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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.

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-amyloid

Sickness behavior is a normal immune response of body to fight infection, accompanied by endocrine and behavioral alterations. Lipopolysaccharide (LPS) causes sickness behavior in rodents through the increase of proinflammatory cytokines, generating peripheral inflammation and thus overactivation of kynurenine pathway (KP). In the present study we investigated the effects of dietary hydrogenated vegetable fat (HVF) in sickness behavior induced by LPS in aged mice. Male C57BJ/6 aged mice received a supplementation with HVF for six months. After HVF supplementation mice were treated with LPS (0.15 mg/kg; i. p. injection). Twenty-four hours post LPS injection mice were submitted to behavioral tests and then, the hippocampus, striatum and prefrontal cortex were removed for neurochemical determinations. Our results showed that dietary HVF did not exacerbate the behavioral alterations induced by LPS. Although HVF did not modulate the proinflammatory cytokines analyzed, it caused a potentiation in the increase of brain tumor necrosis factor-alpha levels induced by LPS. Moreover, dietary HVF aggravated LPS-induced KP activation in the brain of mice, mainly by further increase of neurotoxic metabolite quinolinic acid and further decrease of kynurenic acid/kynurenine ratio, a marker of neuroprotective branch of KP. Overall, our study demonstrated that dietary HVF did not worsen the sickness behavioral induced by LPS administration. However, HVF aggravated the activation of KP and exacerbated the shift of KP metabolism towards the neurotoxic branch.

An increasing body of evidence indicates that the activation of indoleamine-2,3-dyoxigenase (IDO), a first and rate-limiting enzyme in the kynurenine (KYN) pathway, is involved in Aβ1–42-neurotoxicity and AD pathogenesis. We have reported for the first time that brain IDO activation is related to Aβ1–42 exposure in young mice. Because aging is characterized by a brain dyshomeostasis and because it remains the most dominant risk factor for AD, the purpose of this study was to determine whether aging is associated with a higher sensitivity to behavioural and neurochemical alterations elicited by an intracerebroventricular (i.c.v.) injection of Aβ1–42 (400 pmol/mice), and whether KYN pathway is involved in these effects. We confirmed that aged mice displayed higher cognitive deficit in the object recognition test and higher anxiety-like behaviour in the elevated plus-maze and open field tests after the Aβ1–42 administration. Aged mice also responded to Aβ1–42 with a higher deficiency of brain-derived neurotrophic factor, glutathione levels and total radical-trapping antioxidant capacity, a higher IDO activity, and a higher KYN and KYN/tryptophan ratio in the prefrontal cortex and hippocampus. These effects of Aβ1–42 were associated with a higher proinflammatory status, as measured by higher levels of interleukin-6, lower levels of interleukin-10 and higher expression of glial fibrillary acidic protein (GFAP) and allograft inflammatory factor 1 (Iba1) in the brain of aged mice. These results represent primary evidence suggesting that age-associated inflammatory signature and down-regulation of neuroprotectants in the brain render aged mice more vulnerable to Aβ1–42-induced memory loss, anxiety symptoms and KYN pathway dysregulation.

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.

This study has evaluated the action of flavonoid hesperidin on the neurotoxic effects caused by the intake of iron (Fe) in Drosophila melanogaster . Male adult flies, aged 1–3 days, have been divided into four groups of 50 each: (1) control, (2) Hsd 10 μM, (3) Fe 20 mM (4) Hsd 10 μM + Fe 20 mM. During the exposure protocol, the flies have been exposed to a diet containing Hsd and/or Fe for 48 h. The survival and behavioral analyses have been carried out in vivo , and ex vivo . The analyses involved acetylcholinesterase (AChE) activity and Fe levels in the flies' heads and bodies and determination of dopaminergic levels, cellular and mitochondrial viability, activities of superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), reactive species levels (RS), thiobarbituric acid reactive substances (TBARS) and contents of total thiols and non-proteic thiols (NPSH) in the flies' heads. A significant negative correlation between Fe levels in the head of the flies and the survival, dopamine levels and antioxidant enzymes in the head of the flies has been found. Additionally, significant positive correlation between Fe levels in the head of the flies with negative geotaxis RS and AChE activity in the head of the flies has been found. It demonstrates that the flies which had higher levels of Fe in their heads have demonstrated more susceptibility to neurotoxicity. An important result from our study is that Hsd treatment promotes a decrease in Fe concentration in the head, restores dopamine levels and cholinergic activity of the flies and improves motor function caused by Fe. Hsd also ameliorates Fe induced mortality, oxidative stress and mitochondrial dysfunction. Our results have demonstrated the neuroprotective effect of Hsd and it suggests that flavonoid acts in different ways to protect against the Parkinson disease caused by Fe exposure such as the direct scavenging of RS and activation of antioxidant enzymes.

