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Obesity and aging collectively potentiate inflammatory responses, particularly within the central nervous system. Managing obesity presents a significant challenge, even more so considering the context of aging. Caloric restriction (CR) has been extensively documented in the literature for its multiple health benefits. Motivated by these findings, we hypothesized that CR could serve as a valuable intervention to address the brain alterations and cognitive decline associated with obesity in aged rats. Our investigation revealed that cafeteria diet increased hippocampal and hypothalamic transcripts related to neuroinflammation, along with cognitive deficits determined in the object recognition test in 18-month-old male rats. Western blot data indicate that the obesogenic diet may disrupt the blood-brain barrier and lead to an increase in Toll-like receptor 4 in the hippocampus, events that could contribute to the cognitive deficits observed. Implementing CR after the onset of obesity mitigated neuroinflammatory changes and cognitive impairments. We found that CR increases GABA levels in the hippocampus of aged animals, as demonstrated by liquid chromatography coupled with mass spectrometry analysis. These findings underscore the potential of CR as a therapeutic opportunity to ameliorate the neuroinflammatory and cognitive alterations of obesity, especially in the context of aging.
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Mild cognitive impairment (MCI) is defined as inter-stage between normal cognitive aging and major neurocognitive disorder (MND). This state of decay is a crucial factor in treatment to prevent the progression to MND. In this study, our group developed a virtual screening process to evaluate 2568 phytochemical compounds against 5 key proteins associated with MCI and MND. As a result, two potential candidates were identified: carpaine, found in Carica papaya leaves, and punicalagin, present in Punica granatum. A model of cognitive impairment (CI) was developed in 10-month-old male Sprague Dawley rats by administering aluminum chloride (AlCl3) at a dose of 100 mg/kg/day for 30 days. After AlCl3 administration period, one of the groups received carpaine and punicalagin in a phytochemical extract (PE) by oral gavage for 30 days. Novel object recognition test (NOR) was assessed at three different time points (T1 - before CI, T2 - after CI, and T3 - after PE treatment). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were identified in the hippocampus of rats at the end of the study period. After administration of AlCl3, a reduction in discrimination index vs control rats (CI = 0.012 ± 0.08 vs Control = 0.076 ± 0.03), was observed. After phytochemical extract treatment, a significant increase in discrimination index values was observed in the PE group 0.4643 ± 0.13 vs CI group 0.012 ± 0.08. Additionally, the evaluation of immunohistochemistry showed an increase in GFAP positivity in the hippocampus of the CI groups, while a slight decrease was observed in the PE group. This work addressed a comprehensive methodology that utilized in silico tools to identify phytochemical compounds (carpaine and punicalagin) as potential candidates for affecting key proteins in CI. The phytochemical extract containing carpaine and punicalagin resulted in a trend in the decrease of GFAP expression in the hippocampus and improved recognition memory in rats with CI induced by age and AlCl3 administration.
Assuntos
Carica , Disfunção Cognitiva , Taninos Hidrolisáveis , Punica granatum , Camundongos , Ratos , Masculino , Animais , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Carica/química , Modelos Animais de Doenças , Ratos Sprague-Dawley , Disfunção Cognitiva/tratamento farmacológico , Compostos Fitoquímicos , SementesRESUMO
The prevalence of autism spectrum disorder (ASD), a neurodevelopmental condition that impacts social interaction and sensory processing, is rising. Valproic acid (VPA) exposure during pregnancy causes autistic-like traits in offspring. Olanzapine (OLZ), an atypical antipsychotic, is used to treat ASD. We assessed the impact of OLZ on behavior, neuromorphology, and nitric oxide (NO) levels in the hippocampus using prenatal VPA treatment in rats. It is commonly known that ASD patients exhibit sensory abnormalities. As such, we utilized the tail flick test to validate the ASD model. In the novel object recognition test (NORT), VPA exposure reduces the discrimination index (DI) in the first introduction to the novel object. Moreover, OLZ and vehicle-treated rats perform differently in the second exposition to the DI of the novel object, suggesting that OLZ reverses VPA-induced deficits in recognition memory. The latency to find the hidden platform in the Morris water maze test of memory and learning improves in VPA-exposed rats after OLZ administration, indicating that OLZ improves spatial memory in these rats. Administration of prenatal VPA induces neuronal hypotrophy and reduces spine density in pyramidal neurons of the CA1 region of the hippocampus. Treatment with OLZ corrects the neuromorphological changes brought on by VPA. In the CA1 region of the hippocampus, VPA treatment increases the number of neurons, which normalizes with OLZ treatment. OLZ increases the NO levels in the dorsal hippocampus in control rats. In rats exposed to VPA, the second-generation antipsychotic OLZ reduces memory-related and neuroplastic alterations. The current findings support the use of OLZ in this illness and further validate the use of prenatal VPA as a model of ASD.
