RESUMO
Alzheimer's disease (AD) is a neurodegenerative disease that affects several elderly people per years. AD is a pathology of multifactorial etiology, resulting from multiple environmental and genetic determinants. However, there is no effective pharmacological alternative for the treatment of this illness. In this sense, the purpose of current study was to characterize the mechanisms by which Aß1-42 injection via intracerebroventricular induces neurobehavioral changes in a time-course curve. In addition, suberoylanilide hydroxamic acid (SAHA) inhibitor of histone deacetylase (HDAC) was used to investigate the involvement of epigenetic modifications Aß1-42-caused in aged female mice. In general manner, Aß1-42 injection induced a major neurochemical disturbance in hippocampus and prefrontal cortex of animals and a serious impairment of memory. Overall, SAHA treatment attenuated neurobehavioral changes caused by Aß1-42 injection in aged female mice. The subchronic effects presented of SAHA were through modulation of HDAC activity, regulation of brain-derived neurotrophic factor (BDNF) levels and expression of BDNF mRNA, accompanied by unlocking cAMP/PKA/pCREB pathway in hippocampus and prefrontal cortex of animals.
Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Animais , Feminino , Camundongos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Epigênese Genética , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , VorinostatRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Sida tuberculata R. E. Fries (Malvaceae) is a pioneer species considered a weed in farm fields in Southern Brazil. Widely distributed in South Brazil, S. tuberculata is popularly used to treat inflammatory conditions. AIMS OF THE STUDY: The current study aimed to assess the in vitro cytotoxic and in vivo anti-inflammatory properties of S. tuberculata. MATERIALS AND METHODS: Initially, extracts obtained from leaves (STLE) and roots (STRE) were submitted to cytotoxicity tests using human leukocytes (non-malignant cell line) and HepG2 and MCF-7 (tumor cell lines). In sequence, anti-inflammatory properties were investigated against carrageenan-induced peritonitis model. RESULTS: In vitro analyses displayed a significant decrease in human leukocytes viability without genotoxic damage. IC50 results from tumor cells presented significant decrease in cell viability, slightly more pronounced for STRE. In addition, STLE significantly inhibited the inflammatory and oxidative parameters (TBARS, NPSH, SOD, MPO activity, cell influx, and cytokines release). CONCLUSION: Our findings indicate S. tuberculata extracts have cytotoxic potential more pronounced on tumor cell lines, as well as leaves extract shows a significant reduction in acute inflammation process, as already reported for Sida genus and specifically for this species.
Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Sida (Planta)/química , Animais , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular , Modelos Animais de Doenças , Feminino , Células Hep G2 , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Neoplasias Hepáticas/tratamento farmacológico , Células MCF-7 , Masculino , Camundongos , Peritonite/tratamento farmacológico , Peritonite/patologiaRESUMO
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.
Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/enzimologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/metabolismo , Cinurenina/análogos & derivados , Cinurenina/metabolismo , Quinurenina 3-Mono-Oxigenase/metabolismo , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Oximas/uso terapêutico , Fragmentos de Peptídeos , Ácido Quinolínico/metabolismo , Sulfonamidas/uso terapêutico , Triptofano/metabolismoRESUMO
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 supraphysiologicaldoses of ND in mice.
Assuntos
Anabolizantes/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Depressão/psicologia , Cinurenina/metabolismo , Decanoato de Nandrolona/administração & dosagem , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/enzimologia , Corpo Estriado/metabolismo , Depressão/induzido quimicamente , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/enzimologia , Córtex Pré-Frontal/metabolismo , Triptofano/administração & dosagem , Triptofano/análogos & derivadosRESUMO
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.
Assuntos
Antioxidantes/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Falência Hepática Aguda/prevenção & controle , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenilpropionatos/farmacologia , Acetaminofen , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Fígado/metabolismo , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Masculino , Camundongos , Transdução de SinaisRESUMO
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 ß-amyloid1-42 (Aß1-42) 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 Aß1-42 administration (400 pmol, i.c.v.). Aß1-42 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 Aß1-42, 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.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/farmacologia , Comportamento Animal/efeitos dos fármacos , Flavonoides/farmacologia , Inflamação/tratamento farmacológico , Aprendizagem/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/farmacologia , Envelhecimento/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Peptídeos beta-Amiloides/administração & dosagem , Animais , Modelos Animais de Doenças , Feminino , Flavonoides/administração & dosagem , Inflamação/induzido quimicamente , Lipídeos , Camundongos , Nanocápsulas , Fármacos Neuroprotetores/administração & dosagem , Fragmentos de Peptídeos/administração & dosagemRESUMO
We investigated the effects of chrysin in the experimental autoimmune encephomyelitis (EAE), a multiple sclerosis (MS) animal model. EAE was induced using myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide in C57BL/6 mice. Chrysin reduced weight loss, attenuated clinical signs and blunted the EAE-induced increase in histone deacetylase (HDCA) activity, glycogen synthase kinase-3ß (GSK-3ß) levels and pro-inflammatory cytokine levels as well as in the EAE-induced decrease in histone acetyltransferases 3 and 4 (HAT3, HAT4). Altogether, results demonstrate beneficial effects and potential targets of chrysin in EAE.
Assuntos
Anti-Inflamatórios/farmacologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Flavonoides/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
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 ß-amyloid1-42 (Aß1-42) peptide in aged female mice, and compared these effects with those from free curcumin. Aged female mice received curcumin, free (50â¯mg/kg, p.o.) or loaded nanocapsules (10 or 1â¯mg/kg, p.o.) for 14â¯days after Aß1-42 administration. Aß1-42 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 Aß1-42-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.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Curcumina/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Curcumina/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Lipídeos , Camundongos , Nanocápsulas , Doenças Neurodegenerativas/tratamento farmacológico , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologiaRESUMO
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.