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.

Emerging evidence indicates that the activation of indoleamine-2,3-dioxygenase (IDO), a first and rate-limiting enzyme in the kynurenine (KYN) pathway, is involved in amyloid-beta (Aβ1-42)-neurotoxicity and Alzheimer's disease (AD) pathogenesis. Physical exercise has been considered an effective intervention in AD, attenuating or limiting their progression. Nevertheless, the neurobiological mechanisms underlying the neuroprotective effects of exercise have not yet been fully elucidated. In present study, we investigated the protective effect of an 8-week swimming training (ST) exercise on cognitive and non-cognitive functions and its role in modulating biomarkers of KYN pathway, before an intracerebroventricular (i.c.v.) injection of Aβ1-42 (400pmol/animal; 3μl/site) peptide in mice. Our results demonstrated that ST was effective in preventing the following behavioural disturbances caused by Aβ1-42 injection: memory impairment in the object recognition test and depressive/anxiety-like behaviour in the tail suspension test and elevated plus-maze test, respectively. ST abrogated the neuroinflammatory response and neurotrophic deficiency in the prefrontal cortex and hippocampus induced by Aβ1-42. Also, Aβ1-42 increased IDO activity, KYN and tryptophan (TRP) levels and KYN:TRP ratio in the prefrontal cortex and hippocampus - alterations that were blocked by ST. It can be concluded that ST prevented behavioural and neurobiological deficits induced by Aβ1-42, and suggest that these neuroprotective effects are likely to involve the inhibition of inflammation/IDO activation and up-regulation of neurotrophic factors in brain of mice. Thus, it is possible that physical exercise can be used as a non-pharmacological approach to alleviates both cognitive and non-cognitive symptoms of AD.

There is a lack of information about the molecular events underlying the depressive-like effect of an intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. Elevated activity of the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase (IDO) has been proposed to mediate depression in inflammatory disorders. In this study, we report that ICV-STZ activates IDO in the hippocampus of mice and culminates in depressive-like behaviors, measured by an increased duration in immobility time in the forced swimming test and decreased total time of grooming in the splash test. Indirect blockade of IDO activation with the cytokine inhibitor minocycline prevents the development of depressive-like behaviors and attenuates STZ-induced upregulation of proinflammatory cytokines in the hippocampus. Minocycline abrogates the increase in tryptophan and kynurenine levels as well as prevents serotonin dysfunction in the hippocampus of STZ-injected mice. These results suggest that hippocampal IDO activation in STZ-associated depressive-like behavior is mediated by proinflammatory cytokine-dependent mechanisms. Our study not only extends the evidence that IDO has a critical role in mediating inflammation-induced depression but also supports the notion that neuroinflammation and the kynurenine pathway are important targets of novel therapeutic drugs for depression. In addition, our study provides new insights into the neurobiological mechanisms underlying ICV-STZ and indicates that this model could be employed in the preclinical research of depression.

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.

