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1.
Alzheimers Dement ; 19(6): 2677-2696, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36975090

RESUMO

INTRODUCTION: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODS: The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTS: During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]). DISCUSSION: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Microglia/patologia , Inflamação , Apolipoproteínas E/genética
2.
Neurobiol Dis ; 144: 105027, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32712266

RESUMO

Inflammation has been linked to the development of nonmotor symptoms in Parkinson's disease (PD), which greatly impact patients' quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. We report 5 cases of progressive parkinsonism in non-human primates to gain a broader understanding of MPTP-induced central and peripheral inflammatory dysfunction to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation. Monkeys were also evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Additionally, monkeys were treated with a novel TNF inhibitor XPro1595 (10 mg/kg, n = 3) or vehicle (n = 2) every three days starting 11 weeks after the initiation of MPTP to determine whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. The case studies revealed that earlier and robust [18F]FEPPA PET signals resulted in earlier and more severe parkinsonism, which was seen in male cases compared to female cases. Potential other sex differences were observed in circulating inflammation, microbiota diversity and their metabolites. Additional studies with larger group sizes of both sexes would enable confirmation and extension of these findings. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.


Assuntos
Modelos Animais de Doenças , Microbioma Gastrointestinal , Inflamação/metabolismo , Macaca mulatta , Microglia/metabolismo , Transtornos Parkinsonianos/fisiopatologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Anilidas , Animais , Comportamento Animal , Cognição/fisiologia , Progressão da Doença , Ácidos Graxos Voláteis/metabolismo , Feminino , Imageamento por Ressonância Magnética , Masculino , Microglia/efeitos dos fármacos , Microglia/patologia , Neurotoxinas , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/microbiologia , Tomografia por Emissão de Pósitrons , Piridinas , Inibidores do Fator de Necrose Tumoral/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
3.
Brain Behav Immun ; 81: 305-316, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31251975

RESUMO

Physical and psychosocial maltreatment experienced before the age of 18, termed early life adversity (ELA), affects an estimated 39% of the world's population, and has long-term detrimental health and psychological outcomes. While adult phenotypes vary following ELA, inflammation and altered stress responsivity are pervasive. Cytokines, most notably tumor necrosis factor (TNF), are elevated in adults with a history of ELA. While soluble TNF (solTNF) drives chronic inflammatory disease, transmembrane TNF facilitates innate immunity. Here, we test whether solTNF mediates the behavioral and molecular outcomes of adolescent psychological stress by administering a brain permeable, selective inhibitor of solTNF, XPro1595. Male and female C57BL/6 mice were exposed to an aggressive rat through a perforated translucent ball ('predatory stress') or transported to an empty room for 30 min for 30 days starting on postnatal day 34. Mice were given XPro1595 or vehicle treatment across the last 15 days. Social interaction, sucrose preference, and plasma inflammation were measured at 2 and 4 weeks, and open field behavior, adiposity, and neuroinflammation were measured at 4 weeks. Chronic adolescent stress resulted in increased peripheral inflammation and dysregulated neuroinflammation in adulthood in a sex-specific manner. Abnormal social and open field behavior, fat pad weight, and fecal boli deposition were noted after 30 days; solTNF antagonism ameliorated the effects of stress. Together, these data support our hypothesis, and suggest that targeting solTNF with XPro1595 may improve quality of life for individuals with a history of adolescent stress.


Assuntos
Adiposidade , Inflamação , Fatores Sexuais , Estresse Psicológico , Fator de Necrose Tumoral alfa , Animais , Feminino , Masculino , Camundongos , Adiposidade/efeitos dos fármacos , Fatores Etários , Inflamação/etiologia , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais , Obesidade/etiologia , Obesidade/fisiopatologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
4.
Alzheimers Res Ther ; 12(1): 1, 2019 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-31892368

