and δ-aminolevulinic dehydratase (δ-ALA-D) activities were also determined. The results demonstrated that ebselen at a dose of 25 mg/kg, but not at 10 mg/kg, protected against (1) a decrease in locomotor activity, motor coordination impairment, and body weight loss; (2) striatal oxidative damage, which was characterized by an increase in ROS levels, protein carbonyl content, and GR activity, an inhibition of CAT and GPx activities, and a decrease in GSH levels; and (3) an inhibition of SDH and Na(+)/K(+)-ATPase activities, induced by 3-NP. GST activity and AA levels were not modified by ebselen or 3-NP. Ebselen was not effective against the inhibition of δ-ALA-D activity induced by 3-NP. The results revealed a significant correlation between SDH activity and ROS levels, and SDH activity and latency to fall (rotarod test). The present study highlighted the protective effect of ebselen against 3-NP-induced toxicity in rats.

Hesperidin (4'-methoxy-7-O-rutinosyl-3',5-dihydroxyflavanone), a naturally occurring flavanone glycoside, was previously shown to produce an antidepressant-like effect with modultation of the serotonergic 5-HT1A and kappa-opioid receptors. In this study, the signaling mechanisms underlying their antidepressant-like effects were further evaluated by investigating in acute and chronic treatments. Results showed that chronic treatment of hesperidin or hesperitin (0.1, 0.3 and 1mg/kg, intraperitoneal, i.p.) have an antidepressant-like effect in the mouse tail suspension test (TST) without modified the locomotor activity in the open field test. Pretreatment with l-arginine (a nitric oxide (NO) precursor), sildenafil (a phosphodiesterase 5 inhibitor) or S-nitroso-N-acetyl-penicillamine (a NO donor) significantly reversed the reduction in immobility time elicited by acute treatment with hesperidin (0.3mg/kg) in the TST. Hesperidin (0.01mg/kg, a sub-effective dose in acute treatment) produced an additive antidepressant-like effect with N(G)-nitro-l-arginine (an inhibitor of nitric oxide synthase (NOS)) or 7-nitroindazole (a neuronal NOS inhibitor) in the TST. Pretreatment of animals with methylene blue (an inhibitor of NOS/soluble guanylate cyclase (sGC)) or ODQ (a specific inhibitor sGS) caused an additive effect with hesperidin in the TST. Hesperidin in the acute (1mg/kg) and chronic (0.1, 0.3 and 1mg/kg) treatments caused a significant decrease in nitrate/nitrite (NOX) levels in the hippocampus of mice. Chronic treatment with hesperidin (0.3 and 1mg/kg) also resulted in an increase in hippocampal brain-derived neurotrophic factor (BDNF) levels. These results demonstrated that the antidepressant-like effect of hesperidin is likely mediated by inhibition of l-arginine-NO-cGMP pathway and by increased of the BDNF levels in hippocampus.

Chrysin (5,7-dihydroxyflavone) is a flavonoid, natural component of traditional medicinal herbs, present in honey, propolis and many plant extracts. The objective of this study was to investigate the hypolipidemic properties of chrysin on Triton WR-1339-induced hyperlipidemia in female C57BL/6 mice. Triton WR-1339 was administered intraperitoneally (400 mg/kg) to overnight-fasted mice to develop acute hyperlipidemia. Chrysin was administered orally (10 mg/kg) 30 min before Triton WR-1339. At 24 h after Triton WR-1339 injection, blood samples were collected to measure plasma lipid levels. The hepatic thiobarbituric acid reactive substances (TBARS), carbonyl content, non-protein sulfhydryl (NPSH) and ascorbic acid (AA) levels, as well as catalase (CAT) and superoxide dismutase (SOD) activity were recorded. Chrysin administration significantly decreased total cholesterol levels. In addition, it partially decreased non-high density lipoprotein-cholesterol and triglycerides levels in plasma of hyperlipidaemic mice. In addition chrysin administration prevented the increase on TBARS levels and prevented the decrease in SOD activity induced by Triton WR-1339. These findings indicated that chrysin was able to decrease plasma lipids concentration and that its antioxidant properties was, at least in part, involved in the hypolipidaemic action of chrysin.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of dementia, representing about 60–70% of cases. Curcumin is a natural compound extracted from Curcuma longa Linn, widely used in cooking, presenting several biological activities, including neuroprotection. However, it has low solubility and consequently its bioavailability is limited. In recent years, researchers have focused their attention on delivery systems based on nanotechnology because of their promising potential and advantages over conventional approaches. This study investigated the neuroprotective effects of curcumin loaded lipid-core nanocapsules (LNC) in a model of Alzheimer’s disease (AD) induced by intracerebroventricular injections of β-amyloid1-42 (Aβ1-42) peptide in aged female mice, and compared these effects with those from free curcumin. Aged female mice received curcumin, free (50 mg/kg, p.o.) or loaded nanocapsules (10 or 1 mg/kg, p.o.) for 14 days after Aβ1-42 administration. Aβ1-42 induced significant cognitive deficit (Morris Water Maze test), as well as caused increased the levels of inflammatory cytokines in prefrontal cortex, hippocampus and serum of mice. LNC displayed significant neuroprotection against Aβ1-42-induced behavioral and neurochemical changes in a model of AD. These results provide insights into the neuroprotective actions of curcumin and its nanoencapsulation as a promising approach for application as an neuroprotective agent in the prevention of AD.