Sickness behavior is an expression of a central motivational state triggered by activation of the immune system, being considered a strategy of the organism to fight infection. Sickness behavior is induced by peripheral administration of lipopolysaccharide (LPS). LPS can increase the levels of proinflammatory cytokines, which induce the activation of the kynurenine pathway (KP) and behavioral alterations. Previous studies have shown that omega-3 (n-3) polyunsaturated fatty acid (PUFA) has anti-inflammatory properties. Because of this, the purpose of the present study was to evaluate the protective effect of fish oil (FO) supplementation against LPS-induced sickness behavior in aged mice with respect to anhedonia, locomotor activity and body weight. Moreover, we evaluated the ability of FO treatment on the regulation of neuroinflammation (levels of interleukin-1β, interleukin-6, tumor factor necrosis-α and interferon-γ), KP biomarkers (levels of tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine and quinolinic acid and activities of indoleamine-2,3-dioxygenase, kynurenine monooxygenase and kynurenine aminotransferase) and serotonergic system (levels of serotonin and 5-hydroxyindoleactic acid) in the hippocampus, striatum and prefrontal cortex of LPS-treated mice. We found that FO prevented the LPS-mediated body weight loss, anhedonic behavior, reduction of locomotor activity, up-regulation of the proinflammatory cytokines and serotoninergic alterations. We also found that FO was effective in modulating the KP biomarkers, inhibiting or attenuating KP dysregulation induced by LPS. Together, our results indicated that FO may have beneficial effects on LPS induced sickness-behavior in aged mice either by modulating central inflammation, KP and serotonergic signaling (indirectly effect) or by fatty acids incorporation into neuronal membranes (direct effect).

Depression is one of the most common mental disorders and a primary cause of disability. To better treat patients suffering this illness, elucidation of the underlying psychopathological and neurobiological mechanisms is urgently needed. Based on the above-mentioned evidence, we sought to investigate the effects of neuropeptide Y (NPY) treatment in tricyclic antidepressant treatment-resistant depression induced by adrenocorticotropic hormone (ACTH) administration. Mice were treated with NPY (5.84, 11.7 or 23.4mmol/μl) intracerebroventricularly (i.c.v.) for one or five days. The levels of serum corticosterone, tryptophan (TRP), kynurenine (KYN), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and indoleamine 2,3-dioxygenase (IDO) activity in the hippocampus were analyzed. The behavioral parameters (depressive-like and locomotor activity) were also verified. This study demonstrated that ACTH administration increased serum corticosterone levels, KYN, 5-HIAA levels, IDO activity (hippocampus), immobility in the forced swimming test (FST) and the latency to feed in the novelty suppressed feeding test (NSFT). In addition, ACTH administration decreased the BDNF and NGF levels in the hippocampus of mice. NPY treatment was effective in preventing these hormonal, neurochemical and behavioral alterations. It is suggested that the main target of NPY is the modulation of corticosterone and neuronal plasticity protein levels, which may be closely linked with pharmacological action in a model of tricyclic antidepressant treatment-resistant depression. Thus, this study demonstrated a protective effect of NPY on the alterations induced by ACTH administration in mice, indicating that it could be useful as a therapy for the treatment of tricyclic antidepressant treatment-resistant depression.

Our working hypothesis is that brain neurotrophins and brain Na(+),K(+)-ATPase may be strongly associated with the occurrence of depression in animals subjected to chronic unpredictable mild stress (CUMS). Still, we believe that chrysin, a natural and bioactive flavonoid found in honey and some plants, can provide satisfactory effects on antidepressant therapy. Thus, we aimed to evaluate the effect of CUMS on brain-derived neurotropic factor (BDNF) and nerve growth factor (NGF) levels as well as the Na(+),K(+)-ATPase activity in the hippocampus and prefrontal cortex of female mice. We also aimed to examine the effect of a 28-day oral treatment with chrysin (5 or 20mg/kg) in female mice subjected to CUMS, comparing to the effect of fluoxetine. Results showed that CUMS applied for 28days induced a decrease in BDNF and NGF levels as well as in the Na(+),K(+)-ATPase activity. CUMS also promoted a depressive status in the swimming forced test (FST), in the sucrose preference test, and in corticosterone levels. Chrysin (20mg/kg) and fluoxetine also occasioned the up-regulation of BDNF and NGF levels in non-stressed mice and in mice subjected to CUMS. CUMS decreased non-protein thiol (NPSH) levels and increased reactive oxygen species (ROS) levels. In response to these changes, the glutathione reductase (GR), glutathione peroxidase (GPx) and catalase (CAT) activities were increased in mice exposed to CUMS. Chrysin and fluoxetine treatments protected against all these alterations, suggesting the involvement of the antioxidant function in the antidepressant effect of chrysin and fluoxetine. In conclusion, CUMS decreased BDNF and NGF levels as well as the Na(+),K(+)-ATPase activity in mice. Chrysin presented antidepressant effect in mice on behavioral, neurotrophic and biochemistry parameters equivalent to fluoxetine. Furthermore, we suggest that the up-regulation of BDNF and NGF levels is a mechanism possibly involved in the antidepressant effect of chrysin in mice.

