RESUMEN
The present study employed a randomized crossover design to investigate the effect of strength-training exercise at varying intensities on acute changes in plasma brain-derived neurotrophic factor (BDNF) levels. Fourteen trained male subjects (41.0±5.8 years old) were enrolled in the current study. The strength-training protocol included bench press, leg press, and lat pull-down exercises. Participants performed four sets with repetition failure at 60% or 80% of their one-repetition maximum (1RM), with a two-minute rest period. The order of intensity was randomized among volunteers. Blood samples were collected before, immediately after, and one hour after each exercise protocol. A time-point comparison revealed that a single session of strength training at 60% of 1RM increased lactate plasma concentrations from 1.2 to 16 mmol/L (p<0.0001). However, no significant changes were observed in the plasma BDNF concentration. Conversely, the training session at 80% of 1RM increased lactate concentrations from 1.3 to 14 mmol/L (p<0.0001) and BDNF concentrations from 461 to 1730 pg/ml (p=0.035) one hour after the session's conclusion. These findings support the hypothesis that a single strength-training session at 80% 1RM can significantly enhance circulating levels of BDNF.
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Entrenamiento de Fuerza , Adulto , Humanos , Masculino , Persona de Mediana Edad , Factor Neurotrófico Derivado del Encéfalo , Ejercicio Físico , Ácido Láctico , Fuerza Muscular , Músculo Esquelético , Entrenamiento de Fuerza/métodos , DescansoRESUMEN
OBJECTIVE AND DESIGN: The present study aimed to investigate the neurochemical and behavioral effects of the acute consequences after coronavirus infection through a murine model. MATERIAL: Wild-type C57BL/6 mice were infected intranasally (i.n) with the murine coronavirus 3 (MHV-3). METHODS: Mice underwent behavioral tests. Euthanasia was performed on the fifth day after infection (5 dpi), and the brain tissue was subjected to plaque assays for viral titration, ELISA, histopathological, immunohistochemical and synaptosome analysis. RESULTS: Increased viral titers and mild histological changes, including signs of neuronal degeneration, were observed in the cerebral cortex of infected mice. Importantly, MHV-3 infection induced an increase in cortical levels of glutamate and calcium, which is indicative of excitotoxicity, as well as increased levels of pro-inflammatory cytokines (IL-6, IFN-γ) and reduced levels of neuroprotective mediators (BDNF and CX3CL1) in the mice brain. Finally, behavioral analysis showed impaired motor, anhedonia-like and anxiety-like behaviors in animals infected with MHV-3. CONCLUSIONS: In conclusion, the data presented emulate many aspects of the acute neurological outcomes seen in patients with COVID-19. Therefore, this model may provide a preclinical platform to study acute neurological sequelae induced by coronavirus infection and test possible therapies.
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COVID-19 , Virus de la Hepatitis Murina , Humanos , Animales , Ratones , Ratones Endogámicos C57BL , Virus de la Hepatitis Murina/metabolismo , Citocinas/metabolismo , COVID-19/patología , Encéfalo/metabolismoRESUMEN
Traumatic brain injury (TBI) is a serious public health problem, affecting 69 million people worldwide annually. Mild TBI (mTBI) comprises the majority of the cases and remains the most neglected TBI severity. Its intricate pathophysiology involves complex cellular and molecular processes that remain uncomprehended. Although the renin-angiotensin system (RAS) has its well-known roles in blood pressure regulation and fluid balance, accumulating evidence demonstrates its active expression and signaling in the central nervous system. Over the past years, pre-clinical studies have been supporting the role of RAS in mTBI. However, particularly for human TBI, evidence is still missing. Herein, we investigated peripheral levels of angiotensin II (Ang II) and angiotensin-converting enzyme (ACE), components of RAS classical axis, as well as angiotensin-(1-7) [Ang-(1-7)] and ACE2, components of RAS counter-regulatory axis, in 28 mTBI patients and 24 healthy controls. In the first 24 h, mTBI patients displayed lower ACE (p = 0.0004) and ACE2 (p = 0.0047) concentrations and an increase in Ang II (p = 0.0234) and Ang-(1-7) (p = 0.0225) levels compared to controls. Interestingly, at 30 days follow-up, mTBI patients increased the levels of ACE (p = 0.0415) and ACE2 (p = 0.0416) along with a decrease in Ang II (p = 0.0039) and Ang-(1-7) (p = 0.0015) concentrations compared with their measures at 24 h after TBI. Also, our receiver operating curve (ROC) analysis demonstrated that ACE concentration was a good predictor of mTBI diagnosis (AUC = 0.798, p < 0.0001). The current study provides the first clinical evidence of RAS molecule's involvement in mTBI and their possible role as discriminating biomarkers.
