RESUMO
The aim of this study was to investigate the antiglioma effect of Cecropia pachystachya Trécul (CEC) leaves extract against C6 and U87 glioblastoma (GB) cells and in a rat preclinical GB model. The CEC extract reduced in vitro cell viability and biomass. In vivo, the extract decreased the tumor volume approximately 62%, without inducing systemic toxicity. The deficit in locomotion and memory and an anxiolytic-like behaviors induced in the GB model were minimized by CEC. The extract decreased the levels of reactive oxygen species, nitrites and thiobarbituric acid reactive substances and increased the activity of antioxidant enzymes in platelets, sera and brains of GB animals. The activity of NTPDases, 5'-nucleotidase and adenosine deaminase (ADA) was evaluated in lymphocytes, platelets and serum. In platelets, ATP and AMP hydrolysis was reduced and hydrolysis of ADP and the activity of ADA were increased in the control, while in CEC-treated animals no alteration in the hydrolysis of ADP was detected. In serum, the reduction in ATP hydrolysis was reversed by CEC. In lymphocytes, the increase in the hydrolysis of ATP, ADP and in the activity of ADA observed in GB model was altered by CEC administration. The observed increase in IL-6 and decrease in IL-10 levels in the serum of GB animals was reversed by CEC. These results demonstrate that CEC extract is a potential complementary treatment to GB, decreasing the tumor size, while modulating aspects of redox and purinergic systems.
Assuntos
Cecropia , Glioma , Extratos Vegetais , Folhas de Planta , Ratos Wistar , Animais , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Glioma/tratamento farmacológico , Glioma/patologia , Linhagem Celular Tumoral , Cecropia/química , Masculino , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/metabolismo , Ratos , Modelos Animais de Doenças , Sobrevivência Celular/efeitos dos fármacos , Antioxidantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , 5'-Nucleotidase/metabolismo , Adenosina Desaminase/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêuticoRESUMO
High levels of methionine (Met) and its metabolites, such as methionine sulfoxide (MetO), found in hypermethioninemia, can be detrimental to the body; however, the underlying mechanisms are still uncertain. Using a recently standardized protocol, the aim of this study was to investigate the effects of chronic administration of Met and/or MetO on parameters of oxidative damage in the total brain, liver, and kidney of young mice. Swiss male mice were subcutaneously injected with Met and MetO at concentrations of 0.35-1.2 g/kg body weight and 0.09-0.3 g/kg body weight, respectively, from the 10th-38th day post-birth, while the control group was treated with saline solution. Results showed that Met and/or MetO caused an increase in reactive oxygen species (ROS) and lipoperoxidation, along with a reduction of superoxide dismutase (SOD) and catalase (CAT) activities in the brain. In the liver, Met and/or MetO enhanced ROS and nitrite levels, and reduced SOD, CAT, and delta aminolevulinic dehydratase activities. The effects on the kidney were an increase in ROS production and SOD activity, and a reduction in thiol content and CAT activity. These data demonstrated the contribution of redox imbalance to the systemic changes found in patients with hypermethioninemia. In conclusion, our findings may help future studies to better understand the pathophysiological mechanisms of hypermethioninemia as well as contribute to the search for new therapeutic agents for this pathology.
Assuntos
Antioxidantes , Estresse Oxidativo , Ratos , Camundongos , Masculino , Animais , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ratos Wistar , Catalase/metabolismo , Fígado/metabolismo , Superóxido Dismutase/metabolismo , Rim/metabolismo , Encéfalo/metabolismo , Racemetionina/metabolismo , Racemetionina/farmacologia , Peso CorporalRESUMO
Acetylcholine is an excitatory neurotransmitter that modulates synaptic plasticity and communication, and it is essential for learning and memory processes. This neurotransmitter is hydrolyzed by acetylcholinesterase (AChE), which plays other cellular roles in processes such as inflammation and oxidative stress. Ion pumps, such as Na+/K+-ATPase and Ca2+-ATPase, are highly expressed channels that derive energy for their functions from ATP hydrolysis. Impairment of the cholinergic system and ion pumps is associated with neuropsychiatric diseases. Major depressive disorder (MDD) is an example of a complex disease with high morbidity and a heterogenous etiology. Polyphenols have been investigated for their therapeutic effects, and tannic acid (TA) has been reported to show neuroprotective and antidepressant-like activities. Animal models of depression-like behavior, such as lipopolysaccharide (LPS)-induced models of depression, are useful for investigating the pathophysiology of MDD. In this context, effects of TA were evaluated in an LPS-induced mouse model of depression-like behavior. Animals received TA for 7 days, and on the last day of treatment, LPS (830 µg/kg) was administered intraperitoneally. In vitro exposure of healthy brain to TA decreased the AChE activity. Additionally, this enzyme activity was decreased in cerebral cortex of LPS-treated mice. LPS injection increased the activity of Ca2+-ATPase in the cerebral cortex but decreased the enzyme activity in the hippocampus. LPS administration decreased Na+/K+-ATPase activity in the cerebral cortex, hippocampus, and striatum; however, TA administration prevented these changes. In conclusion, tannins may affect Na+/K+-ATPase and Ca2+-ATPase activities, which is interesting in the context of MDD.