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.

There is a lack of information concerning the molecular events underlying the depressive-like effect of an intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. The elevated activity of the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase (IDO) has been proposed to mediate depression in inflammatory disorders. In the present study, we reported that ICV-STZ activates IDO in the hippocampus of mice and culminates in depressive-like behaviors, as measured by the increased duration of immobility in the tail suspension test and decreased sucrose intake in the sucrose preference test. The blockade of IDO activation by the IDO inhibitor 1-methyltryptophan (1-MT) prevents the development of depressive-like behaviors and attenuates STZ-induced up-regulation of proinflammatory cytokines in the hippocampus. 1-MT abrogates kynurenine production and normalizes brain-derived neurotrophic factor (BDNF) and the kynurenine/tryptophan ratio, but does not protect the biomarkers of the serotonin (5-HT) system in the hippocampus of STZ-injected mice. These results implicate IDO as a critical molecular mediator of STZ-induced depressive-like behavior, likely through activation of the kynurenine pathway and subsequent reduction of BDNF levels. Impairment of the 5-HT system may reflect the inflammatory response induced by STZ and also contributes to observed depression symptoms. The present study not only provides evidence that IDO plays a critical role in mediating inflammation-induced depression but also supports the notion that neuroinflammation and the kynurenine pathway are important targets for novel therapeutic drugs for depression. In addition, this study provides new insights on the neurobiological mechanisms underlying ICV-STZ and indicates that this model could be employed in preclinical research of depression.

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.

Zearalenone (ZEA) is a mycotoxin commonly found as a contaminant in cereals. ZEA toxicity targets mainly the reproductive system, and oxidative stress plays an etiological role in its toxic effects. Therefore, the present study aimed to investigate the effect of lycopene, a potent carotenoid antioxidant, on markers of oxidative stress in liver, kidney and testes, and on reproductive, hematological and histopathological parameters after ZEA administration. Adult Swiss albino male mice received lycopene (20 mg/kg, p.o.) for ten days before a single oral administration of ZEA (40 mg/kg, p.o.), and 48 h thereafter tissues (liver, kidney, testes and blood) were collected for biochemical, hematological and histological analyses. Lycopene prevented ZEA-induced changes in hematological parameters (increased number of leukocytes, segmented neutrophils, sticks, eosinophils and monocytes and decreased number of red blood cells (RBC), number of lymphocytes and platelets). Moreover, lycopene prevented the reduction in the number and motility of spermatozoa and the testicular tissue damage induced by ZEA. In addition, lycopene prevented the decrease in glutathione-S-transferase activity in kidney and testes and increased glutathione-S-transferase activity per se in the liver, kidneys and testes as well as superoxide dismutase activity in the liver. In summary, lycopene was able to prevent ZEA-induced acute toxic effects in male mice, suggesting that this antioxidant carotenoid may represent a promising prophylactic strategy against ZEA toxicity.

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.

