RESUMO
OBJECTIVE: Parkinson's disease (PD) is characterized by deterioration of the nigrostriatal system and associated with chronic neuroinflammation. Glial activation has been associated with regulating the survival of dopaminergic neurons and is thought to contribute to PD through the release of proinflammatory and neurotoxic factors, such as reactive nitric oxide (NO) that triggers or exacerbates neurodegeneration in PD. Polyunsaturated fatty acids (PUFAs) exert protective effects, including antiinflammatory, antiapoptotic, and antioxidant activity, and may be promising for delaying or preventing PD by attenuating neuroinflammation and preserving dopaminergic neurons. The present study investigated the effects of fish oil supplementation that was rich in PUFAs on dopaminergic neuron loss, the density of inducible nitric oxide synthase (iNOS)-immunoreactive cells, and microglia and astrocyte reactivity in the substantia nigra pars compacta (SNpc) and striatal dopaminergic fibers. METHODS: The animals were supplemented with fish oil for 50 days and subjected to unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-induced lesions as a model of PD. RESULTS: Fish oil mitigated the loss of SNpc neurons and nerve terminals in the striatum that was caused by 6-OHDA. This protective effect was associated with reductions of the density of iNOS-immunoreactive cells and microglia and astrocyte reactivity. DISCUSSION: These results suggest that the antioxidant and antiinflammatory properties of fish oil supplementation are closely related to a decrease in dopaminergic damage that is caused by the 6-OHDA model of PD.
Assuntos
Ácidos Graxos Ômega-3/farmacologia , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Doença de Parkinson/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina , Neurônios Dopaminérgicos/efeitos dos fármacos , Óleos de Peixe/farmacologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Degeneração Neural/tratamento farmacológico , Degeneração Neural/etiologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Oxidopamina , Doença de Parkinson/etiologia , Ratos , Ratos WistarRESUMO
Depression is increasingly present in the population, and its pathophysiology and treatment have been investigated with several animal models, including olfactory bulbectomy (Obx). Fish oil (FO) supplementation during the prenatal and postnatal periods decreases depression-like and anxiety-like behaviors. The present study evaluated the effect of FO supplementation on Obx-induced depressive-like behavior and cognitive impairment. Female rats received supplementation with FO during habituation, mating, gestation, and lactation, and their pups were subjected to Obx in adulthood; after the recovery period, the adult offspring were subjected to behavioral tests, and the hippocampal levels of brain-derived neurotrophic factor (BDNF), serotonin (5-HT) and the metabolite 5-hydroxyindoleacetic (5-HIAA) were determined. Obx led to increased anxiety-like and depressive-like behaviors, and impairment in the object location task. All behavioral changes were reversed by FO supplementation. Obx caused reductions in the levels of hippocampal BDNF and 5-HT, whereas FO supplementation restored these levels to normal values. In control rats, FO increased the hippocampal level of 5-HT and reduced that of 5-HIAA, indicating low 5-HT metabolism in this brain region. The present results indicate that FO supplementation during critical periods of brain development attenuated anxiety-like and depressive-like behaviors and cognitive dysfunction induced by Obx. These results may be explained by increased levels of hippocampal BDNF and 5-HT, two major regulators of neuronal survival and long-term plasticity in this brain structure.
Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Fármacos do Sistema Nervoso Central/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Óleos de Peixe/uso terapêutico , Animais , Transtornos de Ansiedade/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/metabolismo , Transtorno Depressivo/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Testes Neuropsicológicos , Bulbo Olfatório/fisiologia , Bulbo Olfatório/cirurgia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Serotonina/metabolismoRESUMO
AIMS: To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI). METHODS: Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin. KEY FINDINGS: Compared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces. SIGNIFICANCE: Our findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI.