Information on the effect of an intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) on noncognitive behaviour in rodents such as depression states is scarce. Thus, the aim of this study was to examine the depressive-like effect of STZ injected by the i.c.v. route in mice and the potential protective effect of fluoxetine, antitumour necrosis factor-α (anti-TNF-α) and thalidomide. Our results indicated that a single injection of STZ (0.1 mg/site) promoted depressive-like behaviour in the tail suspension and sucrose preference tests without altering either locomotor activity or plasma glucose levels. We also showed that STZ increased TNF-α levels in the hippocampus of mice. Fluoxetine (32 mg/kg, intraperitoneally. 30 min before STZ injection), and the anti-TNF-α antibody (0.1 pg/site, i.c.v.) and thalidomide (3 mg/kg, subcutaneously), coadministered with STZ, prevented these effects. This is the first study to report depressive-like effects of STZ using the i.c.v. route in mice. We concluded that fluoxetine, anti-TNF-α antibody and thalidomide were effective in preventing depressive-like behaviour and the increase in TNF-α levels in the hippocampus of mice induced by an i.c.v. injection of STZ, reinforcing the involvement of TNF-α in the pathophysiology of depression. This model and the mechanisms studied may contribute towards the development of new antidepressant drugs and enhance the options for studying depression.

The present study was designed to examine the correlations between behavioural and oxidative parameters in a quinolinic acid model of Huntington’s disease in rats. The protective effect of melatonin against the excitotoxicity induced by quinolinic acid was investigated. Rats were pre-treated with melatonin (5 or 20 mg/kg) before injection of quinolinic acid (240 nmol/site; 1 μl) into their right corpora striata. The locomotor and exploratory activities as well as the circling behaviour were recorded. The elevated body swing test was also performed. After behavioural experiments, biochemical determinations were carried out. Melatonin partially protected against the increase of circling behaviour caused by quinolinic acid injection. No alteration was found in the number of crossings and rearings of animals treated with melatonin and/or quinolinic acid. Melatonin decreased the percentage of contralateral biased swings induced by quinolinic acid. Melatonin protected against the increase in reactive species and protein carbonyl levels as well as the inhibition of superoxide dismutase activity resulting from quinolinic acid injection. Melatonin was partially effective against the inhibition of striatal catalase activity and a decrease of non-protein thiol levels induced by quinolinic acid. Melatonin was not effective against the inhibition of Na + , K + ATPase activity caused by quinolinic acid injection. There were significant correlations between circling behaviour and oxidative parameters. The antioxidant property of melatonin is involved, at least in part, in its neuroprotective effect. The results reinforce the idea that melatonin could be useful in overwhelming neurotoxicity caused by quinolinic acid, a rat model of Huntington’s disease.

Chrysin is a natural flavonoid which is found in bee propolis, honey and various plants, and antidepressant-like effect of chrysin in chronically stressed mice was previously demonstrated by our group. In this work, we investigated the action of chrysin treatment (5 or 20 mg/kg) for 14 days in the depressant-like behavior and in the hippocampal dysfunction induced by olfactory bulbectomy (OB), an animal model of agitated depression. Results demonstrated that OB occasioned a depressant-like behavior in the splash test, open field test and forced swimming test. Chrysin administration, similarly to fluoxetine (positive control), promoted the attenuation of these behavioral modifications. OB also caused the elevation of tumor necrosis factor-α, interferon-γ, interleukin-1β, interleukin-6, kynurenine (KYN) levels and indoleamine-2,3-dioxygenase activity, as well as occasioned the decrease of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) levels and increase KYN/tryptophan and 5-hydroxyindoleacetic acid/5-HT ratio in the hippocampus. Chrysin therapy prevented against all these alterations in the hippocampus. In addition, chrysin treatment (20 mg/kg) resulted in the up-regulation of BDNF levels in the control animals, reinforcing our hypothesis that up-regulation of BDNF synthesis play a key role in the antidepressant action of chrysin. In conclusion, this study showed that chrysin, similarly to fluoxetine, is capable of promoting the attenuation of depressant-like behavior and hippocampal dysfunction resulting from OB in mice. These results reinforced the potential of chrysin for the treatment or supplementary treatment of depression, as well as showed that chrysin is also effective with 14 days of therapy in a model of agitated depression.

Cerebrovascular diseases, including ischemic stroke, are associated with high mortality worldwide. Oxidative stress and inflammation are important pathophysiological mechanisms involved in post-ischemic cerebral injury. The present study was designed to investigate the potential protective effect of diphenyl diselenide (PhSe)(2), an organoselenium compound with antioxidant and anti-inflammatory properties, against ischemia/reperfusion (I/R) insult in rat brain. The experimental model adopted was that of surgically-induced brain ischemia, performed by means of bilateral common carotid artery occlusion in rats. The effect of a single oral dose of (PhSe)(2) (50 mg/kg), administered 30 min before the onset of ischemia, was investigated by assessing cerebral oxidative stress-related biochemical parameters and pro-inflammatory cytokines in plasma of rats. The results demonstrated an increase in the levels of malondialdehyde (MDA), reactive oxygen species (ROS) and nitrate/nitrite as well as the alteration in the non-enzymatic and enzymatic (catalase and superoxide dismutase) antioxidant defense system induced by I/R insult in rat brain. I/R insult increased the levels of IL-1β, IL-6, TNF-α and INF-γ in plasma of rats. The administration of (PhSe)(2) restored cerebral levels of MDA, ROS, nitrate/nitrite and antioxidant defenses of rats exposed to I/R insult. (PhSe)(2) markedly reduced pro-inflammatory cytokines in plasma of I/R rats. I/R insult increased the plasma levels of tissue damage markers, such as creatine kinase and α-1-acid glycoprotein. Pretreatment with (PhSe)(2) was effective in reducing the levels of these proteins. In addition, (PhSe)(2) attenuated cerebral histological alterations induced by I/R. This study showed for the first time the in vivo protective effect of (PhSe)(2) against oxidative stress and pro-inflammatory cytokines-induced by I/R insult in rats.