RESUMO

BACKGROUND: Insulin impairment and inflammation are two features common to type 2 diabetes and Alzheimer's disease; however, the molecular and signaling interactions underlying this relationship are not well understood. Mounting evidence point to the associations between the disruption of metabolite processing in insulin impairment and neurodegenerative conditions such as Alzheimer's. Although the brain depends partially on metabolites processed in the periphery, to date, little is known about how soluble tumor necrosis factor signaling (solTNF) impacts integrated peripheral immune and metabolic feedback signals in states of energy overload and insulin insensitivity. METHODS: C57Bl/6J mice were fed a high-fat high-carbohydrate diet (HFHC) for 14 weeks. The brain-permeant biologic XPro1595® was used to block solTNF-dependent pathways. Metabolic and immune alterations were evaluated in the gut, liver, and brain. Behavioral tests were performed. Untargeted metabolomics was carried out in the plasma and liver. RESULTS: HFHC diet promotes central insulin impairment and dysregulation of immune-modulatory gene expressed in the brain. Alteration of metabolites associated with type 2 diabetes and Alzheimer's such as butanoate, glutamate, biopterin, branched-chain amino acids, purines, and proteoglycan metabolism was observed in HFHC-fed mice. solTNF inhibition ameliorates hepatic metabolic disturbances and hepatic and intestinal lipocalin-2 levels, and decreases insulin impairment in the brain and behavioral deficits associated with HFHC diet. CONCLUSIONS: Our novel findings suggest that HFHC diet impacts central insulin signaling and immune-metabolic interactions in a solTNF-dependent manner to increase the risk for neurodegenerative conditions. Our novel findings indicate that selective solTNF neutralization can ameliorate peripheral and central diet-induced insulin impairment and identify lipocalin-2 as a potential target for therapeutic intervention to target inflammation and insulin disturbances in obesogenic environments. Collectively, our findings identify solTNF as a potential target for therapeutic intervention in inflammatory states and insulin disturbances in obesogenic environments to lower risk for AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Síndrome Metabólica/fisiopatologia , Obesidade/fisiopatologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Análise de Variância , Animais , Dieta da Carga de Carboidratos , Masculino , Camundongos Endogâmicos C57BL , Fatores de Risco , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
5.
J Neuroinflammation ; 14(1): 164, 2017 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-28821274

RESUMO

BACKGROUND: Efforts to identify fluid biomarkers of Parkinson's disease (PD) have intensified in the last decade. As the role of inflammation in PD pathophysiology becomes increasingly recognized, investigators aim to define inflammatory signatures to help elucidate underlying mechanisms of disease pathogenesis and aid in identification of patients with inflammatory endophenotypes that could benefit from immunomodulatory interventions. However, discordant results in the literature and a lack of information regarding the stability of inflammatory factors over a 24-h period have hampered progress. METHODS: Here, we measured inflammatory proteins in serum and CSF of a small cohort of PD (n = 12) and age-matched healthy control (HC) subjects (n = 6) at 11 time points across 24 h to (1) identify potential diurnal variation, (2) reveal differences in PD vs HC, and (3) to correlate with CSF levels of amyloid ß (Aß) and α-synuclein in an effort to generate data-driven hypotheses regarding candidate biomarkers of PD. RESULTS: Despite significant variability in other factors, a repeated measures two-way analysis of variance by time and disease state for each analyte revealed that serum IFNγ, TNF, and neutrophil gelatinase-associated lipocalin (NGAL) were stable across 24 h and different between HC and PD. Regression analysis revealed that C-reactive protein (CRP) was the only factor with a strong linear relationship between CSF and serum. PD and HC subjects showed significantly different relationships between CSF Aß proteins and α-synuclein and specific inflammatory factors, and CSF IFNγ and serum IL-8 positively correlated with clinical measures of PD. Finally, linear discriminant analysis revealed that serum TNF and CSF α-synuclein discriminated between PD and HC with a minimum of 82% sensitivity and 83% specificity. CONCLUSIONS: Our findings identify a panel of inflammatory factors in serum and CSF that can be reliably measured, distinguish between PD and HC, and monitor inflammation as disease progresses or in response to interventional therapies. This panel may aid in generating hypotheses and feasible experimental designs towards identifying biomarkers of neurodegenerative disease by focusing on analytes that remain stable regardless of time of sample collection.