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Conmoción Encefálica , Sistema Renina-Angiotensina , Angiotensina II/metabolismo , Enzima Convertidora de Angiotensina 2 , Presión Sanguínea , Humanos , Fragmentos de Péptidos , Peptidil-Dipeptidasa A/metabolismo , Sistema Renina-Angiotensina/fisiologíaRESUMEN
Traumatic brain injury (TBI) is the main cause of pediatric trauma death and disability worldwide. Recent studies have sought to identify biomarkers of TBI for the purpose of assessing functional outcomes. The aim of this systematic review was to evaluate the utility of TBI biomarkers in the pediatric population by summarizing recent findings in the medical literature. A total of 303 articles were retrieved from our search. An initial screening to remove duplicate studies yielded 162 articles. After excluding all articles that did not meet the inclusion criteria, 56 studies were gathered. Among the 56 studies, 36 analyzed serum biomarkers; 11, neuroimaging biomarkers; and 9, cerebrospinal fluid (CSF) biomarkers. Most studies assessed biomarkers in the serum, reflecting the feasibility of obtaining blood samples compared to obtaining CSF or performing neuroimaging. S100B was the most studied serum biomarker in TBI, followed by SNE and UCH-L1, whereas in CSF analysis, there was no unanimity. Among the different neuroimaging techniques employed, diffusion tensor imaging (DTI) was the most common, seemingly holding diagnostic power in the pediatric TBI clinical setting. The number of cross-sectional studies was similar to the number of longitudinal studies. Our data suggest that S100B measurement has high sensitivity and great promise in diagnosing pediatric TBI, ideally when associated with head CT examination and clinical decision protocols. Further large-scale longitudinal studies addressing TBI biomarkers in children are required to establish more accurate diagnostic protocols and prognostic tools.
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Lesiones Traumáticas del Encéfalo , Imagen de Difusión Tensora , Biomarcadores , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Niño , Estudios Transversales , Humanos , PronósticoRESUMEN
The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington's disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside a decrease in the levels and activity of the components of the RAS alternative axis ACE2, Ang-(1-7), and Mas receptors in the striatum, prefrontal cortex, and hippocampus. BACHD mice also displayed a significant increase in mRNA expression of the AT1 receptor, a component of the RAS classical arm, in these key brain regions. Moreover, patients with manifest HD presented higher plasma levels of Ang-(1-7). No significant changes were found in the levels of ACE, ACE2, and Ang II. Our findings provided the first evidence that an imbalance in the RAS classical and counter-regulatory arms may play a role in HD pathophysiology.