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Antipsicóticos , Transtorno do Espectro Autista , Transtorno Autístico , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Feminino , Ratos , Masculino , Animais , Humanos , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/tratamento farmacológico , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Olanzapina/efeitos adversos , Transtorno do Espectro Autista/induzido quimicamente , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico , Neurônios , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Modelos Animais de Doenças , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Comportamento Animal , Comportamento SocialRESUMO
The excessive production of pro-inflammatory mediators, characteristic of obesity, leads to neuroinflammation. Zinc (Zn) and the branched-chain amino acids (BCAA) are supplements known for their immunomodulatory properties. Our goal was to evaluate if Zn or BCAA supplementation can affect long-term recognition memory and neuroinflammatory parameters of obese rats after a high-fat diet (HFD). Three-month-old Wistar rats were divided into six groups: Standard diet (SD) + vehicle; SD + Zn; SD + BCAA; High-fat diet (HFD) + vehicle; HFD + Zn; and HFD + BCAA. Diets were administrated for 19 weeks, Zn (1,2 mg/kg/day) or BCAA (750 mg/kg/day) supplementation was conducted in the last 4 weeks. Long-term recognition memory was evaluated by the novel object recognition test. IL-1ß immunoreactivity in the cortex and hippocampus, and IL-6 levels in the cortex tissue were assessed. Astrogliosis were evaluated through GFAP + cell count and morphological analysis (Sholl Method). Zn supplementation improved object recognition memory in HFD-fed rats, which was not observed following BCAA supplementation. The levels of IL-6 in the cerebral cortex were higher after HFD, which was not diminished after neither supplementation. Obesity also led to increased IL-1ß immunoreactivity in the cerebral cortex and hippocampus, which was reduced by Zn. BCAA supplementation also diminished IL-1ß immunoreactivity, but only in the hippocampus. We also showed that astrocyte reactivity caused by HFD is area-dependent, being the cerebral cortex more susceptible to the diet. Even though BCAA and Zn can affect IL-1ß immunoreactivity and astrocyte morphology, only Zn improved memory. Future studies are needed to clarify the pathways by which Zn improves cognition in obesity.
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Aminoácidos de Cadeia Ramificada , Zinco , Aminoácidos de Cadeia Ramificada/farmacologia , Aminoácidos de Cadeia Ramificada/uso terapêutico , Animais , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Inflamação/tratamento farmacológico , Interleucina-6 , Obesidade/tratamento farmacológico , Ratos , Ratos Wistar , Zinco/farmacologiaRESUMO
Stress-related disorders display differences at multiple levels according to sex. While most studies have been conducted in male rodents, less is known about comparable outcomes in females. In this study, we found that the chronic restraint stress model (2.5 h/day for 14 days) triggers different somatic responses in male and female adult rats. Chronic restraint produced a loss in sucrose preference and novel location preference in male rats. However, chronic restraint failed to produce loss of sucrose preference in females, while it improved spatial performance. We then characterized the molecular responses associated with these behaviors in the hippocampus, comparing the dorsal and ventral poles. Notably, sex- and hippocampal pole-specific transcriptional signatures were observed, along with a significant concordance between the female ventral and male dorsal profiles. Functional enrichment analysis revealed both shared and specific terms associated with each pole and sex. By looking into signaling pathways that were associated with these terms, we found an ample array of sex differences in the dorsal and, to a lesser extent, in the ventral hippocampus. These differences were mainly present in synaptic TrkB signaling, Akt pathway, and glutamatergic receptors. Unexpectedly, the effects of stress on these pathways were rather minimal and mostly dissociated from the sex-specific behavioral outcomes. Our study suggests that female rats are resilient and males susceptible to the restraint stress exposure in the sucrose preference and object location tests, while the activity of canonical signaling pathways is primarily determined by sex rather than stress in the dorsal and ventral hippocampus.