Assuntos
Mediadores da Inflamação/sangue , Mediadores da Inflamação/líquido cefalorraquidiano , Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , alfa-Sinucleína/sangue , alfa-Sinucleína/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Doença de Parkinson/diagnóstico , Índice de Gravidade de Doença
6.
Brain Behav Immun ; 59: 158-172, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27592562

RESUMO

The mechanisms underlying the association between chronic psychological stress, development of metabolic syndrome (MetS), and behavioral impairment in obesity are poorly understood. The aim of the present study was to assess the effects of mild chronic psychological stress on metabolic, inflammatory, and behavioral profiles in a mouse model of diet-induced obesity. We hypothesized that (1) high-fat high-fructose diet (HFHF) and psychological stress would synergize to mediate the impact of inflammation on the central nervous system in the presence of behavioral dysfunction, and that (2) HFHF and stress interactions would impact insulin and lipid metabolism. C57Bl/6 male mice underwent a combination of HFHF and two weeks of chronic psychological stress. MetS-related conditions were assessed using untargeted plasma metabolomics, and structural and immune changes in the gut and liver were evaluated. Inflammation was measured in plasma, liver, gut, and brain. Our results show a complex interplay of diet and stress on gut alterations, energetic homeostasis, lipid metabolism, and plasma insulin levels. Psychological stress and HFHF diet promoted changes in intestinal tight junctions proteins and increases in insulin resistance and plasma cholesterol, and impacted the RNA expression of inflammatory factors in the hippocampus. Stress promoted an adaptive anti-inflammatory profile in the hippocampus that was abolished by diet treatment. HFHF increased hippocampal and hepatic Lcn2 mRNA expression as well as LCN2 plasma levels. Behavioral changes were associated with HFHF and stress. Collectively, these results suggest that diet and stress as pervasive factors exacerbate MetS-related conditions through an inflammatory mechanism that ultimately can impact behavior. This rodent model may prove useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders.


Assuntos
Comportamento Animal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Frutose/efeitos adversos , Redes Reguladoras de Genes/efeitos dos fármacos , Inflamação/genética , Metabolismo/genética , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Animais , Peso Corporal , Química Encefálica/genética , Metabolismo Energético/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipocalina-2/biossíntese , Lipocalina-2/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Comportamento Social
7.
J Neurochem ; 134(2): 222-32, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25866285

RESUMO

Dopamine (DA) replacement therapy with L-DOPA continues to be the primary treatment of Parkinson's disease; however, long-term therapy is accompanied by L-DOPA-induced dyskinesias (LID). Several experimental and clinical studies have established that Propranolol, a ß-adrenergic receptor antagonist, reduces LID without affecting L-DOPA's efficacy. However, the exact mechanisms underlying these effects remain to be elucidated. The aim of this study was to evaluate the anti-dyskinetic profile of Propranolol against a panel of DA replacement strategies, as well as elucidate the underlying neurochemical mechanisms. Results indicated that Propranolol, in a dose-dependent manner, reduced LID, without affecting motor performance. Propranolol failed to alter dyskinesia produced by the D1 receptor agonist, SKF81297 (0.08 mg/kg, sc), or the D2 receptor agonist, Quinpirole (0.05 mg/kg, sc). These findings suggested a pre-synaptic mechanism for Propranolol's anti-dyskinetic effects, possibly through modulating L-DOPA-mediated DA efflux. To evaluate this possibility, microdialysis studies were carried out in the DA-lesioned striatum of dyskinetic rats and results indicated that co-administration of Propranolol (20 mg/kg, ip) was able to attenuate L-DOPA- (6 mg/kg, sc) induced DA efflux. Therefore, Propranolol's anti-dyskinetic properties appear to be mediated via attenuation of L-DOPA-induced extraphysiological efflux of DA.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Dopamina/metabolismo , Discinesia Induzida por Medicamentos/prevenção & controle , Transtornos Parkinsonianos/metabolismo , Propranolol/farmacologia , Animais , Antiparkinsonianos/efeitos adversos , Cromatografia Líquida de Alta Pressão , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/efeitos adversos , Masculino , Microdiálise , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
8.
Behav Brain Res ; 275: 120-5, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25200517

RESUMO

Psychological stress can have devastating and lasting effects on a variety of behaviors, especially those associated with mental illnesses such as anxiety and depression. Animal models of chronic stress are frequently used to elucidate the mechanisms underlying the relationship between stress and mental health disorders and to develop improved treatment options. The current study expands upon a novel chronic stress paradigm for mice: predatory stress. The predatory stress model incorporates the natural predator-prey relationship that exists among rats and mice and allows for greater interaction between the animals, in turn increasing the extent of the stressful experience. In this study, we evaluated the behavioral effects of exposure to 15 days of predatory stress on an array of behavioral indices. Up to 2 weeks after the end of stress, adult male mice showed an increase of anxiety-like behaviors as measured by the open field and social interaction tests. Animals also expressed an increase in depressive-like behavior in the sucrose preference test. Notably, performance on the novel object recognition task, a memory test, improved after predatory stress. Taken as a whole, our results indicate that 15 exposures to this innovative predatory stress paradigm are sufficient to elicit robust anxiety-like behaviors with evidence of co-morbid depressive-like behavior, as well as changes in cognitive behavior in male mice.