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Angiotensina I , Enzima Convertidora de Angiotensina 2 , Enfermedad de Huntington , Fragmentos de Péptidos , Receptor de Angiotensina Tipo 1 , Sistema Renina-Angiotensina , Angiotensina I/genética , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Animales , Modelos Animales de Enfermedad , Humanos , Enfermedad de Huntington/genética , Ratones , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologíaRESUMEN
Sickle cell anemia (SCA) is an important cause of chronic kidney disease, but its pathophysiology is not completely understood. The aim of this study was to compare inflammatory biomarkers in urine samples of SCA children with and without albuminuria, and to explore correlations with renin-angiotensin system (RAS) molecules. A cross-sectional study of 213 children selected from the Minas Gerais state cohort were assigned to two groups: Group 1-89 children with SCA who had albuminuria; Group 2-124 children with SCA and normal albuminuria matched by age and sex with group 1. A subset of 89 children was prospectively followed for a median time of 1.1â¯year. Inflammatory biomarkers (chemokines and cytokines) in urine were measured using cytometric beads array, and RAS molecules were measured by ELISA. Children with albuminuria had significantly higher urinary levels of IP-10/CXCL10, MCP-1/CCL2, MIG/CXCL9, IL-8/CXCL8, IL-12p70, TNF, IL-10, and IL-6 than patients with normal albuminuria. In the correlation analysis, albumin/creatinine ratio was significantly and positively correlated with IP-10/CXCL10, MCP-1/CCL2, MIG/CXCL9, IL-8/CXCL8, TNF, IL-10, and IL-6. Significant correlations were found between inflammatory and RAS molecules. In the prospective analysis, cumulative risk of persistent albuminuria was higher for children with urinary levels of IP-10/CXCL10 or IL-6 above the 50th percentile. Our data showed that inflammatory markers and RAS molecules might contribute to the occurrence of albuminuria in children with SCA, suggesting that both pathways interact in sickle cell nephropathy.
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Albuminuria/metabolismo , Anemia de Células Falciformes/metabolismo , Quimiocinas/orina , Citocinas/orina , Enfermedades Renales/metabolismo , Sistema Renina-Angiotensina , Adolescente , Biomarcadores/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Niño , Preescolar , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Lactante , Inflamación/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Estudios Prospectivos , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
Ischemic stroke represents a major cause of adult death and severe neurological disability worldwide. Reperfusion following brain ischemia produces an inflammatory cascade that increases brain damage. In this context, matrix metalloproteinases (MMPs) play an important role as pro-inflammatory mediators. The MMP 2 up-regulation seems to promote matrix degradation, blood-brain barrier (BBB) disruption and facilitates the influx of peripheral inflammatory cells to the brain after stroke. However, there are not studies about MMP-1 in this condition. The aim of this study is to evaluate the association of brain damage, inflammatory response and the immunostaining profile of matrix metalloproteinases 1 and 2 after transient global cerebral ischemia. Mice were submitted to bilateral common carotid arterial occlusion (BCCAo) during 25 min. After three days of reperfusion, the neurological deficit score was evaluated and the animals were euthanized. Brain samples were collected in order to analyze the histopathological damage, MMPs 1 and 2 immunostaining and cytokines and chemokines levels. Ischemic group showed neurological deficits associated with brain lesions, characterized by necrotic core and penumbra zone three days after reperfusion. Higher brain immunostaining of MMP-1 and MMP-2 was observed in BCCAo samples than in sham samples. Ischemic group also exhibited increased brain levels of the cytokines tumoral necrosis factor (TNF) and interleukin 1ß (IL-1ß), chemokine (C-X-C motif) ligand 1 (CXCL1), and chemokine (C-C motif) ligand 5 (CCL5) in comparison to sham group. Our results suggest that the MMP-1 and MMP-2 raise, associated with the up-regulation of inflammatory mediators, contributes to brain damage and neurological deficits after global brain ischemia followed by three days of reperfusion in mice.
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Encéfalo/enzimología , Citocinas/metabolismo , Ataque Isquémico Transitorio/enzimología , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Animales , Encéfalo/patología , Encéfalo/fisiopatología , Quimiocina CCL5/metabolismo , Quimiocina CXCL1/metabolismo , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Ataque Isquémico Transitorio/patología , Ataque Isquémico Transitorio/fisiopatología , Masculino , Ratones Endogámicos C57BL , Necrosis , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
Chagas disease (CD) is a tropical zoonosis caused by the protozoan Trypanosoma cruzi. Severe autonomic dysfunction like reduced cardiac catecholamine-containing or acetylcholinesterase-positive innervation have been reported in CD. Renin-angiotensin system (RAS) seems to participate in the regulation of adrenal catecholamine secretion by adrenal medullary chromaffin cells, which might be dependent of nitric oxide (NO) pathways. To investigate the levels of RAS components in the adrenal gland during the acute infection with Y strain T. cruzi and in response to acute administration of an inhibitor of the enzyme NO synthase, L-NAME. Male Holtzman rats were inoculated intraperitoneally with Y strain T. cruzi and received L-NAME or tap water from one day before the infection until 13 or 17 days post-inoculation (dpi). The concentration of RAS molecules in the adrenal tissue was evaluated by ELISA immunoassay. Angiotensin converting enzyme 1 (ACE1) levels were significantly lower at 17 dpi when compared to 13 dpi. No significant differences were found compared with baseline, and no changes were detected in adrenal tissue levels of angiotensin converting enzyme 2 (ACE2), angiotensin II, or angiotensin-(1-7). Moreover, the treatment with L-NAME did not influence the levels of RAS components in adrenal tissue during the course of T. cruzi infection. We provided the first evidence that levels of RAS molecules change in the adrenal gland during acute phase of T. cruzi infection. Future studies are necessary to fully address the role of NO in RAS-associated adrenal gland function in CD.