Assuntos
Acetilcolinesterase , Transtorno Depressivo Maior , Acetilcolinesterase/metabolismo , Animais , Hipocampo/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/metabolismo , Taninos/farmacologia , Taninos/uso terapêuticoRESUMO
The aim of the present study was to evaluate the anti-glioma activity of 3-(4-fluorobenzyl)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (AV23) in a preclinical model of glioblastoma, as well as behavioral parameters and toxicological profile. The implantation of C6 cells in the left striatum of male Wistar rats was performed by stereotaxic surgery. After recovery, animals were treated with vehicle (canola oil) or AV23 (10 mg/kg/day) intragastrically for 15 days. It was found that AV23 reduced tumor volume by 90%. Serum biochemical parameters such as triglycerides, cholesterol, HDL-cholesterol, LDL-cholesterol, albumin, aspartate aminotransferase, urea, creatinine and total proteins were not changed; however, there was a slight increase in alanine aminotransferase. The compound AV23 reverted the hypoglycemia and the reduction in body weight caused by glioblastoma. Additionally, AV23 was able to revert the reduction of locomotion caused by the tumor implantation. Therefore, the compound AV23 can be considered a promising candidate in the treatment of glioblastoma.
Assuntos
Glioblastoma , Tiazolidinedionas , Animais , Glioblastoma/tratamento farmacológico , Masculino , Ratos , Ratos Wistar , TiazolidinasRESUMO
Glioblastoma (GB) is a highly aggressive and invasive brain tumor; its treatment remains palliative. Tannic acid (TA) is a polyphenol widely found in foods and possesses antitumor and neuroprotective activities. This study aimed to investigate the effect of TA on oxidative stress parameters and the activity of ectonucleotidases in the serum, platelets, and lymphocytes and/or in the brain of rats with preclinical GB. Rats with GB were treated intragastrically with TA (50 mg/kg/day) for 15 days or with a vehicle. In the platelets of the animals with glioma, the adenosine triphosphate (ATP) and adenosine monophosphate (AMP) hydrolysis and the catalase (CAT) activity decreased. Besides, the adenosine diphosphate (ADP) hydrolysis, adenosine (Ado) deamination, and the reactive oxygen species (ROS) and nitrite levels were increased in glioma animals; however, TA reversed ROS and nitrite levels and AMP hydrolysis alterations. In lymphocytes from animals with glioma, the ATP and ADP hydrolysis, as well as Ado deamination were increased; TA treatment countered this increase. In the brain of the animals with glioma, the ROS, nitrite, and thiobarbituric acid reactive substance (TBARS) levels increased and the thiol (SH) levels and CAT and superoxide dismutase (SOD) activities were decreased; TA treatment decreased the ROS and TBARS levels and restored the SOD activity. In the serum of the animals with glioma, the ATP hydrolysis decreased; TA treatment restored this parameter. Additionally, the ROS levels increased and the SH and SOD activity decreased by glioma implant; TA treatment enhanced nitrite levels and reversed SOD activity. Altogether, our results suggest that TA is an important target in the treatment of GB, as it modulates purinergic and redox systems.
