RESUMO
Inflammation has been associated with cardiovascular diseases and the key point is the generation of reactive oxygen species (ROS). Exercise modulates medullary neurons involved in cardiovascular control. We investigated the effect of chronic exercise training (Tr) in treadmill running on gene expression (GE) of ROS and inflammation in commNTS and RVLM neurons. Male Wistar rats (N = 7/group) were submitted to training in a treadmill running (1 h/day, 5 days/wk/10 wks) or maintained sedentary (Sed). Superoxide dismutase (SOD), catalase (CAT), neuroglobin (Ngb), Cytoglobin (Ctb), NADPH oxidase (Nox), cicloxigenase-2 (Cox-2), and neuronal nitric oxide synthase (NOS1) gene expression were evaluated in commNTS and RVLM neurons by qPCR. In RVLM, Tr rats increased Ngb (1.285 ± 0.03 vs. 0.995 ± 0.06), Cygb (1.18 ± 0.02 vs.0.99 ± 0.06), SOD (1.426 ± 0.108 vs. 1.00 ± 0.08), CAT (1.34 ± 0.09 vs. 1.00 ± 0.08); and decreased Nox (0.55 ± 0.146 vs. 1.001 ± 0.08), Cox-2 (0.335 ± 0.05 vs. 1.245 ± 0.02), NOS1 (0.51 ± 0.08 vs. 1.08 ± 0.209) GE compared to Sed. In commNTS, Tr rats increased SOD (1.384 ± 0.13 vs. 0.897 ± 0.101), CAT GE (1.312 ± 0.126 vs. 0.891 ± 0.106) and decreased Cox-2 (0.052 ± 0.011 vs. 1.06 ± 0.207) and NOS1 (0.1550 ± 0.03559 vs. 1.122 ± 0.26) GE compared to Sed. Therefore, GE of proteins of the inflammatory process reduced while GE of antioxidant proteins increased in the commNTS and RVLM after training, suggesting a decrease in oxidative stress of downstream pathways mediated by nitric oxide.
Assuntos
Encefalite/fisiopatologia , Bulbo/fisiopatologia , Estresse Oxidativo , Condicionamento Físico Animal/fisiologia , Núcleo Solitário/fisiopatologia , Animais , Antioxidantes/metabolismo , Encefalite/genética , Expressão Gênica , Masculino , Bulbo/metabolismo , Estresse Oxidativo/genética , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Comportamento Sedentário , Núcleo Solitário/metabolismoRESUMO
BACKGROUND: Chronic brain inflammation has been implicated in the pathogenesis of various neurodegenerative diseases and disorders. For example, overexpression of pro-inflammatory cytokines has been associated with impairments in hippocampal-dependent memory. Lipopolysaccharide (LPS) injection is a widely used model to explore the pathobiology of inflammation. LPS injection into mice causes systemic inflammation, neuronal damage, and poor memory outcomes if the inflammation is not controlled. Activation of the alpha-7 nicotinic receptor (α7) plays an anti-inflammatory role in the brain through vagal efferent nerve signaling. 4R-cembranoid (4R) is a natural compound that crosses the blood-brain barrier, induces neuronal survival, and has been shown to modulate the activity of nicotinic receptors. The purpose of this study is to determine whether 4R reduces the deleterious effects of LPS-induced neuroinflammation and whether the α7 receptor plays a role in mediating these beneficial effects. METHODS: Ex vivo population spike recordings were performed in C57BL/6J wild-type (WT) and alpha-7-knockout (α7KO) mouse hippocampal slices in the presence of 4R and nicotinic receptor inhibitors. For in vivo studies, WT and α7KO mice were injected with LPS for 2 h, followed by 4R or vehicle for 22 h. Analyses of IL-1ß, TNF-α, STAT3, CREB, Akt1, and the long-term novel object recognition test (NORT) were performed for both genotypes. In addition, RNA sequencing and RT-qPCR analyses were carried out for 12 mRNAs related to neuroinflammation and their modification by 4R. RESULTS: 4R confers neuroprotection after NMDA-induced neurotoxicity in both WT and α7KO mice. Moreover, hippocampal TNF-α and IL-1ß levels were decreased with 4R treatment following LPS exposure in both strains of mice. 4R restored LPS-induced cognitive decline in NORT. There was a significant increase in the phosphorylation of STAT3, CREB, and Akt1 with 4R treatment in the WT mouse hippocampus following LPS exposure. In α7KO mice, only pAkt levels were significantly elevated in the cortex. 4R significantly upregulated mRNA levels of ORM2, GDNF, and C3 following LPS exposure. These proteins are known to play a role in modulating microglial activation, neuronal survival, and memory. CONCLUSION: Our results indicate that 4R decreases the levels of pro-inflammatory cytokines; improves memory function; activates STAT3, Akt1, and CREB phosphorylation; and upregulates the mRNA levels of ORM2, GDNF, and C3. These effects are independent of the α7 nicotinic receptor.