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Glándulas Suprarrenales/metabolismo , Enfermedad de Chagas/metabolismo , Óxido Nítrico/metabolismo , Sistema Renina-Angiotensina/fisiología , Trypanosoma cruzi/fisiología , Animales , Modelos Animales de Enfermedad , Masculino , NG-Nitroarginina Metil Éster/administración & dosificación , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
CONTEXT: Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neuronal survival, differentiation, and maturation. PURPOSE: To evaluate the levels of BDNF in the acute phase of stroke and their potential association with neurological impairment. METHODS: Patients in the acute phase of ischemic stroke were evaluated with the following clinical tools: National Institutes of Health Stroke Scale, modified Rankin scale, Gugging Swallowing Screen and Alberta Stroke Program Early CT Score. Blood samples were collected at 3 different moments of hospital stay. BDNF was measured through enzyme-linked immunosorbent assay. RESULTS: Patients who were discharged after 10 days had worse clinical outcomes and higher levels of BDNF since admission. There was correlation between BDNF levels and clinical parameters. CONCLUSION: BDNF levels were associated with clinical prognosis in the acute phase of ischemic stroke.
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Isquemia Encefálica/sangre , Factor Neurotrófico Derivado del Encéfalo/sangre , Accidente Cerebrovascular/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/fisiopatología , Deglución , Evaluación de la Discapacidad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Pronóstico , Recuperación de la Función , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/fisiopatología , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Epidemiologic data suggest that individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing neuropsychiatric disorders, cognitive impairment, and dementia. This risk is generally explained by the high prevalence of both symptomatic and subclinical ischemic cerebrovascular lesions. However, other potential mechanisms, including cytokine/chemokine release, production of reactive oxygen species (ROS), circulating and local formation of trophic factors and of renin-angiotensin system (RAS) molecules, could also be involved, especially in the absence of obvious cerebrovascular disease. In this review, we discuss experimental and clinical evidence for the role of these mechanisms in kidney-brain cross-talk. In addition, we hypothesize potential pathways for the interactions between kidney and brain and their pathophysiological role in neuropsychiatric and cognitive changes found in patients with CKD. Understanding the pathophysiologic interactions between renal impairment and brain function is important in order to minimize the risk for future cognitive impairment and to develop new strategies for innovative pharmacological treatment.
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Mediadores de Inflamación/metabolismo , Trastornos Neurocognitivos/etiología , Insuficiencia Renal Crónica/psicología , Encéfalo/inmunología , Citocinas/metabolismo , Humanos , Riñón/inmunología , Trastornos Neurocognitivos/inmunología , Estrés Oxidativo/fisiología , Insuficiencia Renal Crónica/inmunología , Sistema Renina-Angiotensina/fisiologíaRESUMEN
OBJECTIVE: Changes in immune system have been reported in schizophrenia. This study aimed to evaluate the involvement of IL-33, a member of the IL-1 cytokine family, in schizophrenia and its association with cognitive performance in these patients. METHODS: Forty patients with chronic schizophrenia and 40 healthy subjects participated in the study. Serum levels of IL-33 and sST2 (soluble form of the IL-33 receptor) were measured using enzyme-linked immunosorbent assay (ELISA). Patients were evaluated with the Brief Assessment of Cognition in Schizophrenia (BACS) and the Schizophrenia Cognition Rating Scale (SCoRS). RESULTS: Patients with schizophrenia and controls presented similar serum levels of IL-33 and sST2. Levels of both markers were positively correlated with cognitive performance in patients with schizophrenia. CONCLUSION: We found a significant correlation between IL-33 and sST2 levels and cognition in schizophrenia. Our results might help in the understanding of how immune markers are associated with cognitive impairment in schizophrenia. It remains to be determined whether the association between IL-33/sST2 and cognition is restricted to patients with schizophrenia.