Parkinson's disease (PD) is characterized by progressive dopamine (DA) depletion in the striatum. Exercise has been shown to be a promising non-pharmacological approach to reduce the risk of neurodegeneration diseases. This study was designed to investigate the potential neuroprotective effect of swimming training (ST) in a mouse model of PD induced by 6-hydroxydopamine (6-OHDA) in mice. The present study demonstrated that a 4-week ST was effective in attenuating the following impairments resulting from 6-OHDA exposure: (i) depressive-like behavior in the tail suspension test; (ii) increase in the number of falls in the rotarod test; (iii) impairment on long-term memory in the object recognition test; (iv) increase of the reactive species and interleukin 1-beta (IL-1β) levels; (v) inhibition of the glutathione peroxidase (GPx) activity; (vi) rise of the glutathione reductase (GR) and glutathione S-transferase (GST) activities and vii) decrease of DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. The mechanisms involved in this study are the modulation of GPx, GR and GST activities as well as IL-1β level in a PD model induced by 6-OHDA, protecting against the decrease of DA, DOPAC and HVA levels in the striatum of mice. These findings reinforce that one of the effects induced by exercise on neurodegenerative disease, such as PD, is due to antioxidant and anti-inflammatory properties. We suggest that exercise attenuates cognitive and motor declines, depression, oxidative stress, and neuroinflammation induced by 6-OHDA supporting the hypothesis that exercise can be used as a non-pharmacological tool to reduce the symptoms of PD.

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.

This study was designed to investigate the potential neuroprotective effect of exercise in a mouse model of Alzheimer's disease (AD) induced by intracerebroventricular (i.c.v.) injection of beta-amyloid₁₋₄₀ (Aβ₁₋₄₀) peptide. For this aim, male Swiss Albino mice were submitted to swimming training (ST) with progressive increase in intensity and duration for 8 weeks before Aβ₁₋₄₀ administration (400 pmol/animal; 3 μl/site, i.c.v. route). The cognitive behavioral, oxidative stress, and neuroinflammatory markers in hippocampus and prefrontal cortex of mice were assessed 7 days after Aβ₁₋₄₀ administration. Our results demonstrated that ST was effective in preventing impairment in short- and long-term memories in the object recognition test. ST attenuated the increased levels of reactive species and decreased non-protein thiol levels in hippocampus and prefrontal cortex induced by Aβ₁₋₄₀. Also, Aβ₁₋₄₀ inhibited superoxide dismutase activity and increased glutathione peroxidase, glutathione reductase, and glutathione S-transferase activities in hippocampus and prefrontal cortex-alterations that were mitigated by ST. In addition, ST was effective against the increase of tumor necrosis factor-alpha and interleukin-1 beta levels and the decrease of interleukin-10 levels in hippocampus and prefrontal cortex. This study confirmed the hypothesis that exercise is able to protect against some mechanisms of Aβ₁₋₄₀-induced neurotoxicity. In conclusion, we suggest that exercise can prevent the cognitive decline, oxidative stress, and neuroinflammation induced by Aβ₁₋₄₀ in mice supporting the hypothesis that exercise can be used as a non-pharmacological tool to reduce the symptoms of AD.

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.

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.

The consumption of a high-fat diet (HFD) causes alteration in normal metabolism affecting lifespan of flies; however molecular mechanism associated with this damage in flies is not well known. This study evaluates the effects of ingestion of a diet supplemented with 10% and 20% of coconut oil, which is rich in saturated fatty acids, on oxidative stress and cells stress signaling pathways. After exposure to the diet for seven days, cellular and mitochondrial viability, lipid peroxidation and antioxidant enzymes SOD and CAT activity, and mRNA expression of antioxidant enzymes HSP83 and MPK2 were analyzed. To confirm the damage effect of diet on flies, survival and lifespan were investigated. The results revealed that the HFD augmented the rate of lipid peroxidation and SOD and CAT activity and induced a higher expression of HSP83 and MPK2 mRNA. In parallel, levels of enzymes involved in lipid metabolism (ACSL1 and ACeCS1) were increased. Our data demonstrate that association among metabolic changes, oxidative stress, and protein signalization might be involved in shortening the lifespan of flies fed with a HFD.