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Alzheimer's disease (AD) causes dementia and memory loss in the elderly. Deposits of beta-amyloid peptide and hyperphosphorylated tau protein are present in a brain with AD. A filtrate of Helicobacter pylori's culture was previously found to induce hyperphosphorylation of tau in vivo, suggesting that bacterial exotoxins could permeate the blood-brain barrier and directly induce tau's phosphorylation. H. pylori, which infects ~60% of the world population and causes gastritis and gastric cancer, produces a pro-inflammatory urease (HPU). Here, the neurotoxic potential of HPU was investigated in cultured cells and in rats. SH-SY5Y neuroblastoma cells exposed to HPU (50-300 nM) produced reactive oxygen species (ROS) and had an increased [Ca2+]i. HPU-treated BV-2 microglial cells produced ROS, cytokines IL-1ß and TNF-α, and showed reduced viability. Rats received daily i.p., HPU (5 µg) for 7 days. Hyperphosphorylation of tau at Ser199, Thr205 and Ser396 sites, with no alterations in total tau or GSK-3ß levels, and overexpression of Iba1, a marker of microglial activation, were seen in hippocampal homogenates. HPU was not detected in the brain homogenates. Behavioral tests were performed to assess cognitive impairments. Our findings support previous data suggesting an association between infection by H. pylori and tauopathies such as AD, possibly mediated by its urease.
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Doença de Alzheimer , Helicobacter pylori , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Helicobacter pylori/metabolismo , Fosforilação/fisiologia , Ratos , Espécies Reativas de Oxigênio , Urease/metabolismo , Proteínas tau/metabolismoRESUMO
The α7-nicotinic acetylcholine receptor (α7-nAChR) is a recognized target for the treatment of dementia associated with aging and certain developmental disorders. This study evaluates memory improvement in a rat model by the effects of polyunsaturated fatty acids EPA and DHA mediated by α7-nAChR, as well as identifying the minimum dose of EPA/DHA required to generate an effect in the improvement of cognition through α7-nAChR in rats. The modiï¬ed Y-maze and object recognition behavioral tests were performed in scopolamine-induced amnesic rats, in order to study the effects of long-term supplementation (10, 15, 30, and 60â mg/kg) of the two polyunsaturated fatty acids in improving cognitive impairment. Cognitive enhancement by EPA and DHA is mediated through α7-nAChRs, as evidenced by memory recovery after treatment with a selective α7-nAChR antagonist, methyllycaconitine (MLA). Tacrine, a centrally active acetylcholinesterase inhibitor, and PNU282987, an α7-nAChR agonist, are employed as reference standards. Our data demonstrate that 15â mg/kg EPA and DHA can affect cholinergic neurotransmission positively through memory and cognition and, thus, can exert a beneficial action on learning and memory deficits.
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Acetilcolinesterase , Receptor Nicotínico de Acetilcolina alfa7 , Animais , Cognição , Ácidos Graxos Insaturados/farmacologia , Agonistas Nicotínicos/farmacologia , Agonistas Nicotínicos/uso terapêutico , RatosRESUMO
BACKGROUND: It has been studied that nutrition can influence Alzheimer's disease (AD) onset and progression. Some studies on rodents using intraventricular streptozotocin (STZ) injection showed that this toxin changes cerebral glucose metabolism and insulin signaling pathways. OBJECTIVE: The aim of the present study was to evaluate whether a nutritional formulation could reduce cognitive impairment in STZ-induced animals. METHODS: The rats were randomly divided into two groups: sham and STZ. The STZ group received a single bilateral STZ-ICV injection (1âmg/kg). The sham group received a bilateral ICV injection of 0.9% saline solution. The animals were treated with AZ1 formulation (Instanth® NEO, Prodiet Medical Nutrition) (1âg/kg, PO) or its vehicle (saline solution) for 30 days, once a day starting one day after the stereotaxic surgery (nâ=â6-10). The rats were evaluated using the open field test to evaluate locomotor activity at day 27 after surgery. Cognitive performance was evaluated at day 28 using the object recognition test and the spatial version of the Y-maze test. At day 30, the rats were anesthetized with chloral hydrate (400âmg/kg, i.p) and euthanized in order to evaluate IBA1 in the hippocampus. The differences were analyzed using one-way ANOVA with Bonferroni's or Kruskal Wallis with Dunn's post-hoc test. RESULTS/CONCLUSION: STZ-lesioned rats present memory impairment besides the increased microglial activation. The treatment with AZ1 formulation reversed the memory impairment observed in the object recognition test and Y-maze and also reduced IBA1 in CA1 and DG.