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Trastornos del Conocimiento/sangre , Trastornos del Conocimiento/psicología , Proteína 1 Similar al Receptor de Interleucina-1/sangre , Interleucina-33/sangre , Esquizofrenia/sangre , Psicología del Esquizofrénico , Adulto , Biomarcadores/sangre , Cognición/fisiología , Trastornos del Conocimiento/diagnóstico , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esquizofrenia/diagnósticoRESUMEN
The inflammatory response plays a crucial role in infectious diseases, and the intestinal microbiota is linked to maturation of the immune system. However, the association between microbiota and the response against fungal infections has not been elucidated. Our aim was to evaluate the influence of microbiota on Cryptococcus gattii infection. Germ-free (GF), conventional (CV), conventionalized (CVN-mice that received feces from conventional animals), and LPS-stimulated mice were infected with C. gattii. GF mice were more susceptible to infection, showing lower survival, higher fungal burden in the lungs and brain, increased behavioral changes, reduced levels of IFN-γ, IL-1ß and IL-17, and lower NFκBp65 phosphorylation compared to CV mice. Low expression of inflammatory cytokines was associated with smaller yeast cells and polysaccharide capsules (the main virulence factor of C. gattii) in the lungs, and less tissue damage. Furthermore, macrophages from GF mice showed reduced ability to engulf, produce ROS, and kill C. gattii. Restoration of microbiota (CVN mice) or LPS administration made GF mice more responsive to infection, which was associated with increased survival and higher levels of inflammatory mediators. This study is the first to demonstrate the influence of microbiota in the host response against C. gattii.
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Criptococosis/inmunología , Criptococosis/patología , Cryptococcus gattii/inmunología , Susceptibilidad a Enfermedades , Microbioma Gastrointestinal/inmunología , Inflamación/patología , Animales , Proteínas Reguladoras de la Apoptosis , Encéfalo/microbiología , Encéfalo/patología , Recuento de Colonia Microbiana , Citocinas/metabolismo , Modelos Animales de Enfermedad , Vida Libre de Gérmenes , Pulmón/microbiología , Pulmón/patología , Macrófagos/inmunología , Ratones , Fagocitosis , Receptores Inmunológicos , Receptores Depuradores , Análisis de Supervivencia , Proteína del Síndrome de Wiskott-AldrichRESUMEN
Establishing prevention and therapeutic strategies for osteoarthritis (OA) is necessary to minimize functional disability and the impact of the disease on society. The aim of this study was to determine the effects of an exercise therapy protocol on inflammatory markers, perception of pain, and physical performance in individuals with OA of the knee. The protocol consisted of flexibility training and muscle strengthening over 12 weeks with three 80-min sessions per week. Peripheral blood was collected to determine serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and soluble forms of the TNF-α receptor (sTNFR1 and sTNFR2). A clinical assessment of the musculoskeletal system and Western Ontario and McMaster Universities (WOMAC) questionnaire were applied to evaluate the specific symptoms of knee OA. Pain intensity was evaluated using a visual analog scale (VAS). All measurements were taken before and after the intervention. Twenty-two individuals (mean age 58.8 ± 6.4 years) completed the protocol. A decrease in the perception of pain was evident on VAS (p < 0.001) and pain subscale of the WOMAC (p < 0.001). In addition, there was a reduction in serum levels of IL-6 (p < 0.001). However, changes in the levels of the TNF-α and its soluble receptors were not statistically significant. Physical function subscale score and the WOMAC global score improved significantly (p < 0.001). The training also promoted an increase in the progression load for all muscles groups analyzed (p < 0.001). Our data suggest that the exercise therapy protocol could be a strategy for reducing IL-6 levels, managing pain, and improving function in individuals with OA of the knee. However, more studies are necessary to investigate the issue.