Assuntos
Glioblastoma , Adenosina/farmacologia , Difosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Antioxidantes/farmacologia , Encéfalo/metabolismo , Glioblastoma/tratamento farmacológico , Nitritos , Estresse Oxidativo , Ratos , Espécies Reativas de Oxigênio , Superóxido Dismutase , Taninos/farmacologia , Taninos/uso terapêutico , Substâncias Reativas com Ácido TiobarbitúricoRESUMO
This study investigated the effects of inosine on memory acquisition and consolidation, cholinesterases activities, redox status and Na+, K+-ATPase activity in a rat model of scopolamine-induced cognitive impairment. Adult male rats were divided into four groups: control (saline), scopolamine (1 mg/kg), scopolamine plus inosine (50 mg/kg), and scopolamine plus inosine (100 mg/kg). Inosine was pre-administered for 7 days, intraperitoneally. On day 8, scopolamine was administered pre (memory acquisition protocol) or post training (memory consolidation protocol) on inhibitory avoidance tasks. The animals were subjected to the step-down inhibitory avoidance task 24 hours after the training. Scopolamine induced impairment in the acquisition and consolidation phases; however, inosine was able to prevent only the impairment in memory consolidation. Also, scopolamine increased the activity of acetylcholinesterase and reduced the activity of Na+, K+-ATPase and the treatment with inosine protected against these alterations in consolidation protocol. In the animals treated with scopolamine, inosine improved the redox status by reducing the levels of reactive oxygen species and thiobarbituric acid reactive substances and restoring the activity of the antioxidant enzymes, superoxide dismutase and catalase. Our findings suggest that inosine may offer protection against scopolamine-induced memory consolidation impairment by modulating brain redox status, cholinergic signaling and ion pump activity. This compound may provide an interesting approach in pharmacotherapy and as a prophylactic against neurodegenerative mechanisms involved in Alzheimer's disease.
Assuntos
Disfunção Cognitiva , Consolidação da Memória , Acetilcolinesterase/metabolismo , Animais , Colinérgicos/efeitos adversos , Inosina/efeitos adversos , Bombas de Íon/farmacologia , Bombas de Íon/uso terapêutico , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/prevenção & controle , Oxirredução , Estresse Oxidativo , Ratos , Ratos Wistar , Escopolamina/farmacologiaRESUMO
The aim of this study was to investigate the anticancer potential of blueberry extract (Vaccinium virgatum) against a C6 rat glioma lineage. Cultures of the C6 cells were exposed to blueberry extract at concentrations of 50 to 600 µg/mL for 12, 24, 48, or 72 h and then evaluated for cell viability, proliferation, migration, colony formation and oxidative stress. We also evaluated the effects of blueberry extract on primary rat cortical astrocytes. Our results show that treatment with blueberry extract did not alter the viability or proliferation of normal primary astrocytes but it did significantly reduce the viability in 21.54 % after 48 h and proliferation in 8.59 % after 24 h of C6 cells at 200 µg/mL. We also observed a reduction in the size of the colonies of 29.99 % at 100 µg/mL when compared to the control cells and cell migration was also reduced at 50 µg/mL. After 72 h, there was a reduction in the reactive oxygen species levels ranging from 46.26 to 34.73 %, in addition to a 380.2 % increase in total thiol content. Superoxide dismutase, catalase, and glutathione S-transferase activities were also enhanced when compared to the control. Taken together this data suggests that blueberry extract exerts some selective anticancer activity in C6 glioma cells.
Assuntos
Mirtilos Azuis (Planta) , Glioma , Animais , Antioxidantes/farmacologia , Glioma/tratamento farmacológico , Oxirredução , Estresse Oxidativo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , RatosRESUMO
OBJECTIVE: Major depressive disorder is a debilitating and recurrent psychiatric disorder. Blueberries have several biological properties, including neuroprotective effects, through antioxidant and anti-inflammatory actions. The aim of this study was to evaluate the effect of blueberry extract on depressive-like behavior and lipopolysaccharide (LPS)-induced neurochemical changes. METHODS: Mice were pretreated with vehicle, fluoxetine (20â mg/kg) or blueberry extract (100 or 200â mg/kg) intragastrically for seven days before intraperitoneal LPS (0.83â mg/kg) injection. Twenty-four hours after LPS administration, mice were submitted to behavioral tests. Oxidative stress and neuroinflammatory parameters were evaluated in the cerebral cortex, hippocampus, and striatum. RESULTS: Our data showed that blueberry extract or fluoxetine treatment protected against LPS-induced depressive-like behavior in tail suspension and splash tests (P < 0.05), without changes in locomotor activity (P > 0.05). LPS induced an increase in the levels of reactive oxygen species (P < 0.001), nitrite (P < 0.05) and thiobarbituric acid reactive substances (P < 0.01), as well as a reduction in total sulfhydryl content (P < 0.05) and catalase activity (P < 0.05) in brain structures; blueberry extract restored these alterations (P < 0.05). In addition, blueberry extract attenuated the increase in tumor necrosis factor-alpha (TNF-α) levels induced by LPS administration (P < 0.05). CONCLUSION: This study showed that blueberry extract exerted antidepressant-like effects, protected the brain against oxidative damage, and modulated TNF-α levels induced by LPS.