In this study, the antioxidant and antidepressant-like effects of α-(phenylselanyl) acetophenone (PSAP), an organoselenium compound, were investigated. To assess the in vitro antioxidant properties, PSAP was evaluated in four test systems (DPPH, ABTS, FRAP and inhibition of lipid peroxidation). PSAP (100-500 μM) showed potent antioxidant activity and protected against lipid peroxidation. Additionally, we investigated whether PSAP, when administered in mice (100, 200 and 400mg/kg, per oral, p.o.), could cause acute toxicity. Our results demonstrated that PSAP did not cause the death of any animal, significantly reduce body weight or cause any oxidative tissue stress following treatment. This study also evaluated the effect of PSAP (0.1-10 mg/kg, p.o) on mice in a forced swim test (FST) and tail suspension test (TST), assays that are predictive of depressant activity and motor activity in the open-field. PSAP (5-10 mg/kg) significantly reduced immobility time in the FST and TST without affecting motor activity. In addition, the antidepressant-like effect caused by PSAP (5m/kg, p.o) in mice during the TST was dependent on an interaction with the serotonergic system (5-HT(1A) receptors), but not with the noradrenergic, dopaminergic or adenosinergic system. Together, these results suggest that PSAP possesses antioxidant and antidepressant-like properties and may be of interest as a therapeutic agent for the treatment of depressive disorders.

The aim of this study was to investigate the effect of SCH 58261, a selective adenosine A(2A) receptor (A(2A)R) antagonist, on kainic acid (KA)-induced seizures in 21-day-old rats. Rats were pretreated with SCH 58261 (1 or 3 mg/kg) by intraperitoneal (i.p.) route 30 min before KA (10 mg/kg, i.p.) administration. The appearance of clonic seizures, the latency for the onset of the first clonic seizure episode, and the number of deaths induced by KA were evaluated. To test the hypothesis of the oxidative imbalance induced by KA exposure, reactive species (RS) levels, catalase (CAT), glutathione peroxidase (GPx), and glutathione S-transferase (GST) activities in the brains of rats were measured. Both doses of SCH 58261 prolonged the latency for the onset of the first clonic seizure episode. SCH 58261, at the highest dose, decreased the appearance of clonic seizures as well as the mortality rate induced by KA administration. SCH 58261, at the dose of 3 mg/kg, was also effective in protecting against alterations in oxidative stress parameters (RS levels, CAT, GPx, and GST activities) in the brains of young rats exposed to KA. Our data reveal that SCH 58261 was protective against the neurotoxicity induced by KA. Therefore, the blockade of A(2A)R might represent a novel approach for the treatment of seizures.

In the present study we investigated the role of potassium (K + ) channels and peroxisome proliferator-activated receptor gamma (PPARγ) in the antidepressant-like effect of bis selenide in the mouse tail suspension test (TST). Intracerebroventricular (i.c.v.) pretreatment with tetraethyl ammonium (TEA, a non-specific inhibitor of K + channels, 25 pg/site), glibenclamide (an ATP-sensitive K + channel inhibitor, 0.5 pg/site), charybdotoxin (a large and intermediate conductance calcium-activated K + channel inhibitor, 25 pg/site) or apamin (a small-conductance calcium-activated K + channel inhibitor, 10 pg/site) produced a synergistic action with a sub effective dose of bis selenide (0.1 mg/kg, per oral – p.o.). Picrotoxin (1 mg/kg, intraperitoneally – i.p.) pretreatment did not prevent the reduction in immobility time elicited by bis selenide (1 mg/kg, p.o.) in the TST. The reduction in the immobility time elicited by an effective dose of bis selenide (1 mg/kg, p.o.) was prevented by the pretreatment of mice with cromakalim, minoxidil (K + channel openers, 10 μg/site, i.c.v.) and GW 9662 (a PPARγ antagonist, 10 μg/site, i.c.v.). The findings clearly suggest that an acute oral dose of bis selenide produced an antidepressant-like effect in the mouse TST by a mechanism that involves the K + channels and PPARγ receptors.

The in vitro effect of (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD) was evaluated through iron/EDTA-induced thiobarbituric acid reactive species (TBARS) and reactive species (RS) determinations as well as of the scavenging 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical quantification. BPD at the concentrations of 10 and 50 μΜ decreased RS and TBARS levels, respectively. The antioxidant activity was not related to the scavenging DPPH radical mechanism. A second objective of this study was to investigate the hepatoprotective action of BPD, administered by oral route, against oxidative damage induced by 2-nitropropane (2-NP) (100 mg/kg of body weight) in liver of rats. At the dose of 50 mg/kg, BPD protected against the increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) activities induced by 2-NP. BPD (10 and 50 mg/kg) protected against the increase in TBARS levels and alkaline phosphatase (ALP) activity. Sections of liver from 2-NP-exposed rats presented intense infiltration of inflammatory cells and loss of cellular architecture. BPD (10 and 50 mg/kg) attenuated 2-NP-induced hepatic histological alterations. The inhibition of δ-aminolevulinic dehydratase (δ-ALA-D), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) activities and the decreased GSH levels caused by 2-NP were protected by BPD (50 mg/kg). Catalase activity and ascorbic acid levels were not altered by 2-NP. These results demonstrated the antioxidant and hepatoprotective effects of BPD in liver of rats.