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Artralgia/rehabilitación , Terapia por Ejercicio/métodos , Osteoartritis de la Rodilla/rehabilitación , Entrenamiento de Fuerza/métodos , Anciano , Artralgia/fisiopatología , Biomarcadores , Femenino , Humanos , Interleucina-6/inmunología , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/inmunología , Osteoartritis de la Rodilla/fisiopatología , Dimensión del Dolor , Estudios Prospectivos , Rango del Movimiento Articular , Receptores Tipo I de Factores de Necrosis Tumoral/inmunología , Receptores Tipo II del Factor de Necrosis Tumoral/inmunología , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
INTRODUCTION: Inflammasome complexes, especially NLRP3, have gained great attention as a potential therapeutic target in mood disorders. NLRP3 triggers a caspase 1-dependent release of the inflammatory cytokines IL-1ß and IL-18, and seems to interact with purinergic and kynurenine pathways, all of which are implicated in mood disorders development and progression. AREAS COVERED: Emerging evidence supports NLRP3 inflammasome as a promising pharmacological target for mood disorders. We discussed the available evidence from animal models and human studies and provided a reflection on drawbacks and perspectives for this novel target. EXPERT OPINION: Several studies have supported the involvement of NLRP3 inflammasome in MDD. However, most of the evidence comes from animal models. The role of NLRP3 inflammasome in BD as well as its anti-manic properties is not very clear and requires further exploration. There is evidence of anti-manic effects of P2×R7 antagonists associated with reduction in the brain levels of IL-1ß and TNF-α in a murine model of mania. The involvement of other NLRP3 inflammasome expressing cells besides microglia, like astrocytes, and of other inflammasome complexes in mood disorders also deserves further investigation. Preclinical and clinical characterization of NLRP3 and other inflammasomes in mood disorders is needed before considering translational approaches, including clinical trials.
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Modelos Animales de Enfermedad , Inflamasomas , Terapia Molecular Dirigida , Trastornos del Humor , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Trastornos del Humor/tratamiento farmacológico , Trastornos del Humor/fisiopatología , Ratones , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/fisiopatología , Antagonistas del Receptor Purinérgico P2X/farmacología , Antagonistas del Receptor Purinérgico P2X/administración & dosificación , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/fisiopatologíaRESUMEN
BACKGROUND: Neuropsychiatric disorders, such as mood disorders, schizophrenia, and Alzheimer's disease (AD) and related dementias, are associated to significant morbidity and mortality worldwide. The pathophysiological mechanisms of neuropsychiatric disorders remain to be fully elucidated, which has hampered the development of effective therapies. The Renin Angiotensin System (RAS) is classically viewed as a key regulator of cardiovascular and renal homeostasis. The discovery that RAS components are expressed in the brain pointed out a potential role for this system in central nervous system (CNS) pathologies. The understanding of RAS involvement in the pathogenesis of neuropsychiatric disorders may contribute to identifying novel therapeutic targets. AIMS: We aim to report current experimental and clinical evidence on the role of RAS in physiology and pathophysiology of mood disorders, schizophrenia, AD and related dementias. We also aim to discuss bottlenecks and future perspectives that can foster the development of new related therapeutic strategies. CONCLUSION: The available evidence supports positive therapeutic effects for neuropsychiatric disorders with the inhibition/antagonism of the ACE/Ang II/AT1 receptor axis or the activation of the ACE2/Ang-(1-7)/Mas receptor axis. Most of this evidence comes from pre-clinical studies and clinical studies lag much behind, hampering a potential translation into clinical practice.
