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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.

Background: ultraviolet radiation types A and B (UV) (400–315nm and 315–280nm respectively) are the main components present in sunlight known to cause skin injuries. Arnica montana is a plant that ...

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.

Hesperidin is a flavonoid glycoside that is frequently found in citrus fruits. Our group have demonstrated that hesperidin has neuroprotective effect in 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease (PD), mainly by antioxidant mechanisms. Although the pathophysiology of PD remains uncertain, a large body of evidence has demonstrated that mitochondrial dysfunction and apoptosis play a critical role in dopaminergic nigrostriatal degeneration. However, the ability of hesperidin in modulating these mechanisms has not yet been investigated. In the present study, we examined the potential of a 28-day hesperidin treatment (50 mg/kg/day, p.o.) in preventing behavioral alterations induced by 6-OHDA injection via regulating mitochondrial dysfunction, apoptosis and dopaminergic neurons in the substantia nigra pars compacta (SNpc) in C57BL/6 mice. Our results demonstrated that hesperidin treatment improved motor, olfactory and spatial memory impairments elicited by 6-OHDA injection. Moreover, hesperidin treatment attenuated the loss of dopaminergic neurons (TH+ cells) in the SNpc and the depletion of dopamine (DA) and its metabolities 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of 6-OHDA-lesioned mice. Hesperidin also protected against the inhibition of mitochondrial respiratory chain complex-I, -IV and V, the decrease of Na + -K + -ATPase activity and the increase of caspase-3 and -9 activity in the striatum. Taken together, our findings indicate that hesperidin mitigates the degeneration of dopaminergic neurons in the SNpc by preventing mitochondrial dysfunction and modulating apoptotic pathways in the striatum of 6-OHDA-treated mice, thus improving behavioral alterations. These results provide new insights on neuroprotective mechanisms of hesperidin in a relevant preclinical model of PD.

The mechanisms underlying the neuroprotective effects of hesperidin in a murine model of PD are not fully elucidated. The current study was carried out to investigate the ability of hesperidin in modulating proinflammatory cytokines, neurotrophic factors, and neuronal recovery in 6-hydroxydopamine (6-OHDA)-induced nigral dopaminergic neuronal loss. Adult male C57BL/6 mice were randomly assigned into four groups: (I) sham/vehicle, (II) sham/hesperidin, (III) 6-OHDA/vehicle, and (IV) 6-OHDA/hesperidin. Mice received a unilateral intrastriatal injection of 6-OHDA and treated with hesperidin (50 mg/kg; per oral) for 28 days. After hesperidin treatment, mice were submitted to behavioral tests and had the striatum removed for neurochemical assays. Our results demonstrated that oral treatment with hesperidin ameliorated the anxiety-related and depressive-like behaviors in 6-OHDA-lesioned mice (p

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.

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.

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.

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.

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.

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 Aβ

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 (Aβ

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.

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.

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.

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 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.

The present study investigated a possible antidepressant-like activity of hesperidin using two predictive tests for antidepressant effect in mice: the forced swimming test (FST) and the tail suspension test (TST). Results demonstrated that hesperidin (0.1, 0.3 and 1 mg/kg, intraperitoneal, i.p.) decreased the immobility time in the FST and TST without affecting the locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3 mg/kg) on the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (pCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis) and WAY100635 (0.1 mg/kg, subcutaneous, s.c., a selective 5-HT(1A) receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an α(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α(2)-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), AMPT (100 mg/kg, i.p., an inhibitor of tyrosine hydroxylase), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist), ketanserin (1mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist) or MDL72222 (1 mg/kg, i.p., a 5-HT(3) receptor antagonist) did not block the antidepressant-like effect of hesperidin (0.3 mg/kg, i.p.) in the TST. Administration of hesperidin (0.01 mg/kg, i.p.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. The antidepressant-like effect caused by hesperidin in mice in the TST was dependent on an interaction with the serotonergic 5-HT(1A) receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like property and may be of interest source for therapeutic agent for the treatment of depressive disorders.

In this study, we investigated the therapeutic effects of treatment with (R)-Se-phenyl thiazolidine-4-carboselenoate (Se-PTC), an organic selenium compound with antinociceptive properties, against mechanical and thermal hyperalgesia induced by brachial plexus avulsion (BPA), a neuropathic model in mice. The involvement of cannabinoid CB(1) and CB(2) receptors in the Se-PTC anti-hyperalgesic effect was also investigated. Se-PTC treatment at (25 and 50mg/kg, per oral, p.o.) lowered (BPA model) induced mechanical and thermal hyperalgesia in mice. Pretreatment with cannabinoid CB(1) (AM251; 1mg/kg, intraperitoneally, i.p.), or CB(2) (AM630; 3mg/kg, i.p.) receptor antagonists reverted the mechanical and thermal anti-hyperalgesic effect of Se-PTC (25mg/kg) in the BPA model. Selective CB(1) (ACEA, 10mg/kg, i.p.) and CB(2) (JWH-133, 10mg/kg, i.p.) receptor agonists lowered mechanical and thermal hyperalgesia in the BPA model, and this effect was prevented by selective CB(1) and CB(2) receptor antagonists. Gabapentin (70mg/kg, p.o.), positive control administration also lowered mechanical and thermal hyperalgesia in the BPA model. The results suggest that the mechanical and thermal hyperalgesia observed following BPA in mice is dependent on cannabinoid receptors. The results indicate that modulating cannabinoid receptors represent a valuable approach for the treatment of neuropathic pain. In conclusion, the results suggested that Se-PTC produces pronounced mechanical and thermal anti-hyperalgesic effects in neuropathic models in mice by modulating CB(1) and CB(2) receptors.