Aim This study investigated the in vitro antioxidant activity of (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD), the anticonvulsant effect of BPD on seizures induced by pilocarpine (PC), pentylenetetrazole (PTZ) and 4-aminopyridine (4-AMP) and the mechanism involved. Methods BPD antioxidant activity in vitro was investigated using sodium nitroprusside (SNP) and malonate-induced thiobarbituric acid reactive species (TBARS) and sodium azide-induced reactive species (RS) production. Thiol peroxidase and oxidase as well as δ-aminolevulinate dehydratase (δ-ALA-D) activities were examined. Mice were pretreated via oral route (p.o.) with BPD (1–100 mg/kg) before intraperitoneal (i.p.) administration of PC (400 mg/kg), PTZ (80 mg/kg) or 4-AMP (12 mg/kg). To investigate the antioxidant effect of BPD on oxidative stress induced by PC, the activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST) and catalase (CAT) as well as the levels of RS and TBARS were determined in brains of mice. δ-ALA-D, acetylcholinesterase (AChE) and Na + , K + ATPase activities were verified. Key findings BPD (5 μM) reduced RS production and lipid peroxidation induced by SNP and malonate. BPD (1–50 μM) did not show thiol peroxidase and oxidase activities and did not alter δ-ALA-D activity. BPD (5 mg/kg) increased the latency to the seizure onset on PTZ and 4-AMP models. BPD (100 mg/kg) abolished seizures and death induced by PC in mice. BPD protected against the increase in RS and TBARS levels. The activity of Na + , K + ATPase and AChE inhibited by PC remained unaltered in the BPD group. Significance BPD showed anticonvulsant and antioxidant effects on seizures induced by PC in mice.

Objectives This study investigated the involvement of different types of K+ channels and PPARγ receptors in the antidepressant-like effect of diphenyl diselenide in mice. Methods Mice were pretreated with subeffective doses of K+ channel inhibitors (tetraethylammonium, glibenclamide, charybdotoxin and apamin), openers (cromakalim, minoxidil), GW 9662 (a PPARγ antagonist) or vehicle. Thirty minutes later the mice received diphenyl diselenide in either an effective or a subeffective dose, 30 min before a tail-suspension test. Key findings Pre-treatment with tetraethylammonium, charybdotoxin or apamin combined with a subeffective dose of diphenyl diselenide was effective in decreasing the immobility time in the mouse tail-suspension test. The reduction in the immobility time elicited by an effective dose of diphenyl diselenide in this test was prevented by the pretreatment of mice with minoxidil and GW 9662. Conclusions Diphenyl diselenide elicited an antidepressant-like effect and this action was mediated, at least in part, by modulation of K+ channels and PPARγ receptors.

The present study investigated a possible antidepressant-like effect of bis selenide by using the forced swimming and the tail suspension tests. The involvement of the l -arginine–nitric oxide–cyclic guanosine monophosphate signaling pathway in the antidepressant-like action of bis selenide was investigated. Bis selenide, given by oral route at doses of 0.5–5 mg/kg, decreased the immobility time in the forced swimming and tail suspension tests. Pretreatment with l -arginine (750 mg/kg, intraperitoneal, i.p., a nitric oxide precursor), sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor) or S-nitroso-N-acetyl-penicillamine (25 μg/site, intracerebroventricular, i.c.v., a nitric oxide donor) reversed the reduction in the immobility time elicited by bis selenide (1 mg/kg, p.o.) in the tail suspension test. Bis selenide (0.1 mg/kg, p.o., a subeffective dose) produced a synergistic antidepressant-like effect with N G -nitro- l -arginine (0.3 mg/kg, i.p., an inhibitor of nitric oxide synthase) or 7-nitroindazole (25 mg/kg, i.p., a specific neuronal nitric oxide synthase inhibitor) in the tail suspension test. Pretreatment of animals with methylene blue (10 mg/kg, i.p., an inhibitor of nitric oxide synthase and soluble guanylate cyclase) or 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (30 pmol, i.c.v., a specific inhibitor of soluble guanylate cyclase), at subeffective doses, caused a synergistic effect with bis selenide in the tail suspension test. Bis selenide (1 mg/kg, p.o.), at an effective dose in the forced swimming and tail suspension tests, caused a significant decrease in the mouse cerebral nitrate/nitrite levels. The antidepressant-like effect of bis selenide in the tail suspension test is dependent on the inhibition of the l -arginine–nitric oxide–cyclic guanosine monophosphate pathway.

Organoselenium compounds display important antioxidant activity and many biological activities interesting from pharmacological point of view. The aim of this study was to evaluate the hepatoprotective effect of p-methoxyl-diphenyl diselenide, a disubstituted diaryl diselenide, on acute liver injury induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) in mice. The animals received p-methoxyl-diphenyl diselenide (10, 50 and 100 mg/kg; per oral, p.o.) and 1 h after d-GalN (500 mg/kg) and LPS (50 microg/kg) were administered by intraperitoneal route (i.p.). Twenty-four hours after LPS/d-GalN exposure the animals were euthanized to the biochemical and histological analysis. Pretreatment with p-methoxyl-diphenyl diselenide (50 and 100 mg/kg; p.o.) protected against the increase in aspartate aminotransferase (AST) activity induced by LPS/d-GalN exposure in mice. p-Methoxyl-diphenyl diselenide at the doses of 50 and 100 mg/kg protected against the increase in alanine aminotransferase (ALT) activity induced by LPS/D-GalN exposure. In this study, no alteration in ascorbic acid levels was observed in livers of mice exposed to LPS/D-GalN. Glutathione-S-transferase (GST) activity was stimulated by LPS/D-GalN exposure and p-methoxyl-diphenyl diselenide, at all doses, protected against this alteration. p-Methoxyl-diphenyl diselenide was effective in ameliorating inhibition of catalase activity induced by LPS/d-GalN exposure. Histological data showed that sections of livers from LPS/D-GalN-treated mice presented massive hemorrhage, inflammatory cells and necrosis. p-Methoxyl-diphenyl diselenide significantly attenuated LPS/D-GalN-induced hepatic histopathological alterations. Based on the results, we suggest the hepatoprotective effect of p-methoxyl-diphenyl diselenide on acute liver injury induced by LPS/d-GalN exposure in mice.