Assuntos
Mirtilos Azuis (Planta) , Transtorno Depressivo Maior , Animais , Comportamento Animal , Mirtilos Azuis (Planta)/química , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Depressão/prevenção & controle , Transtorno Depressivo Maior/tratamento farmacológico , Hipocampo , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , Estresse Oxidativo , Extratos Vegetais/uso terapêutico , Substâncias Reativas com Ácido TiobarbitúricoRESUMO
In the present study, we aimed to investigate the protective effect of blueberry extract on behavioral, biochemical, and morphological changes in an experimental model of lipopolysaccharide (LPS)-induced depressive behavior. Male Swiss mice were pretreated with the vehicle, fluoxetine (20 mg/kg), or Vaccinium virgatum extract (100 mg/kg and 200 mg/kg) for seven days. On day 7, the animals were administered an LPS injection (0.83 mg/kg) or vehicle. Pretreatment with blueberry extract prevented LPS-induced depressive-like behavior. Moreover, LPS increased serum levels of total cholesterol; however, V. virgatum did not prevent the increase in total cholesterol levels. Furthermore, the extract prevented the LPS-induced elevation in serum reactive oxygen species. Also, V. virgatum extract increased the HDL cholesterol levels. Additionally, this extract prevented the LPS-induced decrease in glucose levels and serum adenosine deaminase activity. Collectively, V. virgatum extract has a potential protective effect against changes similar to those observed in patients with depression. PRACTICAL APPLICATIONS: Vaccinium virgatum, popularly known as blueberry, has been effective in preventing or treating neuropsychiatric diseases owing to its antioxidant, anti-inflammatory, and neuroprotective properties. Fluoxetine is a known drug used to treat depression; however, its adverse effects result in therapeutic non-adherence. Thus, the search for new natural compounds possessing antidepressant activities while lacking adverse effects is crucial for identifying novel therapeutic alternatives against depression.
Assuntos
Mirtilos Azuis (Planta) , Animais , Antidepressivos/farmacologia , Humanos , Lipopolissacarídeos/toxicidade , Camundongos , Estresse Oxidativo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
Bipolar disorder (BD) is a complex psychiatric disease characterized by mood swings that include episodes of mania and depression. Given its cyclical nature, BD is especially hard to model; however, the standard practice has been to mimic manic episodes in animal models. Despite scientific advances, the pathophysiology of BD is not fully understood, and treatment remains limited. In the last years, natural products have emerged as potential neuroprotective agents for the treatment of psychiatric diseases. Thus, the aim of this review was to explore the therapeutic potential of natural compounds and derivatives against BD, taking into account preclinical and clinical studies. Reliable articles indexed in databases such as PubMed, Web of Science and Science Direct were used. In clinical studies, treatment with herbal plants extracts, omega-3, inositol, n-acetylcysteine and vitamin D has been associated with a clinical improvement in symptoms of mania and depression in BD patients. In animal models, it has been shown that red fruits extracts, curcumin, quercetin, gallic acid, alpha-lipoic acid and carvone can modulate many neurochemical pathways involved in the pathophysiology of manic episodes. Thus, this review appointed the advances in the consumption of natural compounds and derivatives as an important therapeutic strategy to mitigate the symptoms of BD.
