RESUMEN
Glutaric acidemia type I (GA1) is caused by severe deficiency of glutaryl-CoA dehydrogenase activity, resulting in an accumulation of glutaric acid and glutarylcarnitine (C5DC) in the organism. Patients affected by GA1 are asymptomatic in the neonate period but usually manifest chronically progressive neurodegeneration apart from severe encephalopathic crises associated with acute striatum necrosis. Neurological manifestations like dyskinesia, dystonia, hypotonia, muscle stiffness, and spasticity are present. Treatment is based on protein/lysine restriction and l-carnitine supplementation. In this work, we evaluated markers of neurodegeneration and inflammation, namely BDNF (brain-derived neurotrophic factor), NCAM (neuronal adhesion molecule), PDGF-AA (platelet-derived growth factor), and cathepsin-d in plasma of six treated GA1 patients. We first found marked increases of plasma C5DC concentrations in GA1 patients, as well as increased levels of the markers BDNF and cathepsin-d as compared to those of age-matched healthy children. Furthermore, C5DC concentrations were highly correlated with the levels of cathepsin-d. These results may demonstrate that brain tissue degeneration is present in GA1 patients and that there is a relationship between increased metabolites concentrations with this process. To the best of our knowledge, this is so far the first study showing altered peripheral parameters of neurodegeneration and inflammation in GA1 patients.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/sangre , Encefalopatías Metabólicas/sangre , Factor Neurotrófico Derivado del Encéfalo/sangre , Catepsina D/sangre , Glutaril-CoA Deshidrogenasa/deficiencia , Degeneración Nerviosa/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Biomarcadores/sangre , Encefalopatías Metabólicas/complicaciones , Niño , Preescolar , Femenino , Glutaril-CoA Deshidrogenasa/sangre , Humanos , Lactante , Recién Nacido , Masculino , Degeneración Nerviosa/sangre , Degeneración Nerviosa/etiología , Moléculas de Adhesión de Célula Nerviosa/sangre , Factor de Crecimiento Derivado de Plaquetas/metabolismoRESUMEN
BACKGROUND: The inflammatory process has been described as a crucial mechanism in the pathophysiology of temporal lobe epilepsy. The anti-inflammatory protein annexin A1 (ANXA1) represents an interesting target in the regulation of neuroinflammation through the inhibition of leukocyte transmigration and the release of proinflammatory mediators. In this study, the role of the ANXA1-derived peptide Ac2-26 in an experimental model of status epilepticus (SE) was evaluated. METHODS: Male Wistar rats were divided into Naive, Sham, SE and SE+Ac2-26 groups, and SE was induced by intrahippocampal injection of pilocarpine. In Sham animals, saline was applied into the hippocampus, and Naive rats were only handled. Three doses of Ac2-26 (1 mg/kg) were administered intraperitoneally (i.p.) after 2, 8 and 14 h of SE induction. Finally, 24 h after the experiment-onset, rats were euthanized for analyses of neuronal lesion and inflammation. RESULTS: Pilocarpine induced generalised SE in all animals, causing neuronal damage, and systemic treatment with Ac2-26 decreased neuronal degeneration and albumin levels in the hippocampus. Also, both SE groups showed an intense influx of microglia, which was corroborated by high levels of ionised calcium binding adaptor molecule 1(Iba-1) and monocyte chemoattractant protein-1 (MCP-1) in the hippocampus. Ac2-26 reduced the astrocyte marker (glial fibrillary acidic protein; GFAP) levels, as well as interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and growth-regulated alpha protein (GRO/KC). These effects of the peptide were associated with the modulation of the levels of formyl peptide receptor 2, a G-protein-coupled receptor that binds to Ac2-26, and the phosphorylated extracellular signal-regulated kinase (ERK) in the hippocampal neurons. CONCLUSIONS: The data suggest a neuroprotective effect of Ac2-26 in the epileptogenic processes through downregulation of inflammatory mediators and neuronal loss.