Administration of tramadol elicited an antidepressant-like effect in the rat forced swimming test (FST) by a mechanism dependent on the inhibition of the L-arginine-nitric oxide (NO)-guanylate cyclase pathway. Since it has been reported that NO can activate different types of potassium (K + ) channels in several tissues, the present study investigated the possibility of synergistic interactions between different types of K + channel inhibitors and tramadol in the mouse FST. Intracerebroventricular pretreatment of mice with tetraethylammonium (TEA, a non-specific inhibitor of K + channels, 25 pg/site), glibenclamide (an ATP-sensitive K + channel inhibitor, 0.5 pg/site) or charybdotoxin (a large- and intermediate conductance calcium-activated K + channel inhibitor, 25 pg/site) was able to produce a synergistic action of a subeffective dose of tramadol (1 mg/kg, p.o.). Conversely, pretreatment with apamin (a small-conductance calcium-activated K + channel inhibitor, 10 pg/site) did not modify the action of a subeffective dose of tramadol (1 mg/kg, p.o.). Administration of tramadol and the K + channel inhibitors, alone or in combination, did not affect the number of crossings and rearings in the open field test (OFT). Reduction in the immobility time elicited by an active dose of tramadol (40 mg/kg, p.o.) in the FST was prevented by pretreatment of mice with cromakalim (a K + channel opener, 10 µg/site, i.c.v.), without affecting the number of crossings and rearings in the OFT. Thus, our findings clearly suggest that oral acute administration of tramadol produces antidepressant-like effect on the FST in mice by a mechanism that involves the K + channels.

Organoselenium are compounds with important antioxidant activity and with many biological activities interesting from pharmacological point of view. The aim of this study was to evaluate the protective effect of diphenyl diselenide (PhSe) 2 on hepatotoxicity caused by administration of acetaminophen (AA) in rats. Rats received (PhSe) 2 orally (31mg/kg, dissolved in canola oil) for 2 days. After the second day of treatment, rats received AA orally (2g/kg) in unique dose. Twenty-four hours after the last administration of AA, plasma was used for biochemical assays aspartate (AST) and alanine aminotransferases (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyl transferase (γ-GT) activities. Glutathione- S -transferase (GST), δ-aminolevulinic dehydratase (δ-ALA-D) and catalase activities as well as ascorbic acid and TBARS levels were determined in the liver of rats. (PhSe) 2 protected against the increase in AST, ALT, ALP, LDH and γ-GT activities induced by AA exposure to rats. The histological data showed that sections of liver from AA-exposed rats presented intense cellular necrosis, characterized by the presence of Kupffer cells and other infiltrating cells, mainly around of the centrilobular vein. (PhSe) 2 significantly attenuated AA-induced hepatic histopathological alterations. Administration of (PhSe) 2 protected against the increase in TBARS levels and the decrease in δ-ALA-D and GST activities as well as ascorbic acid content induced by AA exposure in rats. Catalase activity remained unaltered in all treated groups. The protective effect of (PhSe) 2 against hepatotoxicity caused by AA exposure in rats was demonstrated.

Objectives The present study examined the mechanisms involved in the antinociceptive effects of bis selenide [(Z)-2,3-bis(4-chlorophenylselanyl)prop-2-en-1-ol]. Methods The effects of oral bis selenide were tested against licking behaviour and oedema in mice induced by formalin, serotonin, histamine, glutamate, phorbol 12-myristate 13-acetate (PMA), 8-bromoadenosine 3′,5′-cyclic monophosphate (8-BrcAMP) and pros-taglandin E2. The effects of a variety of receptor antagonists on the antinociceptive activity were tested to determine the likely mechanism of action of bis selenide. Key findings Bis selenide caused antinociception on the first and second phases of the formalin test, with mean ID50 values of 34.21 (29.66–39.45) and 15.86 (12.17–20.67) mg/kg and maximal inhibition of 65 ± 3% and 90 ± 1%, respectively. At 50 mg/kg bis selenide significantly inhibited (31 ± 2%) paw oedema induced by intraplantar injection of formalin. At 25 mg/kg given 5 min after the formalin injection, bis selenide caused a significant inhibition (42 ± 5%) in the second phase of the formalin test, whereas the prophylactic treatment caused more intense inhibition (64 ± 3%). Oral administration of bis selenide reduced licking and paw oedema induced by serotonin, histamine, glutamate, PGE2, PMA and 8-BrcAMP. The antinociceptive effect of bis selenide (25 mg/kg, p.o.) on the formalin test was reversed by i.p. administration of p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis), ketanserin (a selective 5-HT2a receptor antagonist), ondansetron (a 5-HT3 receptor antagonist) and ranitidine (a histamine H2-receptor antagonist). Conclusions Glutamatergic, prostaglandin E2, serotonergic (5-HT2a and 5-HT3) and histamine H2 receptors are involved in the antinociceptive effects of bis selenide in mice. The interaction of bis selenide with protein kinase C and A signalling pathways was also demonstrated.