Assuntos
Produtos Biológicos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Mania/tratamento farmacológico , Animais , Modelos Animais de Doenças , Ácidos Graxos Ômega-3/uso terapêutico , Ácido Gálico/uso terapêutico , Humanos , Inositol/uso terapêutico , Extratos Vegetais/uso terapêutico , Quercetina/uso terapêuticoRESUMO
Neuroinflammation is an event that occurs in several pathologies of brain. Rubus sp. (blackberry) is a powerful antioxidant fruit, and its extract has neuroprotective activity. The aim of this study was to investigate the blackberry extract properties on lipopolysaccharide (LPS)-induced neuroinflammation, in relation to oxidative parameters and acetylcholinesterase activity in the brain structures of mice. We also investigated interleukin-10 levels in serum. Mice were submitted to Rubus sp. extract treatment once daily for 14 days. On the fifteenth day, LPS was injected in a single dose. LPS induced oxidative brain damage and the blackberry extract demonstrated preventive effects in LPS-challenged mice. LPS administration increased reactive oxygen species levels in the cerebral cortex and striatum, as well as lipid peroxidation in the cerebral cortex. However, the blackberry extract prevented all these parameters. Furthermore, LPS decreased thiol content in the striatum and hippocampus, while a neuroprotective effect of blackberry extract treatment was observed in relation to this parameter. The blackberry extract also prevented a decrease in catalase activity in all the brain structures and of superoxide dismutase in the striatum. An increase in acetylcholinesterase activity was detected in the cerebral cortex in the LPS group, but this activity was decreased in the Rubus sp. extract group. Serum IL-10 levels were reduced by LPS, and the extract was not able to prevent this change. Finally, we observed an antioxidant effect of blackberry extract in LPS-challenged mice suggesting that this anthocyanin-rich extract could be considered as a potential nutritional therapeutic agent for preventive damage associated with neuroinflammation.
Assuntos
Antioxidantes/uso terapêutico , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Acetilcolinesterase/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Frutas/química , Proteínas Ligadas por GPI/metabolismo , Inflamação/metabolismo , Interleucina-10/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Rubus/químicaRESUMO
Hypermethioninemia is characterized by high plasma concentrations of methionine (Met) and its metabolites, such as methionine sulfoxide (MetO), and neurological changes, such as cerebral edema and cognitive deficits. The aim of this study was to analyze the redox status and acetylcholinesterase (AChE) activity in the hippocampus, striatum, and cerebellum of young Wistar rats subjected to an acute hypermethioninemia protocol. The animals received, by subcutaneous injection, a single dose of Met (0.4 g/kg), MetO (0.1 g/kg), and Met + MetO, and 1 or 3 hr after administration, the animals were euthanatized for brain structure obtaining. In the hippocampus, an increase in lipid peroxidation and glutathione peroxidase (GPx) activity was observed at 1 hr in the MetO and Met + MetO groups, and a reduction in the superoxide dismutase activity was found in the Met + MetO group. Met and/or MetO induced a decrease in the thiol content and GPx activity and enhanced the lipid peroxidation at 3 hr. In the striatum, a reduction in the thiol content and GPx activity, an increase in lipid peroxidation, and AChE activity were induced by Met and/or MetO at 1 or 3 hr. Additionally, in the cerebellum, an increase in the AChE in the MetO and Met + MetO groups 1 hr after administration was observed. These data help to better understand the pathophysiological mechanisms that underlie the neurological changes found in hypermethioninemia patients.
Assuntos
Acetilcolinesterase/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Cerebelo/metabolismo , Corpo Estriado/metabolismo , Glicina N-Metiltransferase/deficiência , Hipocampo/metabolismo , Animais , Glicina N-Metiltransferase/metabolismo , Homeostase/fisiologia , Peroxidação de Lipídeos/fisiologia , Oxirredução , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/metabolismoRESUMO
Bipolar disorder is characterized by episodes of depression and mania, and oxidative stress has been associated with the observed neurochemical changes in this disease. We evaluated the effects of gallic acid on hyperlocomotion, acetylcholinesterase activity, and oxidative stress in an animal model of ketamine-induced mania. Rats were pretreated orally with vehicle, gallic acid (50 or 100 mg/kg), or lithium (45 mg/kg twice a day) for 14 days. Between days 8 and 14, the animals also received ketamine (25 mg/kg) or saline daily. On the 15th day, hyperlocomotion was assessed, following which the animals were euthanized, and brains were collected. Results showed that ketamine-induced hyperlocomotion and caused oxidative damage by increasing reactive oxygen species levels, lipid peroxidation, and nitrite levels, and decreasing the total thiol content and the activities of catalase, superoxide dismutase, and glutathione peroxidase in the brain. Pretreatment with gallic acid and lithium prevented hyperlocomotion and brain oxidative damage. Further, ketamine increased the acetylcholinesterase activity in the hippocampus and striatum, whereas gallic acid and lithium ameliorated this alteration. Thus, gallic acid may provide effective protection against manic-like behavior by reducing oxidative stress and preventing cholinergic signaling dysfunction in the brain regions involved in emotion regulation.