Assuntos
Diterpenos/farmacologia , Encefalite/prevenção & controle , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Lipopolissacarídeos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Anti-Inflamatórios , Citocinas/imunologia , Encefalite/fisiopatologia , Hipocampo/imunologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismoRESUMO
Temporal lobe epilepsy is the most common form of intractable epilepsy in adults. More than 30% of individuals with epilepsy have persistent seizures and have drug-resistant epilepsy. Based on our previous findings, treatment with bone marrow mononuclear cells (BMMC) could interfere with early and chronic phase epilepsy in rats and in clinical settings. In this pilocarpine-induced epilepsy model, animals were randomly assigned to two groups: control (Con) and epileptic pre-treatment (Ep-pre-t). The latter had status epilepticus (SE) induced through pilocarpine intraperitoneal injection. Later, seizure frequency was assessed using a video-monitoring system. Ep-pre-t was further divided into epileptic treated with saline (Ep-Veh) and epileptic treated with BMMC (Ep-BMMC) after an intravenous treatment with BMMC was done on day 22 after SE. Analysis of neurobehavioral parameters revealed that Ep-BMMC had significantly lower frequency of spontaneous recurrent seizures (SRS) in comparison to Ep-pre-t and Ep-Veh groups. Hippocampus-dependent spatial and non-spatial learning and memory were markedly impaired in epileptic rats, a deficit that was robustly recovered by treatment with BMMC. Moreover, long-term potentiation-induced synaptic remodeling present in epileptic rats was restored by BMMC. In addition, BMMC was able to reduce abnormal mossy fiber sprouting in the dentate gyrus. Molecular analysis in hippocampal tissue revealed that BMMC treatment down-regulates the release of inflammatory cytokine tumor necrosis factor-α (TNF-α) and Allograft inflammatory factor-1 (AIF-1) as well as the Rho subfamily of small GTPases [Ras homolog gene family member A (RhoA) and Ras-related C3 botulinum toxin substrate 1 (Rac)]. Collectively, delayed BMMC treatment showed positive effects when intravenously infused into chronic epileptic rats.
Assuntos
Transplante de Medula Óssea , Cognição , Encefalite/fisiopatologia , Epilepsia/fisiopatologia , Epilepsia/psicologia , Nucleotídeos de Guanina/antagonistas & inibidores , Recuperação de Função Fisiológica , Animais , Comportamento Animal , Transplante de Medula Óssea/métodos , Modelos Animais de Doenças , Epilepsia/terapia , Infusões Intravenosas , Potenciação de Longa Duração , Masculino , Ratos WistarRESUMO
Miller-Fisher syndrome and Bickerstaff brainstem encephalitis, among others, constitute the anti-GQ1b syndrome, with a common immune pathophysiologic pathway characterized by the presence of anti-GQ1b antibodies, which react against the different nervous system GQ1b sites according to their different accessibility. The Miller-Fisher syndrome has a prevalence of 0.09 cases per 100 000 people-year but there are not epidemiological studies about Bickerstaff brainstem encephalitis, that it seems to be less frequent. In spite of having a good natural outcome, the immunoglobulin administration has been established as efficacious at improving it. A twelveyear- old boy suffering from Miller-Fisher-Bickerstaff syndrome after an acute Campylobacter jejuni diarrhea with positive titers of anti-GQ1b and anti-QGT1a antibodies is presented. We communicate a very uncommon pediatric disease with the aim of warning about the importance of its early suspicion and the need of specific laboratory determinations.