The objective of this study was to extend our previous findings by investigating in greater detail the mechanisms that might be involved in the antinociceptive action of p -methoxyl-diphenyl diselenide, (MeOPhSe) 2 , in mice. The pretreatment with nitric oxide precursor, l -arginine (600 mg/kg, intraperitoneal, i.p.), reversed antinociception caused by (MeOPhSe) 2 (10 mg/kg, p.o.) or N G -nitro- l -arginine ( l -NOARG, 75 mg/kg, i.p.) in the glutamate test. Ondansetron (0.5 mg/kg, i.p., a 5-HT 3 receptor antagonist) and SCH23390 (0.05 mg/kg, i.p.., a D 1 receptor antagonist) blocked the antinociceptive effect caused by (MeOPhSe) 2 . Conversely, pindolol (1 mg/kg, i.p., a 5-HT 1A / 1B receptor/β adrenoceptor antagonist), WAY 100635 (0.7 mg/kg, i.p., a selective 5-HT 1A receptor antagonist), ketanserin (0.3 mg/kg, i.p., a selective 5-HT 2A receptor antagonist), prazosin (0.15 mg/kg, i.p., an α 1 -adrenoreceptor antagonist), yohimbine (1.0 mg/kg, i.p., an α 2 -adrenoreceptor antagonist), sulpiride (5 mg/kg, i.p., a D 2 receptor antagonist), naloxone (1 mg/kg, i.p., a non-selective opioid receptor antagonist) and caffeine (3 mg/kg, i.p., a non-selective adenosine receptor antagonist) did not change the antinociceptive effect of (MeOPhSe) 2 . (MeOPhSe) 2 significantly inhibited nociception induced by intraplantar (i.pl.) injection of bradykinin (10 nmol/paw) and Des-Arg 9 -bradykinin (10 nmol/paw, a B 1 receptor agonist). (MeOPhSe) 2 significantly inhibited phorbol myristate acetate (PMA, 0.03 μg/paw, a protein kinase C (PKC) activator)-induced licking response. These results indicate that (MeOPhSe) 2 produced antinociception in mice through mechanisms that involve an interaction with nitrergic system, 5-HT 3 and D 1 receptors. The antinociceptive effect is related to (MeOPhSe) 2 ability to interact with kinin B 1 and B 2 receptors and PKC pathway mediated mechanisms.

This study investigated the mechanisms involved in the antinociceptive action induced by diphenyl diselenide ((PhSe)2) in the formalin test. Mice were pre-treated with (PhSe)2 by the oral route (0.1–100 mg kg−1), 30 min before formalin injection. To address some of the mechanisms by which (PhSe)2 inhibits formalin-induced nociception mice were treated with different drugs. The antinociceptive effect of (PhSe)2 was shown in the first and second phases of the formalin test. The antinociceptive effect caused by (PhSe)2 (10 mg kg−1, p.o.) was prevented by intrathecal injection of K+ channel blockers such as apamin and charybdotoxin (small- and large-conductance Ca2+-activated K+ channel inhibitors, respectively) and tetraethylammonium (TEA, a non-selective voltage-dependent K+ channel inhibitor), but not glib-enclamide (an ATP-sensitive K+ channel inhibitor). The antinociceptive action caused by (PhSe)2 (10 mg kg−1, p.o.) was also blocked by a nitric oxide (NO) synthase inhibitor (Nω-nitro-l-arginine, L-NOARG) and the soluble guanylate cyclase inhibitors 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and methylene blue. These results suggest the participation of NO/cyclic GMP/Ca2+ and K+ channel pathways in the antinociceptive effect caused by (PhSe)2.

This study investigated the possible antidepressant-like and anxiolytic-like effects of diphenyl diselenide, (PhSe)(2) in mice. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the antidepressant-like effect was also evaluated. The immobility times in the tail suspension test (TST) and forced swimming test (FST) were reduced by (PhSe)(2) (5-100 mg/kg; oral route, p.o.). The antiimmobility effect of (PhSe)(2) (5 mg/kg, p.o.) in the TST was prevented by pretreatment of mice with L-arginine [a substrate for nitric oxide synthase (NOS)], methylene blue [an inhibitor of NO synthase and sGC] and sildenafil [a phosphodiesterase 5 inhibitor]. Furthermore, a sub-effective dose of (PhSe)(2) (0.1 mg/kg, p.o.) produced a synergistic antidepressant-like effect with N(G)-nitro-L-arginine [L-NNA; 0.3mg/kg, i.p. inhibitor of NOS], (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one [ODQ; 30 pmol/site i.c.v., a specific inhibitor of soluble guanylate cyclase (sGC)], fluoxetine and imipramine in the TST. (PhSe)(2) (50-100 mg/kg, p.o.) induced anxiolytic-like effect in the elevated plus-maze test and light/dark box. Together the results indicate that (PhSe)(2) elicited significant antidepressant-like and anxiolytic-like effects. The antidepressant-like action caused by (PhSe)(2) seems to involve an interaction with L-arginine-NO-cGMP pathway.

Experiments were designed to address whether diphenyl diselenide (PhSe)(2) has antiallodynic and antihyperalgesic properties. The neuropathic pain was caused by a partial tying (2/3) of sciatic nerve and the inflammatory pain was induced by an intraplantar (i.pl.) injection of 20 microl of Freund's Complete Adjuvant (CFA) in mice. Seven days after sciatic nerve constriction and 24 h after CFA intraplantar (i.pl.) injection, mouse pain threshold was evaluated through tactile allodynia, using Von Frey Hair (VHF) filaments. The acute thermal hyperalgesia was induced by intrathecal (i.t.) injection of glutamate, N-methyl-d-aspartate (NMDA), bradykinin (BK) and prostaglandin E(2) (PGE(2)), and the nociceptive response was assessed using hot-plate test. (PhSe)(2) administered by oral route (p.o.) (10 mg/kg) decreased the paw withdrawal response on the ipsilateral side of the partial sciatic nerve ligation 30 min after drug administration (64+/-7%) and this effect was kept for 1 h after treatment. (PhSe)(2) (10 mg/kg, p.o.) produced a reduction in mechanical allodynia induced by CFA started 30 min after (PhSe)(2) administration (71+/-5%) and this effect was maintained for up 4 h. (PhSe)(2) (0.1-50 mg/kg, p.o.) caused a significant inhibition of glutamate-, NMDA- and BK-(PGE(2))-induced acute thermal hyperalgesia in mice. Together, the present results indicate that (PhSe)(2) produces systemic antiallodynic action when assessed in mechanical stimulus (VHF) in the hindpaw and also attenuates acute thermal hyperalgesia. Thus, this compound might be potentially interesting in the development of new clinically relevant drugs for the management of pain.