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Ácido Gálico/uso terapêutico , Hipocampo/efeitos dos fármacos , Lítio/uso terapêutico , Mania/tratamento farmacológico , Animais , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Ácido Gálico/farmacologia , Hipocampo/metabolismo , Lítio/farmacologia , Masculino , Mania/metabolismo , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
We investigated the ability of tannic acid (TA) to prevent oxidative and nitrosative damage in the brain, liver, kidney, and serum of a rat model of acute hypermethioninemia. Young Wistar rats were divided into four groups: I (control), II (TA 30 mg/kg), III (methionine (Met) 0.4 g/kg + methionine sulfoxide (MetO) 0.1 g/kg), and IV (TA/Met + MetO). Rats in groups II and IV received TA orally for seven days, and rats of groups I and III received an equal volume of water. After pretreatment with TA, rats from groups II and IV received a single subcutaneous injection of Met + MetO, and were euthanized 3 h afterwards. In specific brain structures and the kidneys, we observed that Met + MetO led to increased reactive oxygen species (ROS), nitrite, and lipid peroxidation levels, followed by a reduction in thiol content and antioxidant enzyme activity. On the other hand, pretreatment with TA prevented both oxidative and nitrosative damage. In the serum, Met + MetO caused a decrease in the activity of antioxidant enzymes, which was again prevented by TA pretreatment. In contrast, in the liver, there was a reduction in ROS levels and an increase in total thiol content, which was accompanied by a reduction in catalase and superoxide dismutase activities in the Met + MetO group, and pretreatment with TA was able to prevent only the reduction in catalase activity. Conclusively, pretreatment with TA has proven effective in preventing oxidative and nitrosative changes caused by the administration of Met + MetO, and may thus represent an adjunctive therapeutic approach for treatment of hypermethioninemia.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Glicina N-Metiltransferase/deficiência , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Taninos/farmacologia , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Glutationa Peroxidase/genética , Glicina N-Metiltransferase/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estresse Nitrosativo/genética , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/genética , Ratos , Espécies Reativas de Oxigênio/metabolismo , Soro/efeitos dos fármacos , Soro/metabolismo , Superóxido Dismutase/genéticaRESUMO
Depression is an emotional disorder that causes mental and physical changes, and has limited pharmacotherapy. Tannic acid (TA) is a polyphenol with previously described antioxidant and neuroprotective properties. The aim of this study was to evaluate the effects of TA on lipopolysaccharide (LPS)-induced depressive-like behavior, as well as oxidative stress parameters and TNF-α levels in the brains of mice. Animals were pretreated once daily, with TA (30 or 60 mg/kg), fluoxetine (20 mg/kg) or vehicle for 7 days. On the 7th day, the animals received a single injection of LPS (830 µg/kg). After 24 h, open field, forced swimming, tail suspension, and splash tests were conducted. The endotoxin induced depressive-like behavior in these mice and this was attenuated by TA. In the cerebral cortex, hippocampus, and striatum, LPS increased lipid peroxidation and reactive oxygen species production, and this was also prevented by TA administration. TA treatment also prevented a decrease in catalase activity within the striatum. Further, LPS administration caused increased levels of TNF-α in all brain structures, and this was prevented in the cortex by TA treatment. In conclusion, TA shows many neuroprotective properties, with demonstrated antioxidant, anti-inflammatory and antidepressant effects in this animal model of acute depressive-like behavior. Therefore, this compound could provide an alternative therapeutic approach for the treatment of depression.