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Cafeteria diet (CAF) mimics human Western diet and has been used in animal models to study obesity. The purpose of this study is to demonstrate that our CAF model induces metabolic disorder related to obesity and affects recognition memory in Wistar rats. We also compared the intake of two different soft drinks, as part of the CAF, on recognition memory. Our results demonstrate that CAF-fed rats increased weight gain and visceral adiposity, and exhibited hyperglycemia, hypertriglyceridemia, high leptin and low insulin plasma levels. Moreover, CAF animals showed higher lipid peroxidation in the liver and developed non-alcoholic fatty liver disease. Surprisingly, the group fed with cola-based soft drinks presented an improvement in recognition memory, whereas animals fed with orange-based soft drinks showed worse performance in this task. Our data indicates that CAF induces obesity and affects recognition memory, but the composition of the diet interfere when the neurological function is evaluated.
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Dieta Ocidental/efeitos adversos , Preferências Alimentares , Transtornos da Memória/fisiopatologia , Obesidade/complicações , Animais , Bebidas Gaseificadas/efeitos adversos , Peroxidação de Lipídeos/fisiologia , Fígado/patologia , Fígado/fisiopatologia , Masculino , Transtornos da Memória/etiologia , Memória de Longo Prazo/fisiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Reconhecimento Visual de Modelos/fisiologia , Ratos WistarRESUMO
OBJECTIVES: To determine whether the drug saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor which is utilized for the treatment of Diabetes Mellitus, has neuroprotective effects in the animal model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA) in rats. METHODS: Male Wistar rats (weighing 280-300 g) received a bilateral infusion of 6-OHDA in the substantia nigra. Twenty-four hours later, they were treated with saxagliptin (1 mg/kg, p.o) once daily, for 21 days. The motor function was evaluated using the open field and rotarod (RT) tests. In addition, cognition was assessed with the novel object recognition test (ORT). After the evaluation of the behavioural tests, the animals were transcardially perfused to perform immunohistochemistry staining for tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc). KEY FINDINGS: Saxagliptin impaired the memory of animals in the sham group. CONCLUSIONS: Saxagliptin treatment did not exhibit neuroprotection and it did not improve the cognitive and motor deficits in the 6-OHDA model of PD. Interestingly, when saxagliptin was administered to the sham animals, a cognitive decline was observed. Therefore, this drug should be investigated as a possible treatment for PTSD.
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Adamantano/análogos & derivados , Comportamento Animal/efeitos dos fármacos , Dipeptídeos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Adamantano/administração & dosagem , Adamantano/uso terapêutico , Animais , Dipeptídeos/administração & dosagem , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Masculino , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/fisiopatologia , Ratos Wistar , Resultado do TratamentoRESUMO
Obesity is a multifactorial disease characterized by the abnormal or excessive fat accumulation, which is caused by an energy imbalance between consumed and expended calories. Obesity leads to an inflammatory response that may result in peripheral and central metabolic changes, including insulin and leptin resistance. Insulin and leptin resistance have been associated with metabolic and cognitive dysfunctions. Obesity and some neurodegenerative diseases that lead to dementia affect mainly women. However, the effects of diet-induced obesity on memory consolidation in female rats are poorly understood. Therefore, the aim of this study was to evaluate the effect of a hypercaloric diet on the object recognition memory of female rats and on possible related metabolic changes. The animals submitted to the hypercaloric diet presented a higher food intake in grams and in calories, resulting in increased weight gain and liposomatic index in comparison with the animals exposed to the control diet. These animals presented a memory deficit in the object recognition test and increased serum levels of glucose and leptin. However, no significant differences were found in the serum levels of insulin, TNF-α and IL-1ß, in the index of insulin resistance (HOMA), in the hippocampal levels of insulin, TNF-α and IL-1ß, as well as on Akt expression or activation in the hippocampus. Our findings indicate that adult female rats submitted to a hypercaloric diet present memory consolidation impairment, which could be associated with diet-induced weight gain and leptin resistance, even without the development of insulin resistance.