The present study was designed to investigate further the mechanisms involved in the antinociception caused by diphenyl diselenide in behavioral model of pain in mice. Diphenyl diselenide (1-100 mg/kg), given orally, produced significant inhibition of the biting behavior induced by intrathecal (i.t.) injection of glutamate (175 nmol/site) and N-methyl-d-aspartate (NMDA; 450 pmol/site), with mean ID(50) values of 45.92 (39.74-60.4) and 55.77 (36.52-77.5) mg/kg respectively. However, diphenyl diselenide completely failed to affect the nociception induced by alpha-amino-3-hydroxy-5-mehtyl-4-isoxazolepropionic acid (AMPA; 135 pmol/site), (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 50 nmol/site) and kainate (110 pmol/site). This compound also reduced the nociceptive response induced by substance P (SP) (135 ng/site, i.t.), interleukin 1beta (IL-1beta; 1 pg/site), tumor necrosis factor-alpha (TNF-alpha; 0.1 pg/site), bradykinin (BK; 0.1 microg/site) and capsaicin (30 ng/site) with mean ID(50) values of 16.22, 7.06, 6.06, 4.18 and 7.90 mg/kg, respectively. Together, these results indicate that diphenyl diselenide produced antinociception at spinal sites, with a possible interaction with glutamatergic pathways, more specifically via interaction with NMDA receptors, peptidergic or vanilloid systems.

In this study, the antidepressant-like effect caused by diphenyl diselenide on rat forced swimming test (FST) was investigated. The involvement of the monoaminergic system in the antidepressant-like effect was also evaluated. Diphenyl diselenide (0.1-30 mg/kg), given by oral route (p.o.), 30 min earlier, reduced the immobility time in the FST, without accompanying changes in ambulation when assessed in an open field. The anti-immobility effect of diphenyl diselenide (1 mg/kg, p.o.) on the FST was prevented by pretreatment of rats with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis, given once a day, for 3 consecutive days), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), ketanserin (1 mg/kg, i.p., a 5-HT(2A)/(2C) receptor antagonist), ondasentron (1 mg/kg, i.p., a 5-HT(3) receptor antagonist), haloperidol (1 mg/kg, i.p., a D(1), D(2) and D(3) receptor antagonist), SCH233390 (0.05 mg/kg, s.c., a D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a D(2) receptor antagonist), prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist). However, the anti-immobility effect caused by diphenyl diselenide (1 mg/kg, p.o.) on the FST was not affected by pretreatment with propanolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist). Furthermore, monoamine oxidase (MAO) activity was inhibited (39%) in the animals treated with diphenyl diselenide (30 mg/kg, p.o.) when compared to the control group. Taken together these data demonstrated that the antidepressant-like effect caused by diphenyl diselenide seems to be mediated by involvement of the central monoaminergic system.

The administration of hesperidin elicits an antidepressant-like effect in mice by a mechanism dependent on an interaction with the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, whose stimulation is associated with the activation of potassium (K(+)) channels. Thus, this study investigated the involvement of different types of K(+) channels in the antidepressant-like effect of hesperidin in the mice tail suspension test (TST). The intracerebroventricular administration of tetraethylammonium (TEA, a nonspecific blocker of K(+) channels), glibenclamide (an ATP-sensitive K(+) channel blocker), charybdotoxin (a large- and intermediate-conductance calcium-activated K(+) channel blocker) or apamin (a small-conductance calcium-activated K(+) channel blocker) combined with a subeffective dose of hesperidin (0.01 mg/kg, intraperitoneally [i.p.]) was able to produce a synergistic antidepressant-like effect in the mice TST. Moreover, the antidepressant-like effect elicited by an effective dose of hesperidin (0.3 mg/kg, i.p.) in TST was abolished by the treatment of mice with pharmacological compounds K(+) channel openers (cromakalim and minoxidil). Results showed that the antidepressant-like effect of hesperidin in TST may involve, at least in part, the modulation of neuronal excitability through inhibition of K(+) channels and may act through a mechanism dependent on the inhibition of L-arginine-NO pathway.

The organoselenium compounds have been described to demonstrate several biological activities, including pain management.This study investigated the antinociceptive, hyperalgesic, and toxic effects of oral administration of bis(4-methylbenzoyl) diselenide (BMD) in mice.The antinociceptive and anti-hyperalgesic effects of BMD (1, 5, 10, 25, and 50 mg/kg, p.o.) were evaluated using models of nociception: formalin, capsaicin, bradykinin (BK), cinnamaldehyde, phorbol myristate acetate (PMA), 8-bromo-cAM, and glutamate-induced nociception; and mechanical hyperalgesia induced by carrageenan (Cg) or complete Freund's adjuvant (CFA). The acute toxicity was evaluated by biochemical markers for hepatic and renal damages.BMD significantly inhibited the licking time of the injected paw in the early and late phases of a formalin test with ED50 values of 14.2 and 10.8 mg/kg, respectively. This compound reduced nociception produced by capsaicin (ED50 of 32.5 mg/kg), BK (ED50 of 24.6 mg/kg), glutamate (ED50 of 28.7 mg/kg), cinnamaldehyde (ED50 of 18.9 mg/kg), PMA (ED50 of 9.6 mg/kg), and 8-bromo-cAMP (ED50 of 24.8 mg/kg). In the glutamate test, the pretreatment with nitric oxide (NO) precursor, L-arginine, reversed antinociception caused by BMD or N(ω)-nitro-L-arginine (L-NOARG), but the effect of BMD was not abolished by naloxone. Mechanical hyperalgesia induced by Cg and CFA was attenuated by BMD, 70 ± 4% and 65 ± 4%, respectively. Furthermore, a single oral dose of BMD did not change plasma aspartate (AST) and alanine aminotransferase (ALT) activities or urea and creatinine levels.BMD demonstrated as a promising compound because of the antinociceptive and anti-hyperalgesic properties in mice.