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Inflamação/tratamento farmacológico , Taninos/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Depressão/induzido quimicamente , Inflamação/induzido quimicamente , Lipopolissacarídeos , Masculino , Camundongos , Teste de Campo Aberto/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Hypermethioninemia is a disorder characterized by high plasma levels of methionine (Met) and its metabolites such as methionine sulfoxide (MetO). Studies have reported associated inflammatory complications, but the mechanisms involved in the pathophysiology of hypermethioninemia are still uncertain. The present study aims to evaluate the effect of chronic administration of Met and/or MetO on phenotypic characteristics of macrophages, in addition to oxidative stress, purinergic system, and inflammatory mediators in macrophages. In this study, Swiss male mice were subcutaneously injected with Met and MetO at concentrations of 0.35-1.2 g/kg body weight and 0.09-0.3 g/kg body weight, respectively, from the 10th-38th day post-birth, while the control group was treated with saline solution. The results revealed that Met and/or MetO induce an M1/classical activation phenotype associated with increased levels of tumor necrosis factor alpha and nitrite, and reduced arginase activity. It was also found that Met and/or MetO alter the activity of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, as well as the levels of thiol and reactive oxygen species in macrophages. The chronic administration of Met and/or MetO also promotes alteration in the hydrolysis of ATP and ADP, as indicated by the increased activity of ectonucleotidases. These results demonstrate that chronic administration of Met and/or MetO promotes activated pro-inflammatory profile by inducing M1/classical macrophage polarization. Thus, the changes in redox status and purinergic system upon chronic Met and/or MetO exposure may contribute towards better understanding of the alterations consistent with hypermethioninemic patients.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/imunologia , Glicina N-Metiltransferase/deficiência , Macrófagos/imunologia , Metionina/análogos & derivados , Animais , Catalase/metabolismo , Polaridade Celular , Glutationa Peroxidase/metabolismo , Glicina N-Metiltransferase/imunologia , Macrófagos/efeitos dos fármacos , Masculino , Metionina/administração & dosagem , Metionina/metabolismo , Metionina/farmacologia , Camundongos , Oxirredução , Estresse Oxidativo , Fenótipo , Superóxido Dismutase/metabolismoRESUMO
Autism is a neuropathology characterized by behavioral disorders. Considering that oxidative stress is involved in the pathophysiology of this disease, we evaluated the effects of quercetin, a flavonoid with antioxidant and neuroprotective properties, in an experimental model of autism induced by valproic acid (VPA). Twelve pregnant female rats were divided into four groups (control, quercetin, VPA, and VPA+quercetin). Quercetin (50 mg/kg) was administered orally to the animals from gestational days 6.5 to 18.5, and VPA (800 mg/kg) was administered orally in a single dosage on gestational day 12.5. Behavioral tests such as open field, social interaction, and tail flick nociceptive assays were performed on pups between 30 and 40 days old, after which the animals were euthanized. Cerebral cortex, hippocampus, striatum, and cerebellum were collected for evaluation of oxidative stress parameters. The pups exposed to VPA during the gestational period showed reduced weight gain, increased latency in the open field and tail flick tests, reduced time of social interaction, accompanied by changes in oxidative stress parameters mainly in the hippocampus and striatum. Prenatal treatment with quercetin prevented the behavioral changes and damage caused by oxidative stress, possibly due to its antioxidant action. Our findings demonstrated that quercetin has neuroprotective effects in an animal model of autism, suggesting that this natural molecule could be an important therapeutic agent for treatment of autism spectrum disorders (ASDs).
Assuntos
Transtorno Autístico/prevenção & controle , Transtorno Autístico/psicologia , Química Encefálica , Sintase do Porfobilinogênio/metabolismo , Quercetina/uso terapêutico , Animais , Anticonvulsivantes , Transtorno Autístico/induzido quimicamente , Feminino , Atividade Motora , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Medição da Dor , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Interação Social , Ácido Valproico , Aumento de PesoRESUMO
The aim of this study was to investigate the effect of the chronic administration of methionine (Met) and/or its metabolite, methionine sulfoxide (MetO), on the behavior and neurochemical parameters of young rats. Rats were treated with saline (control), Met (0.2-0.4 g/kg), MetO (0.05-0.1 g/kg), and/or a combination of Met + MetO, subcutaneously twice a day from postnatal day 6 (P6) to P28. The results showed that Met, MetO, and Met + MetO impaired short-term and spatial memories (P < 0.05), reduced rearing and grooming (P < 0.05), but did not alter locomotor activity (P > 0.05). Acetylcholinesterase activity was increased in the cerebral cortex, hippocampus, and striatum following Met and/or MetO (P < 0.05) treatment, while Na+, K+-ATPase activity was reduced in the hippocampus (P < 0.05). There was an increase in the level of thiobarbituric acid reactive substances (TBARS) in the cerebral cortex in Met-, MetO-, and Met + MetO-treated rats (P < 0.05). Met and/or MetO treatment reduced superoxide dismutase, catalase, and glutathione peroxidase activity, total thiol content, and nitrite levels, and increased reactive oxygen species and TBARS levels in the hippocampus and striatum (P < 0.05). Hippocampal brain-derived neurotrophic factor was reduced by MetO and Met + MetO compared with the control group. The number of NeuN-positive cells was decreased in the CA3 in Met + MetO group and in the dentate gyrus in the Met, MetO, and Met + MetO groups compared to control group (P < 0.05). Taken together, these findings further increase our understanding of changes in the brain in hypermethioninemia by elucidating behavioral alterations, biological mechanisms, and the vulnerability of brain function to high concentrations of Met and MetO.