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Enfermedad de Alzheimer , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/fisiología , Peptidil-Dipeptidasa A/metabolismo , Peptidil-Dipeptidasa A/uso terapéutico , Riñón/metabolismo , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Sistema Nervioso Central/metabolismoRESUMEN
The factor RasGEF1b is a Ras guanine exchange factor involved in immune responses. Studies have also implicated RasGEF1b in the CNS development. It is still limited the understanding of the role of RasGEF1b in CNS functioning. Using RasGEF1b deficient mice (RasGEF1b-cKO), we investigated the impact of this gene deletion in behavior, cognition, brain neurochemistry and microglia morphology. We showed that RasGEF1b-cKO mice display spontaneous hyperlocomotion and anhedonia. RasGEF1b-cKO mice also exhibited compulsive-like behavior that was restored after acute treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (5 mg/kg). A down-regulation of mRNA of dopamine receptor (Drd1, Drd2, Drd4 and Drd5) and serotonin receptor genes (5Htr1a, 5Htr1b and 5Htr1d) was observed in hippocampus of RasGEF1b-cKO mice. These mice also had reduction of Drd1 and Drd2 in prefrontal cortex and 5Htr1d in striatum. In addition, morphological alterations were observed in RasGEF1b deficient microglia along with decreased levels of hippocampal BDNF. We provided original evidence that the deletion of RasGEF1b leads to unique behavioral features, implicating this factor in CNS functioning.
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Encéfalo , Inhibidores Selectivos de la Recaptación de Serotonina , Animales , Ratones , Cognición , Fluoxetina/farmacología , Corteza Prefrontal , Receptores de Dopamina D5RESUMEN
CXCL12 is a key chemokine implicated in neuroinflammation, particularly during Zika virus (ZIKV) infection. Specifically, CXCL12 is upregulated in circulating cells of ZIKV infected patients. Here, we developed a lipid nanoparticle (LNP) to deliver siRNA in vivo to assess the impact of CXCL12 silencing in the context of ZIKV infection. The biodistribution of the LNP was assessed in vivo after intravenous injection using fluorescently tagged siRNA. Next, we investigated the ability of the developed LNP to silence CXCL12 in vivo and assessed the resulting effects in a murine model of ZIKV infection. The LNP encapsulating siRNA significantly inhibited CXCL12 levels in the spleen and induced microglial activation in the brain during ZIKV infection. This activation was evidenced by the enhanced expression of iNOS, TNF-α, and CD206 within microglial cells. Moreover, T cell subsets exhibited reduced secretion of IFN-É£ and IL-17 following LNP treatment. Despite no observable alteration in viral load, CXCL12 silencing led to a significant reduction in type-I interferon production compared to both ZIKV-infected and uninfected groups. Furthermore, we found grip strength deficits in the group treated with siRNA-LNP compared to the other groups. Our data suggest a correlation between the upregulated pro-inflammatory cytokines and the observed decrease in strength. Collectively, our results provide evidence that CXCL12 silencing exerts a regulatory influence on the immune response in the brain during ZIKV infection. In addition, the modulation of T-cell activation following CXCL12 silencing provides valuable insights into potential protective mechanisms against ZIKV, offering novel perspectives for combating this infection.
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Infección por el Virus Zika , Virus Zika , Humanos , Ratones , Animales , ARN Interferente Pequeño , Distribución Tisular , Encéfalo , Inmunidad , Quimiocina CXCL12/genéticaRESUMEN
Recent evidence has supported a pathogenic role for neuroinflammation in Parkinson's disease (PD). Inflammatory response has been associated with symptoms and subtypes of PD. However, it is unclear whether immune changes are involved in the initial pathogenesis of PD, leading to the non-motor symptoms (NMS) observed in its prodromal stage. The current study aimed to characterize the behavioral and cognitive changes in a toxin-induced model of prodromal PD-like syndrome. We also sought to investigate the role of neuroinflammation in prodromal PD-related NMS. Male mice were subjected to bilateral intranasal infusion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or saline (control group), followed by comprehensive behavioral, pathological and neurochemical analysis. Intranasal MPTP infusion was able to cause the loss of dopaminergic neurons in the substantia nigra (SN). In parallel, it induced impairment in olfactory discrimination and social memory consolidation, compulsive and anxiety-like behaviors, but did not influence motor performance. Iba-1 and GFAP expressions were increased in the SN, suggesting an activated state of microglia and astrocytes. Consistent with this, MPTP mice had increased levels of IL-10 and IL-17A, and decreased levels of BDNF and TrkA mRNA in the SN. The striatum showed increased IL-17A, BDNF, and NFG levels compared to control mice. In conclusion, neuroinflammation may play an important role in the early stage of experimental PD-like syndrome, leading to cognitive and behavioral changes. Our results also indicate that intranasal administration of MPTP may represent a valuable mouse model for prodromal PD.