In this study, the effect of Chrysin (5,7-dihydroxyflavone), an important member of the flavonoid family, on memory impairment, oxidative stress and BDNF reduction generated by aging in mice were investigated. Young and aged mice were treated daily per 60days with Chrysin (1 and 10mg/kg; per oral, p.o.) or veichle (10ml/kg; p.o.). Mice were trained and tested in Morris Water Maze task. After the behavioural test, the levels of reactive species (RS), the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as the activity of Na(+), K(+)-ATPase and the levels of brain-derived neurotrophic factor (BDNF) were determined in the prefrontal cortex (PFC) and hippocampus (HC) of mice. Results demonstrated that the age-related memory decline was partially protected by Chrysin at a dose of 1mg/kg, and normalized at the dose of 10mg/kg (p

The excitotoxin 3-nitropropionic acid (3-NP) induces a suitable experimental model of Huntington's disease (HD). This compound induces neurodegeneration via glutamatergic activation and oxidative stress, suggesting that the metabotropic glutamate receptor blockage and free radical scavenging are potential therapeutic targets in HD. In this study, we evaluated the role of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP), a selective mGlu5 receptor antagonist, in a 3-NP model of HD.We administered 3-NP (20 mg/kg, intraperitoneal) to rats for 4 days. MTEP at doses of 2·5 and 5 mg/kg was administered 30 min before 3-NP. Behavioral tests and biochemical experiments were performed to assess the effects of 3-NP and the ability of MTEP to ameliorate these changes.3-NP administration induced body weight loss, decreased locomotor activity, and inhibition of succinate dehydrogenase and Na(+)-K(+) adenosine triphosphate (ATP)ase activities in rat striatum. We also observed increases in reactive species (RS) levels and glutathione reductase activity, decreased non-protein thiol levels, and an inhibition of glutathione peroxidase activity in the striatum of rats treated with 3-NP. Notably, all of these effects were attenuated by MTEP treatment.Our results demonstrate the neuroprotective effect of MTEP and reinforce the involvement of mGluR5 in 3-NP-induced oxidative stress in rat striatum.

Aims The study investigated the antidepressant-like effect and acute toxicity of 4-phenyl-1-(phenylselanylmethyl)-1,2,3-triazole (Se-TZ), an organoselenium-containing heterocycle compound in mice. Main methods The antidepressant-like effect of Se-TZ (1–50 mg/kg) and its mechanism of action, was analyzed in the tail suspension test (TST) in male C57BL/6J mice. Additionally, the levels of the monoamines and their metabolites in cerebral cortex and hippocampus were analyzed by high-performance liquid chromatography. To investigate the potential acute toxicity caused by Se-TZ, the mice received a single oral dose of Se-TZ (1–50 mg/kg), and after 72 h were performed the assays. Key findings The Se-TZ (5-50 mg/kg) significantly reduced immobility time in TST without altering locomotor and exploratory activities. The antidepressant-like effect of Se-TZ (25 mg/kg) in the TST was prevented by pre-treatment of mice with SCH23390, sulpiride and methysergide, but not with prazosin, yohimbine and propranolol. Se-TZ, increased monoamine neurotransmitters dopamine and serotonin levels in the cerebral cortex and hippocampus, whereas norepinephrine turnover was not changed. This study also demonstrated that the Se-TZ, did not cause the acute toxicity in biochemical markers hepatic and renal investigated. The results evidenced that exposure to Se-TZ caused a significant increase in the catalase (CAT) activity in the cerebral cortex and hippocampus, however the glutathione S-transferase (GST) activity increased only in the cerebral cortex. Significance These results suggest that Se-TZ demonstrated antidepressant-like effect, mediated via the central dopaminergic and serotoninergic neurotransmitter systems which may be of interest as a therapeutic agent for the treatment of depressive disorders.

The opioid system has been implicated as a contributing factor for major depression and is thought to play a role in the mechanism of action of antidepressants. This study investigated the involvement of the opioid system in the antidepressant-like effect of hesperidin in the mouse forced swimming test. Our results demonstrate that hesperidin (0.1, 0.3 and 1 mg/kg; intraperitoneal) decreased the immobility time in the forced swimming test without affecting locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3 mg/kg) in the forced swimming test was prevented by pretreating mice with naloxone (1 mg/kg, a nonselective opioid receptor antagonist) and 2-(3,4-dichlorophenyl)-Nmethyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl] acetamide (DIPPA (1 mg/kg), a selective κ-opioid receptor antagonist), but not with naloxone methiodide (1 mg/kg, a peripherally acting opioid receptor antagonist), naltrindole (3 mg/kg, a selective δ-opioid receptor antagonist), clocinnamox (1 mg/kg, a selective μ-opioid receptor antagonist) or caffeine (3 mg/kg, a nonselective adenosine receptor antagonist). In addition, a sub-effective dose of hesperidin (0.01 mg/kg) produced a synergistic antidepressant-like effect in the forced swimming test when combined with a sub-effective dose of morphine (1 mg/kg). The antidepressant-like effect of hesperidin in the forced swimming test on mice was dependent on its interaction with the κ-opioid receptor, but not with the δ-opioid, μ-opioid or adenosinergic receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like properties and may be of interest as a therapeutic agent for the treatment of depressive disorders.