El síndrome anti-GQ1b reúne el síndrome de Miller-Fisher y la encefalitis del tronco cerebral de Bickerstaff, entre otras entidades. Tienen etiopatogenia común, constituida por la presencia de anticuerpos anti-GQ1b que reaccionan contra los sitios GQ1b del sistema nervioso según sea su accesibilidad. La prevalencia anual del síndrome de Miller-Fisher es de 0,09 casos por 100 000 habitantes por año y no existen estudios epidemiológicos sobre la encefalitis del tronco cerebral de Bickerstaff, que sería menos frecuente. De evolución natural hacia la mejoría, se beneficia del tratamiento con gammaglobulina endovenosa. Se presenta a un paciente de 12 años con síndrome de Miller- FisherBickerstaff tras un episodio de diarrea aguda por Campylobacter jejuni en el que los anticuerpos anti-GQ1b resultaron positivos. Es nuestro objetivo comunicar sobre un síndrome de presentación poco habitual en pediatría a fin de advertir acerca de la necesidad de su sospecha precoz y solicitud de estudios de laboratorio específicos.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Encefalite/diagnóstico , Gangliosídeos/imunologia , Síndrome de Miller Fisher/diagnóstico , Autoanticorpos/sangue , Autoantígenos/sangue , Biomarcadores/sangue , Criança , Encefalite/sangue , Encefalite/imunologia , Encefalite/fisiopatologia , Humanos , Masculino , Síndrome de Miller Fisher/sangue , Síndrome de Miller Fisher/imunologia , Síndrome de Miller Fisher/fisiopatologia , SíndromeRESUMO
BACKGROUND: In order to modulate microglial phenotypes in vivo, M1 microglia were depleted by administration of gadolinium chloride and the expression of M2 microglia was induced by IL-4 administration in an animal model of sepsis to better characterize the role of microglial phenotypes in sepsis-induced brain dysfunction. METHODS: Wistar rats were submitted to sham or cecal ligation and perforation (CLP) and treated with IL-4 or GdCl3. Animals were submitted to behavioral tests 10 days after surgery. In a separated cohort of animals at 24 h, 3 and 10 days after surgery, hippocampus was removed and cytokine levels, M1/M2 markers and CKIP-1 levels were determined. RESULTS: Modulation of microglia by IL-4 and GdCl3 was associated with an improvement in long-term cognitive impairment. When treated with IL-4 and GdCl3, the reduction of pro-inflammatory cytokines was apparent in almost all analyzed time points. Additionally, CD11b and iNOS were increased after CLP at all time points, and both IL-4 and GdCl3 treatments were able to reverse this. There was a significant decrease in CD11b gene expression in the CLP+GdCl3 group. IL-4 treatment was able to decrease iNOS expression after sepsis. Furthermore, there was an increase of CKIP-1 in the hippocampus of GdCl3 and IL-4 treated animals 10 days after CLP induction. CONCLUSIONS: GdCl3 and IL-4 are able to manipulate microglial phenotype in an animal models of sepsis, by increasing the polarization toward an M2 phenotype IL-4 and GdCl3 treatment was associated with decreased brain inflammation and functional recovery.
Assuntos
Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Encefalite/prevenção & controle , Gadolínio/farmacologia , Hipocampo/efeitos dos fármacos , Interleucina-4/farmacologia , Microglia/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Antígeno CD11b/metabolismo , Proteínas de Transporte/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalite/metabolismo , Encefalite/patologia , Encefalite/fisiopatologia , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Mediadores da Inflamação/metabolismo , Microglia/metabolismo , Microglia/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Fenótipo , Ratos Wistar , Sepse/metabolismo , Sepse/patologia , Sepse/fisiopatologia , Fatores de TempoRESUMO
Hashimoto's encephalopathy is a rare disease, with a reported prevalence of 2.1 per 100 000. Clinical manifestations include confusion, decreased state of consciousness, cognitive deficit, seizures, myoclonus, ataxia, and focal neurological deficits. Due to the wide variety of signs and symptoms, clinical diagnostic suspicion is essential. Diagnosis is based on three pillars: the presence of neurological clinical manifestations after ruling out other causes of encephalopathy. 2) Presence of increased antithyroid antibodies. 3) Significant clinical improvement after the administration of immunomodulation. The treatment of Hashimoto's encephalopathy pursues two objectives: to control the autoimmune process and to control the complications of the disease. Although in most cases recovery is complete with treatment, the risk of relapse can range from 12.5 to 40% in follow-ups to 2 years.
La encefalopatía de Hashimoto es una enfermedad rara. Se reporta una prevalencia de 2,1 por cada 100 000 habitantes. Entre las manifestaciones clínicas se describen confusión, disminución del estado de consciencia, déficit cognitivo, convulsiones, mioclonus, ataxia y/o déficits neurológicos focales. Debido a la amplia variedad de signos y síntomas, la sospecha clínica diagnóstica es fundamental. El diagnóstico se basa en tres pilares: la presencia de manifestaciones clínicas neurológicas, con la exclusión de otras causas de encefalopatía; presencia de anticuerpos antitiroideos aumentados; una mejoría clínica notable luego de la administración de inmunomoduladores. El tratamiento de la encefalopatía de Hashimoto tiene dos objetivos: controlar el proceso autoinmune y controlar las complicaciones de la enfermedad. Aunque en la mayoría de los casos la recuperación es completa con el tratamiento, el riesgo de recaídas puede oscilar entre 12,5 a 40% en seguimientos a dos años.