Assuntos
Ansiedade/etiologia , Depressão/etiologia , Comportamento Predatório , Estresse Psicológico/complicações , Animais , Ansiedade/complicações , Depressão/complicações , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Preferências Alimentares , Relações Interpessoais , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Sacarose/administração & dosagem , Edulcorantes/administração & dosagem , Fatores de Tempo
9.
Magn Reson Imaging ; 32(10): 1301-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25086330

RESUMO

Quantitative MRI of neuromelanin (NM) containing structures (referred to as NM-MRI) in the brainstem, namely the locus coeruleus (LC) and substantia nigra (SN), may assist with the early detection of Parkinson's disease (PD) and Alzheimer's disease (AD) as well as differential diagnosis in the early disease stages. In this study, two gradient echo (GRE) sequences with magnetization transfer contrast (MTC) preparation pulses were developed to simultaneously image the LC and SN. This has been a challenge with NM-MRI techniques used in previous studies due to the relatively high specific absorption rate (SAR) induced by these techniques. In addition, a semi-automated quantitative analysis scheme was applied to estimate volumes and contrast-to-noise ratios (CNR) of the LC and SN based on segmentation of both structures. Compared to a T1-weighted turbo spin echo (TSE) sequence typically used for simultaneous imaging of the LC and SN, the two GRE-MTC sequences exhibited improved performance in terms of higher sensitivity (in CNR) in imaging the SN and lower SAR during the scans. A multiple-measurement protocol was adopted as well so that motion degraded measurements could be removed and artifacts associated with motion could be corrected. The present approach has demonstrated advantages in image acquisition (lower SAR and higher sensitivity), image pre-processing (with motion correction) and quantitative image analysis (segmentation-based estimation of volume and CNR) when compared with existing NM-MRI approaches. This approach has potential for detection and monitoring of neurodegeneration in LC and SN in disease states including AD and PD.


Assuntos
Locus Cerúleo/patologia , Imageamento por Ressonância Magnética/métodos , Melaninas/química , Substância Negra/patologia , Adulto , Doença de Alzheimer/patologia , Artefatos , Diagnóstico Diferencial , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Movimento (Física) , Doença de Parkinson/patologia , Reconhecimento Automatizado de Padrão , Reprodutibilidade dos Testes , Adulto Jovem
10.
J Parkinsons Dis ; 4(3): 349-60, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25061061

RESUMO

BACKGROUND: Parkinson's disease (PD) is a complex multi-system age-related neurodegenerative disorder. Targeting the ongoing neuroinflammation in PD patients is one strategy postulated to slow down or halt disease progression. Proof-of-concept studies from our group demonstrated that selective inhibition of soluble Tumor Necrosis Factor (solTNF) by intranigral delivery of dominant negative TNF (DN-TNF) inhibitors reduced neuroinflammation and nigral dopamine (DA) neuron loss in endotoxin and neurotoxin rat models of nigral degeneration. OBJECTIVE: As a next step toward human clinical trials, we aimed to determine the extent to which peripherally administered DN-TNF inhibitor XPro®1595 could: i) cross the blood-brain-barrier in therapeutically relevant concentrations, ii) attenuate neuroinflammation (microglia and astrocyte), and iii) mitigate loss of nigral DA neurons in rats receiving a unilateral 6-hydroxydopamine (6-OHDA) striatal lesion. METHODS: Rats received unilateral 6-OHDA (20 µg into the right striatum). Three or 14 days after lesion, rats were dosed with XPro®1595 (10 mg/kg in saline, subcutaneous) every third day for 35 days. Forelimb asymmetry was used to assess motor deficits after the lesion; brains were harvested 35 days after the lesion for analysis of XPro®1595 levels, glial activation and nigral DA neuron number. RESULTS: Peripheral subcutaneous dosing of XPro®1595 achieved plasma levels of 1-8 microgram/mL and CSF levels of 1-6 ng/mL depending on the time the rats were killed after final XPro®1595 injection. Irrespective of start date, XPro®1595 significantly reduced microglia and astrocyte number in SNpc whereas loss of nigral DA neurons was attenuated when drug was started 3, but not 14 days after the 6-OHDA lesion. CONCLUSIONS: Our data suggest that systemically administered XPro®1595 may have disease-modifying potential in PD patients where inflammation is part of their pathology.