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Dieta/efeitos adversos , Consolidação da Memória/fisiologia , Transtornos da Memória/etiologia , Obesidade/complicações , Obesidade/etiologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Energia/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Insulina/metabolismo , Leptina/metabolismo , Lipossomos/metabolismo , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Several efforts have been made to understand the involvement of rapid eye movement (REM) sleep for cognitive processes. Consolidation or retention of recognition memories is severely disrupted by REM sleep deprivation (REMSD). In this regard, pedunculopontine tegmental nucleus (PPT) and other brainstem nuclei, such as pontine nucleus (Pn) and oculomotor nucleus (OCM), appear to be candidates to take part in this REM sleep circuitry with potential involvement in cognition. Therefore, the objective of this study was to investigate a possible association between the performance of Wistar rats in a declarative memory and PPT, Pn, and OCM activities after different periods of REMSD. We examined c-Fos and choline acetyltransferase (ChaT) expressions as indicators of neuronal activity as well as a familiarity-based memory test. The animals were distributed in groups: control, REMSD, and sleep rebound (REB). At the end of the different REMSD (24, 48, 72, and 96 h) and REB (24 h) time points, the rats were immediately tested in the object recognition test and then the brains were collected. Results indicated that OCM neurons presented an increased activity, due to ChaT-labeling associated with REMSD that negatively correlated (r = -0.32) with the cognitive performance. This suggests the existence of a cholinergic compensatory mechanism within the OCM during REMSD. We also showed that 24 h of REMSD impacted similarly in memory, compared to longer periods of REMSD. These data extend the notion that REM sleep is influenced by areas other than PPT, i.e., Pn and OCM, which could be key players in both sleep processes and cognition.
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Cognição/fisiologia , Memória/fisiologia , Complexo Nuclear Oculomotor/metabolismo , Privação do Sono/metabolismo , Animais , Colinérgicos/farmacologia , Cognição/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Neurônios/metabolismo , Complexo Nuclear Oculomotor/efeitos dos fármacos , Núcleo Tegmental Pedunculopontino/efeitos dos fármacos , Núcleo Tegmental Pedunculopontino/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Sono REMRESUMO
Hypoxia-ischemia (HI) represents one of the most common causes of neonatal encephalopathy. The central nervous system injury comprises several mechanisms, including inflammatory, excitotoxicity, and redox homeostasis unbalance leading to cell death and cognitive impairment. Exercise during pregnancy is a potential therapeutic tool due to benefits offered to mother and fetus. Swimming during pregnancy elicits a strong metabolic programming in the offspring's brain, evidenced by increased antioxidant enzymes, mitochondrial biogenesis, and neurogenesis. This article aims to evaluate whether the benefits of maternal exercise are able to prevent behavioral brain injury caused by neonatal HI. Female adult Wistar rats swam before and during pregnancy (30min/day, 5 days/week, 4 weeks). At 7(th) day after birth, the offspring was submitted to HI protocol and, in adulthood (60(th) day), it performed the behavioral tests. It was observed an increase in motor activity in the open field test in HI-rats, which was not prevented by maternal exercise. The rats subjected to maternal swimming presented an improved long-term memory in the object recognition task, which was totally reversed by neonatal HI encephalopathy. BDNF brain levels were not altered; suggesting that HI or maternal exercise effects were BDNF-independent. In summary, our data suggest a beneficial long-term effect of maternal swimming, despite not being robust enough to protect from HI injury.
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Hipóxia-Isquemia Encefálica/psicologia , Comportamento Materno , Memória de Longo Prazo , Reconhecimento Psicológico , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/metabolismo , Masculino , Transtornos da Memória/prevenção & controle , Ratos , Ratos Wistar , NataçãoRESUMO
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-1ß) 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-1ß 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.