Assuntos
Disfunção Cognitiva/patologia , Disbiose/patologia , Fadiga/patologia , Microbioma Gastrointestinal , Doenças Neuroinflamatórias/patologia , Síndrome do Golfo Pérsico/tratamento farmacológico , Condicionamento Físico Animal , Brometo de Piridostigmina/toxicidade , Animais , Biomarcadores/análise , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/toxicidade , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Disbiose/etiologia , Disbiose/metabolismo , Endotoxemia/etiologia , Endotoxemia/metabolismo , Endotoxemia/patologia , Fadiga/etiologia , Fadiga/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Gliose/etiologia , Gliose/metabolismo , Gliose/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/etiologia , Neuralgia/metabolismo , Neuralgia/patologia , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/metabolismo , Brometo de Piridostigmina/administração & dosagemRESUMO
AIMS: To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1]. MAIN METHODS: Adult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O. (GW2); topical permethrin (1.3 mg/kg in 100% DMSO) and N,N-diethyl-meta-toluamide (DEET 33% in 70% EtOH) and restraint stress (5 min). Exercise, metabolic and behavioral endpoints were compared to sham stress control (CON/S). KEY FINDINGS: Relative to CON/S, GW2 presented persistent exercise intolerance (through post-treatment (PT) day 161), deficient associative learning/memory, and transient insulin insensitivity. In contrast to GW2, GW1 showed deficient long-term object recognition memory, milder associative learning/memory deficit, and behavioral despair. SIGNIFICANCE: Our findings demonstrate that GW chemicals dose-dependently determine the presentation of exercise fatigue and severity/type of cognitive/mood-deficient phenotypes that show persistence. Our comprehensive mouse model of GWI recapitulates the major multiple symptom domains characterizing GWI, including fatigue and cognitive impairment that can be used to more efficiently develop diagnostic tests and curative treatments for ill Gulf War veterans.
Assuntos
Fadiga , Glucose/metabolismo , Deficiências da Aprendizagem , Síndrome do Golfo Pérsico , Brometo de Piridostigmina/efeitos adversos , Animais , Modelos Animais de Doenças , Fadiga/induzido quimicamente , Fadiga/metabolismo , Fadiga/patologia , Humanos , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/patologia , Masculino , Camundongos , Síndrome do Golfo Pérsico/induzido quimicamente , Síndrome do Golfo Pérsico/metabolismo , Síndrome do Golfo Pérsico/patologia , Brometo de Piridostigmina/farmacologiaRESUMO
AIM: To test the hypothesis that the antidepressant-like effect of omega-3 polyunsaturated fatty acids is related to the Indoleamine-2,3-Dioxygenase (IDO) inhibition. METHODS: Animals were supplemented for 50 days with 3.0 g/kg of Fish Oil (FO) or received water (Control group - C), via gavage. At the end of this period, both groups were injected with LPS 24 h before the modified forced swim test (MFST) and the open field. To assess the possible involvement of IDO in the FO effects, we performed two independent experiments, using two IDO inhibitors: the direct inhibitor 1-methyl-DL-tryptophan (1-MT) and the anti-inflammatory drug minocycline (MINO), administered 23 h, 5 h and 1 h before the tests. After the tests, the animals' hippocampi were removed for quantification of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) by HPLC, and for IDO expression by western blot. RESULTS: LPS induced a depressive-like state in the animals, and this effect was blocked by 1-MT, MINO and FO. Regardless of IDO inhibition, FO supplemented animals displayed an antidepressant-like response by increasing swimming and decreasing immobility frequencies in the MFST when compared to the control group. The immune challenge induced an over-expression of IDO and reduced hippocampal 5-HT levels, both of which were reversed by MINO and FO. CONCLUSION: FO induced a pronounced antidepressant-like effect and prevented LPS-induced depressive-like behavior, and this effect was related to decreased IDO expression and increased 5-HT levels in the hippocampus.