RESUMO
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-1ß and tumor necrosis factor alpha - TNF-α), 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-dihydroxyphenylacetic 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.
Assuntos
Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Flavonoides/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Encéfalo/metabolismo , Dopamina/metabolismo , Feminino , Flavonoides/farmacologia , Ácido Homovanílico/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/psicologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
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 20â¯mg/kg; i.g.) for ten days, and then received a single injection of ZEA (40â¯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-1ß 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.
Assuntos
Fertilidade/efeitos dos fármacos , Flavonoides/farmacologia , Substâncias Protetoras/farmacologia , Zearalenona/toxicidade , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Flavonoides/química , Masculino , Camundongos , Motilidade dos Espermatozoides/efeitos dos fármacos , Testosterona/sangueRESUMO
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 (0.15â¯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.
Assuntos
Gorduras na Dieta , Cinurenina/metabolismo , Verduras/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corticosterona/sangue , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interferon gama/análise , Ácido Cinurênico/análise , Cinurenina/análise , Quinurenina 3-Mono-Oxigenase/metabolismo , Lipopolissacarídeos/toxicidade , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Transaminases/metabolismo , Triptofano/análise , Fator de Necrose Tumoral alfa/análiseRESUMO
This study investigated the effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) at a dose of 1â¯mg/kg in memory impairment and anxiety in an Alzheimer's disease (AD) model induced by amyloid ß-peptide (Aß) (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 (1â¯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 Aß (3â¯nmol/3⯵l/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. Aß 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 Aß, and anticholinesterase and antioxidant actions are involved in the pharmacological effect of the compound.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/toxicidade , Ansiedade/prevenção & controle , Disfunção Cognitiva/prevenção & controle , Modelos Animais de Doenças , Fragmentos de Peptídeos/toxicidade , Quinolinas/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Quinolinas/farmacologia , Distribuição AleatóriaRESUMO
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-1ß, 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).
Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Encéfalo/efeitos dos fármacos , Óleos de Peixe/farmacologia , Cinurenina/metabolismo , Anedonia/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BLRESUMO
The quinolone compounds have been reported for many biological properties, especially as potent antioxidants. This study investigated the antioxidant effect of 7-chloro-4-phenylselenyl-quinoline (PSQ), a quinolone derivative with organoselenium group, against oxidative stress induced by sodium nitroprusside (SNP) in brains of mice. A second objective was to verify the importance of phenylselenyl group presents at position 4 of the quinoline structure to antioxidant effect of compound. So, it was compared the antioxidant effect of PSQ with a quinoline without organoseleniun group (7-chloroquinoline [QN]). Swiss mice were used and received SNP (0.335 µmol/site, intracerebroventricular) 30â¯min after treatment with PSQ or QN, at the doses of 50â¯mg/kg (intragastrically). After 1â¯h, animals were sacrificed and the brains were removed to biochemistry analysis. Thiobarbituric acid reactive species (TBARS), protein carbonyl (PC) and non-protein thiol (NPSH) levels, as well as catalase (CAT), glutathione S transferase (GST) and δ -aminolevulinic acid (δ-ALA-D) activities were determined. SNP increased TBARS and PC levels, and reduced the enzymatic (CAT and GST activity) and non-enzymatic (NPSH levels) antioxidant defenses and inhibited the δ-ALA-D activity. PSQ avoided the increase in the lipid peroxidation and PC levels, as well as the decrease in the NPSH levels, CAT, GST and δ-ALA-D activities QN partially avoided the increase in lipid peroxidation, but it not protected against alterations induced by SNP. In conclusion, phenylselenyl group present in quinoline structure is critical for antioxidant activity of PSQ.
Assuntos
Antioxidantes/farmacologia , Compostos Organosselênicos/farmacologia , Quinolinas/farmacologia , Ácido Aminolevulínico/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
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 Aß1-42-neurotoxicity and AD pathogenesis. We have reported for the first time that brain IDO activation is related to Aß1-42 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 Aß1-42 (400â¯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 Aß1-42 administration. Aged mice also responded to Aß1-42 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 Aß1-42 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 Aß1-42-induced memory loss, anxiety symptoms and KYN pathway dysregulation.
Assuntos
Envelhecimento/fisiologia , Peptídeos beta-Amiloides/metabolismo , Ansiedade/fisiopatologia , Cognição/fisiologia , Transtornos da Memória/fisiopatologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/metabolismo , Córtex Pré-Frontal/metabolismoRESUMO
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.
Assuntos
Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Dopamina/metabolismo , Flavonoides/farmacologia , Hipocampo/efeitos dos fármacos , Hipotireoidismo/complicações , Serotonina/metabolismo , Animais , Depressão/etiologia , Depressão/metabolismo , Feminino , Flavonoides/uso terapêutico , Hipocampo/metabolismo , Camundongos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Hormônios Tireóideos/metabolismoRESUMO
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-1ß, 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.
Assuntos
Flavonoides/farmacologia , Inflamação/prevenção & controle , Fatores de Crescimento Neural/metabolismo , Oxidopamina/efeitos adversos , Doença de Parkinson Secundária/prevenção & controle , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Biomarcadores , Dopamina/metabolismo , Regulação da Expressão Gênica/fisiologia , Ácido Homovanílico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/genética , Distribuição AleatóriaRESUMO
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.
Assuntos
Dopamina/metabolismo , Drosophila melanogaster/efeitos dos fármacos , Hesperidina/farmacologia , Ferro/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Animais , Biomarcadores , Masculino , Metalotioneína/metabolismo , Mitocôndrias , Atividade Motora/efeitos dos fármacos , Oxirredução , Doença de Parkinson Secundária/prevenção & controleRESUMO
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.