Peroxisome proliferator-activated receptor-g (PPAR-g) agonists not only improve metabolic abnormalities ofdiabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimentalmodels. Here, we investigated the effect of PPAR-g agonist pioglitazone against acute renal injury on a cisplatin modelin mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10mgkg –1 ). Pioglitazone wasadministered for six consecutive days in doses of 15 or 30mgkg –1 day –1 , per os (p.o.), starting 3days before cisplatin injection.Cisplatintreatmenttomiceinducedamarkedrenalfailure,characterizedbyasignificantincreaseinserumureaandcreatininelevels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levelsof non-enzymatic antioxidant defenses [glutathione (GSH) and as corbic acid levels] and components of the enzymatic antioxidantdefenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and andglutathione S-transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against theincrease in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazoneadministration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protectedagainst the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These resultsindicated that pioglitazone has a protective effectagainstcisplatin-inducedrenal damagein mice.The protection ismediatedby preventing the decline of antioxidant status. The results have implications in use of PPAR-g agonists in human applicationfor protecting against drugs-induced nephrotoxicity. Copyright © 2012 John Wiley & Sons, Ltd.Keywords: peroxisome proliferator-activated receptor-g; pioglitazone; cisplatin; nephrotoxicity; mice

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.

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by a progressive cognitive decline along with various neuropsychiatric symptoms, including depression and anxiety. Increasing evidence has been proposed the activation of the tryptophan-degrading indoleamine-2,3-dyoxigenase (IDO), the rate-limiting enzyme of kynurerine pathway (KP), as a pathogenic factor of amyloid-beta (Aβ)-related inflammation in AD. In the current study, the effects of an intracerebroventricular (i.c.v.) injection of Aβ1-42 peptide (400pmol/mice; 3μl/site) on the regulation of KP biomarkers (IDO activity, tryptophan and kynurerine levels) and the impact of Aβ1-42 on neurotrophic factors levels were investigated as potential mechanisms linking neuroinflammation to cognitive/emotional disturbances in mice. Our results demonstrated that Aβ1-42 induced memory impairment in the object recognition test. Aβ1-42 also induced emotional alterations, such as depressive and anxiety-like behaviors, as evaluated in the tail suspension and elevated-plus maze tests, respectively. We observed an increase in levels of proinflammatory cytokines in the Aβ1-42-treated mice, which led to an increase in IDO activity in the prefrontal cortex (PFC) and the hippocampus (HC). The IDO activation subsequently increased kynurerine production and the kynurenine/tryptophan ratio and decreased the levels of neurotrophic factors in the PFC and HC, which contributed to Aβ-associated behavioral disturbances. The inhibition of IDO activation by IDO inhibitor 1-methyltryptophan (1-MT), prevented the development of behavioral and neurochemical alterations. These data demonstrate that brain IDO activation plays a key role in mediating the memory and emotional disturbances in an experimental model based on Aβ-induced neuroinflammation.

In this study, we investigated the effects of 2,2=- dithienyl diselenide (DTDS), an organoselenium compound, against seizures induced by kainic acid (KA) in rats. Rats were pretreated with DTDS (50 or 100 mg/kg) by oral route 1 h before KA injection (10 mg/kg, intraperitoneal). Our results showed that DTDS (100 mg/kg) was effective in increasing latency for the onset of the first clonic seizure episode in- duced by KA, as well as in decreasing the appearance of seizures and the Racine's score. DTDS also caused a de- crease in the excitatory electroencephalographic (EEG) changes, resulting from KA exposure in hippocampus and cerebral cortex of rats. Besides, elevated reactive species (RS) and carbonyl protein levels and Na ,K -ATPase activity in hippocampus of rats treated with KA were ameliorated by DTDS (50 and 100 mg/kg). Lastly, as evidenced by Cresyl- Violet stain, DTDS (100 mg/kg) elicited a protective effect against KA-induced neurodegeneration in rat hippocampus 7 days after KA injection. In conclusion, the present study showed that DTDS attenuated KA-induced status epilepticus in rats and the subsequent hippocampal damage. © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

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.