Assuntos
Anti-Inflamatórios/farmacologia , Antidepressivos/farmacologia , Depressão/metabolismo , Depressão/prevenção & controle , Óleos de Peixe/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase , Minociclina/farmacologia , Serotonina/metabolismo , Triptofano/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Antidepressivos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Depressão/induzido quimicamente , Suplementos Nutricionais , Ácidos Graxos Ômega-3/farmacologia , Óleos de Peixe/administração & dosagem , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Minociclina/administração & dosagem , Ratos , Ratos Wistar , Triptofano/administração & dosagemRESUMO
Evidence suggests that idiopathic Parkinson's disease (PD) is the consequence of a neurodevelopmental disruption, rather than strictly a consequence of aging. Thus, we hypothesized that maternal supplement of omega-3 polyunsaturated fatty acids (ω-3 PUFA) may be associated with neuroprotection mechanisms in a self-sustaining cycle of neuroinflammation and neurodegeneration in lipopolysaccharide (LPS)-model of PD. To test this hypothesis, behavioral and neurochemical assay were performed in prenatally LPS-exposed offspring at postnatal day 21. To further determine whether prenatal LPS exposure and maternal ω-3 PUFAs supplementation had persisting effects, brain injury was induced on PN 90 rats, following bilateral intranigral LPS injection. Pre- and postnatal inflammation damage not only affected dopaminergic neurons directly, but it also modified critical features, such as activated microglia and astrocyte cells, disrupting the support provided by the microenvironment. Unexpectedly, our results failed to show any involvement of caspase-dependent and independent apoptosis pathway in neuronal death mechanisms. On the other hand, learning and memory deficits detected with a second toxic exposure were significantly attenuated in maternal ω-3 PUFAs supplementation group. In addition, ω-3 PUFAs promote beneficial effect on synaptic function, maintaining the neurochemical integrity in remaining neurons, without necessarily protect them from neuronal death. Thus, our results suggest that ω-3 PUFAs affect the functional ability of the central nervous system in a complex way in a multiple inflammation-induced neurotoxicity animal model of PD and they disclose new ways of understanding how these fatty acids control responses of the brain to different challenges.
Assuntos
Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Doença de Parkinson/dietoterapia , Doença de Parkinson/metabolismo , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia , Animais , Animais Recém-Nascidos , Suplementos Nutricionais , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Feminino , Inflamação/dietoterapia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Fármacos Neuroprotetores/administração & dosagem , Doença de Parkinson/patologia , Gravidez , Fenômenos Fisiológicos da Nutrição Pré-Natal/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
Diabetes is a chronic disease associated with depression whose pathophysiological mechanisms that associate these conditions are not fully elucidated. However, the activation of the indoleamine-2,3-dioxygenase (IDO), an enzyme that participate of the tryptophan metabolism leading to a decrease of serotonin (5-HT) levels and whose expression is associated with an immune system activation, has been proposed as a common mechanism that links depression and diabetes. To test this hypothesis, diabetic (DBT) and normoglycemic (NGL) groups had the cytokines (TNFα, IL-1ß, and IL-6) and 5-HT and norepinephrine (NE) levels in the hippocampus (HIP) evaluated. Moreover, the effect of the selective serotonin reuptake inhibitor fluoxetine (FLX), IDO direct inhibitor 1-methyl-tryptophan (1-MT), anti-inflammatory and IDO indirect inhibitor minocycline (MINO), or non-selective cyclooxygenase inhibitor ibuprofen (IBU) was evaluated in DBT rats submitted to the modified forced swimming test (MFST). After the behavioral test, the HIP was obtained for IDO expression by Western blotting analysis. DBT rats exhibited a significant increase in HIP levels of TNFα, IL-1ß, and IL-6 and a decrease in HIP 5-HT and NA levels. They also presented a depressive-like behavior which was reverted by all employed treatments. Interestingly, treatment with MINO, IBU, or FLX but not with 1-MT reduced the increased IDO expression in the HIP from DBT animals. Taken together, our data support our hypothesis that neuroinflammation in the HIP followed by IDO activation with a consequent decrease in the 5-HT levels can be a possible pathophysiological mechanism that links depression to diabetes.