Assuntos
Autoanticorpos/imunologia , Encefalite/terapia , Doença de Hashimoto/terapia , Fatores Imunológicos/uso terapêutico , Encefalite/diagnóstico , Encefalite/fisiopatologia , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/fisiopatologia , Humanos , Recidiva , Resultado do TratamentoRESUMO
Alzheimer's disease (AD) is the main form of dementia in the elderly and affects greater than 47 million people worldwide. Care for AD patients poses very significant personal and economic demands on individuals and society, and the situation is expected to get even more dramatic in the coming decades unless effective treatments are found to halt the progression of the disease. Although AD is most commonly regarded as a disease of the memory, the entire brain is eventually affected by neuronal dysfunction or neurodegeneration, which brings about a host of other behavioral disturbances. AD patients often present with apathy, depression, eating and sleeping disorders, aggressive behavior, and other non-cognitive symptoms, which deeply affect not only the patient but also the caregiver's health. These symptoms are usually associated with AD pathology but are often neglected as part of disease progression due to the early and profound impact of disease on memory centers such as the hippocampus and entorhinal cortex. Yet, a collection of findings offers biochemical insight into mechanisms underlying non-cognitive symptoms in AD, and indicate that, at the molecular level, such symptoms share common mechanisms. Here, we review evidence indicating mechanistic links between memory loss and non-cognitive symptoms of AD. We highlight the central role of the pro-inflammatory activity of microglia in behavioral alterations in AD patients and in experimental models of the disease. We suggest that a deeper understanding of non-cognitive symptoms of AD may illuminate a new beginning in AD research, offering a fresh approach to elucidate mechanisms involved in disease progression and potentially unveiling yet unexplored therapeutic targets.
Assuntos
Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Cognição , Encefalite/fisiopatologia , Encefalite/psicologia , Doença de Alzheimer/terapia , Animais , Cognição/fisiologia , Encefalite/terapia , HumanosRESUMO
Diet-induced obesity (DIO) is associated with chronic, low-grade inflammation in the hypothalamus, a key regulator of energy homeostasis. Current studies have revealed the involvement of different cell types, as well as cell and molecular mechanisms, that contribute to diet-induced hypothalamic inflammation (DIHI) and DIO. Subsequent to the discovery that high-fat diet and saturated fatty acids increase the expression of hypothalamic cytokines prior to weight gain, research has focused on understanding the cellular and molecular mechanisms underlying these changes, in addition to the role of inflammation in the pathogenesis of obesity. Recent studies have proposed that the inhibition of pro-inflammatory pathways in microglia and astrocytes is sufficient to protect against DIHI and prevent obesity. In addition, impairment of intracellular and epigenetic mechanisms, such as hypothalamic autophagy and changes in the methylation pattern of certain genes, have been implicated in susceptibility to DIHI and DIO. Interestingly, a sexual dimorphism has been found during DIO in hypothalamic inflammation, glial activation and metabolic diseases, and recent data support an important role of sex steroids in DIHI. These new exciting findings uncover novel obesity pathogenic mechanisms and provide targets to develop therapeutic approaches.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Encefalite/fisiopatologia , Hipotálamo/fisiopatologia , Neuroglia/fisiologia , Neurônios/fisiologia , Obesidade/fisiopatologia , Animais , Autofagia , Encefalite/complicações , Encefalite/etiologia , Epigenômica , Humanos , Obesidade/complicações , Obesidade/etiologiaRESUMO
Autoimmune encephalitis (AIE) is one of the most common causes of noninfectious encephalitis. It can be triggered by tumors, infections, or it may be cryptogenic. The neurological manifestations can be either acute or subacute and usually develop within six weeks. There are a variety of clinical manifestations including behavioral and psychiatric symptoms, autonomic disturbances, movement disorders, and seizures. We reviewed common forms of AIE and discuss their diagnostic approach and treatment.
Assuntos
Encefalite/diagnóstico , Encefalite/terapia , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/terapia , Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Diagnóstico Diferencial , Encefalite/etiologia , Encefalite/fisiopatologia , Feminino , Doença de Hashimoto/etiologia , Doença de Hashimoto/fisiopatologia , Humanos , Imunoterapia , MasculinoRESUMO
ABSTRACT Autoimmune encephalitis (AIE) is one of the most common causes of noninfectious encephalitis. It can be triggered by tumors, infections, or it may be cryptogenic. The neurological manifestations can be either acute or subacute and usually develop within six weeks. There are a variety of clinical manifestations including behavioral and psychiatric symptoms, autonomic disturbances, movement disorders, and seizures. We reviewed common forms of AIE and discuss their diagnostic approach and treatment.
RESUMO As encefalites autoimunes (EAI) são a principal causa de encefalite não-infecciosa. As manifestações neurológicas são variadas, incluindo alterações comportamentais ou psiquiátricas, disautonomia, transtornos do movimento e epilepsia. Habitualmente a instalação dos sintomas ocorre em até 6 semanas, de forma aguda ou subaguda. As EAI podem ser desencadeadas por tumores, quadros infecciosos virais ou ainda apresentar etiologia criptogênica. Este artigo revisa as principais EAI, estratégias de diagnóstico e tratamento.