Assuntos
Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/patologia , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Barreira Hematoencefálica , Contagem de Células , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Encefalite/prevenção & controle , Gliose/prevenção & controle , Masculino , Oxidopamina , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/farmacocinética
11.
Endocrinology ; 154(7): 2489-500, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23671261

RESUMO

The impact of acute stress on inflammatory signaling within the central nervous system is of interest because these factors influence neuroendocrine function both directly and indirectly. Exposure to certain stressors increases expression of the proinflammatory cytokine, Il-1ß in the hypothalamus. Increased IL-1 is reciprocally regulated by norepinephrine (stimulatory) and corticosterone (inhibitory), yet neural pathways underlying increased IL-1 have not been clarified. These experiments explored the impact of bilateral lesions of the ventral noradrenergic bundle (VNAB) on IL-1 expression in the paraventricular nucleus of the hypothalamus (PVN) after foot shock. Adult male Sprague Dawley rats received bilateral 6-hydroxydopamine lesions of the VNAB (VNABx) and were exposed to intermittent foot shock. VNABx depleted approximately 64% of norepinephrine in the PVN and attenuated the IL-1 response produced by foot shock. However, characterization of the hypothalamic-pituitary-adrenal response, a crucial prerequisite for interpreting the effect of VNABx on IL-1 expression, revealed a profound dissociation between ACTH and corticosterone. Specifically, VNABx blocked the intronic CRH response in the PVN and the increase in plasma ACTH, whereas corticosterone was unaffected at all time points examined. Additionally, foot shock led to a rapid and profound increase in cyclooxygenase-2 and IL-1 expression within the adrenal glands, whereas more subtle effects were observed in the pituitary gland. Together the findings were the 1) demonstration that exposure to acute stress increased expression of inflammatory factors more broadly throughout the hypothalamic-pituitary-adrenal axis; 2) implication of a modest role for norepinephrine-containing fibers of the VNAB as an upstream regulator of PVN IL-1; and 3) suggestion of an ACTH-independent mechanism controlling the release of corticosterone in VNABx rats.


Assuntos
Interleucina-1/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Estresse Fisiológico/fisiologia , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Corticosterona/sangue , Corticosterona/metabolismo , Ciclo-Oxigenase 2/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Norepinefrina/metabolismo , Oxidopamina/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Radioimunoensaio , Ratos , Ratos Sprague-Dawley
12.
ASN Neuro ; 5(2): 113-39, 2013 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-23506036

RESUMO

The role of neuroinflammation and the adaptive immune system in PD (Parkinson's disease) has been the subject of intense investigation in recent years, both in animal models of parkinsonism and in post-mortem PD brains. However, how these processes relate to and modulate α-syn (α-synuclein) pathology and microglia activation is still poorly understood. Specifically, how the peripheral immune system interacts, regulates and/or is induced by neuroinflammatory processes taking place during PD is still undetermined. We present herein a comprehensive review of the features and impact that neuroinflamation has on neurodegeneration in different animal models of nigral cell death, how this neuroinflammation relates to microglia activation and the way microglia respond to α-syn in vivo. We also discuss a possible role for the peripheral immune system in animal models of parkinsonism, how these findings relate to the state of microglia activation observed in these animal models and how these findings compare with what has been observed in humans with PD. Together, the available data points to the need for development of dual therapeutic strategies that modulate microglia activation to change not only the way microglia interact with the peripheral immune system, but also to modulate the manner in which microglia respond to encounters with α-syn. Lastly, we discuss the immune-modulatory strategies currently under investigation in animal models of parkinsonism and the degree to which one might expect their outcomes to translate faithfully to a clinical setting.