Assuntos
Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/psicologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Cinurenina/metabolismo , Terapia de Alvo Molecular , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal , Glicemia/metabolismo , Citocinas/metabolismo , Depressão/sangue , Depressão/patologia , Depressão/fisiopatologia , Diabetes Mellitus Experimental/sangue , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Hipocampo/metabolismo , Hipocampo/patologia , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Minociclina/farmacologia , Minociclina/uso terapêutico , Atividade Motora/efeitos dos fármacos , Norepinefrina/metabolismo , Ratos Wistar , Serotonina/metabolismo , Natação , Triptofano/análogos & derivados , Triptofano/farmacologia , Triptofano/uso terapêutico , Aumento de Peso/efeitos dos fármacosRESUMO
The pathophysiology of depression is not completely understood; nonetheless, numerous studies point to serotonergic dysfunction as a possible cause. Supplementation with fish oil rich docosahexaenoic (DHA) and eicosapentaenoic acids (EPA) during critical periods of development produces antidepressant effects by increasing serotonergic neurotransmission, particularly in the hippocampus. In a previous study, the involvement of 5-HT1A receptors was demonstrated and we hypothesized that fish oil supplementation (from conception to weaning) alters the function of post-synaptic hippocampal 5-HT1A receptors. To test this hypothesis, female rats were supplemented with fish oil during habituation, mating, gestation, and lactation. The adult male offspring was maintained without supplementation until 3 months of age, when they were subjected to the modified forced swimming test (MFST) after infusion of vehicle or the selective 5-HT1A antagonist, WAY100635, and frequency of swimming, immobility, and climbing was recorded for 5 min. After the behavioral test, the hippocampi were obtained for quantification of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and for 5-HT1A receptor expression by Western blotting analysis. Fish oil-supplemented offspring displayed less depressive-like behaviors in the MFST reflected by decreased immobility and increased swimming and higher 5-HT hippocampal levels. Although there was no difference in the expression of hippocampal 5-HT1A receptors, intra-hippocampal infusion of a sub-effective dose of 8-OH-DPAT enhanced the antidepressant effect of fish oil in supplemented animals. In summary, the present findings suggest that the antidepressant-like effects of fish oil supplementation are likely related to increased hippocampal serotonergic neurotransmission and sensitization of hippocampal 5-HT1A receptors.
Assuntos
Antidepressivos/farmacologia , Óleos de Peixe/farmacologia , Hipocampo/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Sinapses/metabolismo , Animais , Western Blotting , Cromatografia Líquida de Alta Pressão , Feminino , Hipocampo/efeitos dos fármacos , Imobilização , Masculino , Ratos Wistar , Natação , Sinapses/efeitos dos fármacosRESUMO
Inflammation in Parkinson's disease (PD) is a continuous process and might be implicated in the progression of neuronal degeneration. Taking this into account, we proposed a new protocol with multiple and consecutive intranigral lipopolysaccharide (LPS) administration in order to analyze its effects on cognitive behavior. Additionally, striatal concentrations of the neurotransmitters dopamine (DA) and serotonin and their respective metabolites were assessed in three different time-points with the purpose of identifying the consecutive and cumulative effects of LPS infusions. We demonstrated that with a minimum administered dose there was stabilization of neuronal damage as revealed by absence of synergic effect on DA concentration. Although the DA decrease (-43%) generates an animal model of early phase of PD, without apparent motor impairment, the LPS group exhibited deficit in episodic-like memory behavior from the first time-point until the last one, indicating persisted disturbances in memory-recognition responses. These findings provide evidence that multiple intranigral LPS infusions are not sufficient to cause cumulative and progressive damage to dopaminergic neurons, but confirm that the LPS model can be adopted as a useful tool providing insight about the cognitive impairment observed in pre-motor phase of PD.
Assuntos
Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Cognição/efeitos dos fármacos , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Substância Negra/efeitos dos fármacos , Animais , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Lipopolissacarídeos/administração & dosagem , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Ratos , Reconhecimento Psicológico/efeitos dos fármacos , Serotonina/metabolismoRESUMO
Classically, Parkinson's disease (PD) is considered to be a motor system affliction and its diagnosis is based on the presence of a set of cardinal motor signs (e.g. rigidity, bradykinesia, rest tremor and postural reflex disturbance). However, there is considerable evidence showing that non-motor alterations (e.g. anxiety, depression, sleep, gastrointestinal and cognitive functions) precede the classical motor symptoms seen in PD. The management of these nonmotor symptoms remains a challenge. A pattern of regional neurodegeneration that varies considerably depending upon the neuronal population affected may explain the different symptoms. In fact, differential mechanisms of neuronal vulnerability within the substantia nigra pars compacta (SNpc) suggests that factors other than location contribute to the susceptibility of these neurons. In this review we discuss how these factors interact to ultimately target the SNpc. Remarkably, this region consists of approximately 95% of the tyrosine hydroxylase (TH)-immunoreactive neurons in both human and rat brains, and consequently this implicates elevated levels of dopamine metabolites, free radicals and other hazard species in these neurons. An understanding of how these factors promote neuronal death may be useful for the development of novel neuroprotective and/or neurorestorative strategies for PD.