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Glicina N-Metiltransferase/deficiência , Hipocampo/patologia , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Metionina/análogos & derivados , Espécies Reativas de Oxigênio/metabolismo , Acetilcolinesterase/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/induzido quimicamente , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Animais , Catalase/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Feminino , Glutationa Peroxidase/deficiência , Glicina N-Metiltransferase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Transtornos da Memória/metabolismo , Memória de Curto Prazo/efeitos dos fármacos , Metionina/metabolismo , Metionina/toxicidade , Ratos , Ratos Wistar , Memória Espacial/efeitos dos fármacos , Superóxido Dismutase/deficiência , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Glioblastoma is a devastating tumor affecting the central nervous system with infiltrative capacity, high proliferation rate and chemoresistance. Therefore, it is urgent to find new therapeutic alternatives that improve this prognosis. Herein, we focused on tannic acid (TA) a polyphenol with antioxidant and antiproliferative activities. In this work, the antitumor and antioxidant effects of TA on rat (C6) glioblastoma cells and their cytotoxicity relative to primary astrocyte cultures were evaluated in vitro. Cells were exposed to TA of 6.25 to 75 µM for 24, 48 and/or 72 h. In addition, colony formation, migration and cell adhesion were analyzed and flow cytometry was used to analyze cell death and cell cycle. Next, the action of TA was evaluated in a preclinical glioblastoma model performed on Wistar rats. In this protocol, the animals were treated with a dose of 50 mg/kg/day TA for 15 days. Our results demonstrated that TA induced in vitro selective antiglioma activity, not demonstrating cytotoxicity in astrocyte culture. It induced cell death by apoptosis and cell cycle arrest, reducing formation and size of colonies, cell migration/adhesion and showing to be a potential antioxidant. Interestingly, the antiglioma effect was also observed in vivo, as TA decreased tumor volume by 55%, accompanied by an increase in the area of intratumoral necrosis and infiltration of lymphocytes without causing systemic damage. To the best of our knowledge, this is the first study to report TA activity in a GBM preclinical model. Thus, this natural compound is promising as a treatment for glioblastoma.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Taninos/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Feminino , Glioblastoma/patologia , Masculino , Ratos , Ratos Wistar , Taninos/farmacologiaRESUMO
RATIONALE: Inosine is a naturally occurring purine nucleoside formed by adenosine breakdown. This nucleoside is reported to exert potent effects on memory and learning, possibly through its antioxidant and anti-inflammatory actions. OBJECTIVE: The objective is to evaluate the effects of inosine on the behavioral and neurochemical parameters in a rat model of Alzheimer's disease (AD) induced by streptozotocin (STZ). METHODS: Adult male rats were divided into four groups: control (saline), STZ, STZ plus inosine (50 mg/kg), and STZ plus inosine (100 mg/kg). STZ (3 mg/kg) was administered by bilateral intracerebroventricular injection. The animals were treated intraperitoneally with inosine for 25 days. Memory, oxidative stress, ion pump activities, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT) activities and expression were evaluated in the cerebral cortex and hippocampus. RESULTS: The memory impairment induced by STZ was prevented by inosine. An increase in the Na+, K+-ATPase, and Mg-ATPase activities and a decrease in the Ca2+-ATPase activity were induced by STZ in the hippocampus and cerebral cortex, and inosine could prevent these alterations in ion pump activities. Inosine also prevented the increase in AChE activity and the alterations in AChE and ChAT expression induced by STZ. STZ increased the reactive oxygen species, nitrite levels, and superoxide dismutase activity and decreased the catalase and glutathione peroxidase activities. Inosine treatment conferred protection from these oxidative alterations in the brain. CONCLUSIONS: Our findings demonstrate that inosine affects brain multiple targets suggesting that this molecule may have therapeutic potential against cognitive deficit and tissue damage in AD.