Assuntos
Encéfalo/patologia , Microglia/metabolismo , Neurônios/imunologia , Doença de Parkinson/imunologia , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismo , Animais , Encéfalo/imunologia , Modelos Animais de Doenças , Humanos , Linfócitos/imunologia , Doença de Parkinson/etiologia
13.
Curr Neurol Neurosci Rep ; 12(4): 350-8, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22580742

RESUMO

Generally speaking, inflammation as a key piece to the Parkinson's disease (PD) puzzle is a relatively new concept. Acceptance of this concept has gained ground as studies by various researchers have demonstrated the potential of mitigating nigral cell death by curtailing inflammation in animal models of PD. We propose that the significance of inflammation in PD pathology may extend beyond the nigrostriatal region. In the current review, we present an argument for this based on the Braak staging and discuss how inflammation might contribute to the development of non-motor PD symptoms.


Assuntos
Doença de Parkinson/fisiopatologia , Animais , Dopamina/metabolismo , Humanos , Inflamação/etiologia , Inflamação/fisiopatologia , Degeneração Neural/fisiopatologia , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Sono/fisiologia
14.
J Neuroinflammation ; 9: 9, 2012 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-22248083

RESUMO

BACKGROUND: There is ample evidence that psychological stress adversely affects many diseases. Recent evidence has shown that intense stressors can increase inflammation within the brain, a known mediator of many diseases. However, long-term outcomes of chronic psychological stressors that elicit a neuroinflammatory response remain unknown. METHODS: To address this, we have modified previously described models of rat/mouse predatory stress (PS) to increase the intensity of the interaction. We postulated that these modifications would enhance the predator-prey experience and increase neuroinflammation and behavioral dysfunction in prey animals. In addition, another group of mice were subjected to a modified version of chronic unpredictable stress (CUS), an often-used model of chronic stress that utilizes a combination of stressors that include physical, psychological, chemical, and other. The CUS model has been shown to exacerbate a number of inflammatory-related diseases via an unknown mechanism. Using these two models we sought to determine: 1) whether chronic PS or CUS modulated the inflammatory response as a proposed mechanism by which behavioral deficits might be mediated, and 2) whether chronic exposure to a pure psychological stressor (PS) leads to deficits similar to those produced by a CUS model containing psychological and physical stressors. Finally, to determine whether acute PS has neuroinflammatory consequences, adult mice were examined at various time-points after PS for changes in inflammation. RESULTS: Adolescent mice subjected to chronic PS had increased basal expression of inflammation within the midbrain. CUS and chronic PS mice also had an impaired inflammatory response to a subsequent lipopolysaccharide challenge and PS mice displayed increased anxiety- and depressive-like behaviors following chronic stress. Finally, adult mice subjected to acute predatory stress had increased gene expression of inflammatory factors. CONCLUSION: Our results demonstrate that predatory stress, an ethologically relevant stressor, can elicit changes in neuroinflammation and behavior. The predatory stress model may be useful in elucidating mechanisms by which psychological stress modulates diseases with an inflammatory component.


Assuntos
Envelhecimento , Encefalite/etiologia , Polissacarídeos/efeitos adversos , Estresse Psicológico/complicações , Análise de Variância , Animais , Encéfalo/metabolismo , Corticosterona/sangue , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalite/sangue , Encefalite/patologia , Preferências Alimentares/efeitos dos fármacos , Preferências Alimentares/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Elevação dos Membros Posteriores/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Ratos , Sacarose/administração & dosagem , Edulcorantes/administração & dosagem
15.
Pharmacol Biochem Behav ; 100(3): 607-15, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21978941

RESUMO

While L-3,4-dihydroxyphenylalanine (L-DOPA) remains the standard treatment for Parkinson's disease (PD), long-term efficacy is often compromised by L-DOPA-induced dyskinesia (LID). Recent research suggests that targeting the noradrenergic (NE) system may provide relief from both PD and LID, however, most PD patients exhibit NE loss which may modify response to such strategies. Therefore this investigation aimed to characterize the development and expression of LID and the anti-dyskinetic potential of the α2- and ß-adrenergic receptor antagonists idazoxan and propranolol, respectively, in rats receiving 6-OHDA lesions with (DA lesion) or without desipramaine protection (DA+NE lesion). Male Sprague-Dawley rats (N=110) received unilateral 6-hydroxydopamine lesions. Fifty-three rats received desipramine to protect NE neurons (DA lesion) and 57 received no desipramine reducing striatal and hippocampal NE content 64% and 86% respectively. In experiment 1, the development and expression of L-DOPA-induced abnormal involuntary movements (AIMs) and rotations were examined. L-DOPA efficacy using the forepaw adjusting steps (FAS) test was also assessed in DA- and DA+NE-lesioned rats. In experiment 2, DA- and DA+NE-lesioned rats received pre-treatments of idazoxan or propranolol followed by L-DOPA after which the effects of these adrenergic compounds were observed. Results demonstrated that moderate NE loss reduced the development and expression of AIMs and rotations but not L-DOPA efficacy while anti-dyskinetic efficacy of α2- and ß-adrenergic receptor blockade was maintained. These findings suggest that the NE system modulates LID and support the continued investigation of adrenergic compounds for the improved treatment of PD.


Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Corpo Estriado/fisiopatologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Hipocampo/fisiopatologia , Levodopa/efeitos adversos , Animais , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Desipramina/farmacologia , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/fisiopatologia , Hipocampo/efeitos dos fármacos , Idazoxano/uso terapêutico , Levodopa/uso terapêutico , Masculino , Terapia de Alvo Molecular , Fármacos Neuroprotetores/farmacologia , Oxidopamina , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Propranolol/uso terapêutico , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Simpatectomia Química
16.
J Pharmacol Exp Ther ; 337(3): 755-65, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21402691

RESUMO

Chronic dopamine replacement therapy in Parkinson's disease (PD) leads to deleterious motor sequelae known as L-DOPA-induced dyskinesia (LID). No known therapeutic can eliminate LID, but preliminary evidence suggests that dl-1-isopropylamino-3-(1-naphthyloxy)-2-propanol [(±)propranolol], a nonselective ß-adrenergic receptor (ßAR) antagonist, may reduce LID. The present study used the rat unilateral 6-hydroxydopamine model of PD to characterize and localize the efficacy of (±)propranolol as an adjunct to therapy with L-DOPA. We first determined whether (±)propranolol was capable of reducing the development and expression of LID without impairing motor performance ON and OFF L-DOPA. Coincident to this investigation, we used reverse-transcription polymerase chain reaction techniques to analyze the effects of chronic (±)propranolol on markers of striatal activity known to be involved in LID. To determine whether (±)propranolol reduces LID through ßAR blockade, we subsequently examined each enantiomer separately because only the (-)enantiomer has significant ßAR affinity. We next investigated the effects of a localized striatal ßAR blockade on LID by cannulating the region and microinfusing (±)propranolol before systemic L-DOPA injections. Results showed that a dose range of (±)propranolol reduced LID without deleteriously affecting motor activity. Pharmacologically, only (-)propranolol had anti-LID properties indicating ßAR-specific effects. Aberrant striatal signaling associated with LID was normalized with (±)propranolol cotreatment, and intrastriatal (±)propranolol was acutely able to reduce LID. This research confirms previous work suggesting that (±)propranolol reduces LID through ßAR antagonism and presents novel evidence indicating a potential striatal locus of pharmacological action.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Antiparkinsonianos/toxicidade , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/toxicidade , Atividade Motora/efeitos dos fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Animais , Benzoxazinas , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/diagnóstico , Discinesia Induzida por Medicamentos/metabolismo , Masculino , Feixe Prosencefálico Mediano/efeitos dos fármacos , Terapia de Alvo Molecular , Oxazinas , Oxidopamina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta , Fatores de Tempo
18.
Physiol Behav ; 104(2): 187-98, 2011 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-21406198

RESUMO

Exposure to acute stress has been shown to increase the expression of pro-inflammatory cytokines in brain, blood and peripheral organs. However, the nature of the inflammatory response evoked by acute stress varies depending on the stressor used and species examined. The goal of the following series of studies was to characterize the consequences of social defeat in the Sprague Dawley (SD) rat using three different social defeat paradigms. In Experiments 1 and 2, adult male SD rats were exposed to a typical acute resident-intruder paradigm of social defeat (60 min) by placement into the home cage of a larger, aggressive Long Evans rat and brain tissue was collected at multiple time points for analysis of IL-1ß protein and gene expression changes in the PVN, BNST and adrenal glands. In subsequent experiments, rats were exposed to once daily social defeat for 7 or 21 days (Experiment 3) or housed continuously with an aggressive partner (separated by a partition) for 7 days (Experiment 4) to assess the impact of chronic social stress on inflammatory measures. Despite the fact that social defeat produced a comparable corticosterone response as other stressors (restraint, forced swim and footshock; Experiment 5), acute social defeat did not affect inflammatory measures. A small but reliable increase in IL-1 gene expression was observed immediately after the 7th exposure to social defeat, while other inflammatory measures were unaffected. In contrast, restraint, forced swim and footshock all significantly increased IL-1 gene expression in the PVN; other inflammatory factors (IL-6, cox-2) were unaffected in this structure. These findings provide a comprehensive evaluation of stress-dependent inflammatory changes in the SD rat, raising intriguing questions regarding the features of the stress challenge that may be predictive of stress-dependent neuroinflammation.