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Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Síntomas Prodrómicos , Sustancia Negra , Animales , Masculino , Sustancia Negra/metabolismo , Sustancia Negra/patología , Sustancia Negra/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Enfermedades Neuroinflamatorias/patología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Ratones , Microglía/metabolismo , Microglía/patología , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ansiedad/etiología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacologíaRESUMEN
BACKGROUND: The neuroinflammatory response aimed at clearance of herpes simplex virus-1 (HSV-1) plays a key role in the pathogenesis of neuroaxonal damage in herpetic encephalitis. Leukocytes activated in an adaptive immune response access brain tissue by passing through the blood-brain barrier. The chemokine CCL5/RANTES is involved in recruitment of these cells to the brain acting via the receptors CCR1, CCR3 and mainly CCR5. Here, we evaluated the role of CCR5 on traffic of leukocytes in the brain microvasculature, cellular and cytokines profile in a severe form of herpetic encephalitis. RESULTS: Wild type and mice lacking CCR5 (CCR5-/-) were inoculated intracerebrally with 104 PFU of neurotropic HSV-1. We evaluated the traffic of leukocytes in the brain microvasculature using intravital microscopy and the profile of cytokines by Enzyme-Linked Immunosorbent Assay at 1 day post infection. Flow cytometry and histopathological analyses were also carried out in brain tissue. Absence of CCR5 leads to lower viral load and an increased leukocyte adhesion in brain microvasculature, predominantly of neutrophils (CD11+ Ly6G+ cells). Moreover, there was a significant increase in the levels of MIP-1/CCL2, RANTES/CCL5, KC/CXCL1 and MIG/CXCL9 in the brain of infected CCR5-/- mice. CONCLUSIONS: These results suggest that the absence of CCR5 may boost the immune response with a high neutrophil recruitment which most likely helps in viral clearance. Nonetheless, the elevated immune response may be detrimental to the host.
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Encefalitis por Herpes Simple/inmunología , Encefalitis por Herpes Simple/patología , Regulación de la Expresión Génica/genética , Infiltración Neutrófila/fisiología , Receptores CCR5/deficiencia , Animales , Antígenos Ly/metabolismo , Encéfalo/inmunología , Encéfalo/patología , Encéfalo/virología , Adhesión Celular/genética , Adhesión Celular/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/genética , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Leucocitos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR5/genéticaRESUMEN
Recent evidence has suggested that inflammatory and immune mechanisms may play a role in the pathophysiology of bipolar disorder (BD). Only a few studies have assessed the profile of chemokines, a family of chemotactic cytokines related to the recruitment of leukocytes, in BD. The objective of our study was to evaluate the plasma levels of chemokines in BD patients in different mood states in comparison with healthy controls. Seventy BD type I patients (35 in euthymia and 35 in mania), and 50 healthy controls matched by age, gender, and education level were enrolled in this study. All subjects were assessed by the Mini-International Neuropsychiatry Interview and the patients by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. The plasma levels of CCL2, CCL3, CCL11, CCL24, CXCL8, and CXCL10 were measured by enzyme-linked immunosorbent assay. BD patients presented higher plasma levels of CCL11 (1.69-fold increase; p < 0.001), CCL24 (1.40-fold increase; p = 0.02), CXCL10 (1.45-fold increase; p < 0.001) and decreased plasma levels of CXCL8 (8.68-fold decrease p < 0.001). Logistic regression stressed the main effect of increased plasma levels of CXCL10 (OR = 1.009, 95 % CI = 1.000-1.018, p = 0.042) and CCL11 (OR = 1.002, 95 % CI = 1.001-1.003, p = 0.003) and decreased plasma levels of CXCL8 (OR = 0.995, 95 % CI = 0.990-0.999, p = 0.013) to BD. This study reinforces the view that BD is associated with an immune dysfunction.