Assuntos
Comportamento Animal/fisiologia , Citocinas/sangue , Regulação da Expressão Gênica/fisiologia , Ratos Sprague-Dawley/fisiologia , Meio Social , Estresse Psicológico/sangue , Glândulas Suprarrenais/patologia , Hormônio Adrenocorticotrópico/sangue , Animais , Corticosterona/sangue , Citocinas/genética , Interleucina-1beta/sangue , Masculino , Núcleo Hipotalâmico Paraventricular/metabolismo , RNA Mensageiro/metabolismo , Radioimunoensaio , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley/psicologia , Núcleos Septais/metabolismo , Especificidade da Espécie , Baço/patologia , Natação/psicologia , Fatores de Tempo
19.
Mol Ther ; 19(1): 46-52, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20959812

RESUMO

Parkinson's disease (PD) is a progressive neurodegenerative disorder typified by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Recent evidence indicates that neuroinflammation may play a critical role in the pathogenesis of PD, particularly tumor necrosis factor (TNF). We have previously shown that soluble TNF (solTNF) is required to mediate robust degeneration induced by 6-hydroxydopamine (6-OHDA) or lipopolysaccharide. What remains unknown is whether TNF inhibition can attenuate the delayed and progressive phase of neurodegeneration. To test this, rats were injected in the SNpc with lentivirus encoding dominant-negative TNF (lenti-DN-TNF) 2 weeks after receiving a 6-OHDA lesion. Remarkably, when examined 5 weeks after the initial 6-OHDA lesion, no further loss of nigral DA neurons was observed. Lenti-DN-TNF also attenuated microglial activation. Together, these data suggest that TNF is likely a critical mediator of nigral DA neuron death during the delayed and progressive phase of neurodegeneration, and that microglia may be the principal cell type involved. These promising findings provide compelling reasons to perform DN-TNF gene transfer studies in nonhuman primates with the long-term goal of using it in the clinic to prevent the delayed and progressive degeneration of DA neurons that gives rise to motor symptoms in PD.


Assuntos
Dopamina/metabolismo , Terapia Genética/métodos , Neurônios/patologia , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Substância Negra/patologia , Fator de Necrose Tumoral alfa/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Morte Celular/genética , Modelos Animais de Doenças , Feminino , Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Lentivirus/genética , Microglia/metabolismo , Microglia/patologia , Neurônios/metabolismo , Oxidopamina , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley , Substância Negra/metabolismo , Fator de Necrose Tumoral alfa/biossíntese
20.
Prog Brain Res ; 184: 113-32, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20887872

RESUMO

The molecular mechanisms underlying the pathogenesis of idiopathic Parkinson's disease (PD) have not been completely elucidated; however, some progress has been made in identifying factors that compromise survival of the dopaminergic neurons in the substantia nigra (SN) the death of which give rise to the motor symptoms that enable clinicians to diagnose the disease in its mid- to late stages. The prevailing theory regarding processes that are likely to account for degeneration of the nigrostriatal system centers around mitochondrial dysfunction, oxidative stress, excitotoxicity, and neuroinflammation. Of these, neuroinflammation is one candidate that appears to accumulate more support with each passing year. A number of researchers have attempted to manipulate inflammation in various animal PD models with varying levels of success. Still others have used inflammatory stimuli to elicit nigral cell death (NCD), a disturbing finding that has prompted much interest. In this chapter, we attempt to integrate what is known about the role of neuroinflammation in PD with the factors we feel are critical for understanding how inflammation modulates disease progression.


Assuntos
Inflamação/patologia , Doença de Parkinson/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Dopamina/fisiologia , Humanos , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Intoxicação por MPTP/patologia , Neurônios/metabolismo , Neurônios/patologia , Oxidopamina , Doença de Parkinson/psicologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Praguicidas/toxicidade , Simpatolíticos
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