Asunto(s)
Anexina A1/uso terapéutico , Citocinas/metabolismo , Degeneración Nerviosa/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Péptidos/uso terapéutico , Estado Epiléptico/complicaciones , Estado Epiléptico/tratamiento farmacológico , Animales , Anexina A1/metabolismo , Anticonvulsivantes/uso terapéutico , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/fisiopatología , Diazepam/uso terapéutico , Modelos Animales de Enfermedad , Gliosis/etiología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Agonistas Muscarínicos/toxicidad , Degeneración Nerviosa/etiología , Degeneración Nerviosa/patología , Proteínas del Tejido Nervioso/metabolismo , Neuroglía/patología , Neuronas/efectos de los fármacos , Pilocarpina/toxicidad , Ratas , Ratas Wistar , Receptores de Lipoxina/metabolismo , Estado Epiléptico/inducido químicamenteRESUMEN
OBJECTIVE: Parkinson's disease (PD) is characterized by deterioration of the nigrostriatal system and associated with chronic neuroinflammation. Glial activation has been associated with regulating the survival of dopaminergic neurons and is thought to contribute to PD through the release of proinflammatory and neurotoxic factors, such as reactive nitric oxide (NO) that triggers or exacerbates neurodegeneration in PD. Polyunsaturated fatty acids (PUFAs) exert protective effects, including antiinflammatory, antiapoptotic, and antioxidant activity, and may be promising for delaying or preventing PD by attenuating neuroinflammation and preserving dopaminergic neurons. The present study investigated the effects of fish oil supplementation that was rich in PUFAs on dopaminergic neuron loss, the density of inducible nitric oxide synthase (iNOS)-immunoreactive cells, and microglia and astrocyte reactivity in the substantia nigra pars compacta (SNpc) and striatal dopaminergic fibers. METHODS: The animals were supplemented with fish oil for 50 days and subjected to unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-induced lesions as a model of PD. RESULTS: Fish oil mitigated the loss of SNpc neurons and nerve terminals in the striatum that was caused by 6-OHDA. This protective effect was associated with reductions of the density of iNOS-immunoreactive cells and microglia and astrocyte reactivity. DISCUSSION: These results suggest that the antioxidant and antiinflammatory properties of fish oil supplementation are closely related to a decrease in dopaminergic damage that is caused by the 6-OHDA model of PD.
Asunto(s)
Ácidos Grasos Omega-3/farmacología , Fármacos Neuroprotectores/farmacología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina , Neuronas Dopaminérgicas/efectos de los fármacos , Aceites de Pescado/farmacología , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/etiología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Oxidopamina , Enfermedad de Parkinson/etiología , Ratas , Ratas WistarRESUMEN
Abstract Introduction: The use of mobile phones has become widespread in recent years. Although beneficial from the communication viewpoint, the electromagnetic fields generated by mobile phones may cause unwanted biological changes in the human body. Objective: In this study, we aimed to evaluate the effects of 2100 MHz Global System for Mobile communication (GSM-like) electromagnetic field, generated by an electromagnetic fields generator, on the auditory system of rats by using electrophysiological, histopathologic and immunohistochemical methods. Methods: Fourteen adult Wistar albino rats were included in the study. The rats were divided randomly into two groups of seven rats each. The study group was exposed continuously for 30 days to a 2100 MHz electromagnetic fields with a signal level (power) of 5.4 dBm (3.47 mW) to simulate the talk mode on a mobile phone. The control group was not exposed to the aforementioned electromagnetic fields. After 30 days, the Auditory Brainstem Responses of both groups were recorded and the rats were sacrificed. The cochlear nuclei were evaluated by histopathologic and immunohistochemical methods. Results: The Auditory Brainstem Responses records of the two groups did not differ significantly. The histopathologic analysis showed increased degeneration signs in the study group (p = 0.007). In addition, immunohistochemical analysis revealed increased apoptotic index in the study group compared to that in the control group (p = 0.002). Conclusion: The results support that long-term exposure to a GSM-like 2100 MHz electromagnetic fields causes an increase in neuronal degeneration and apoptosis in the auditory system.
Resumo Introdução: O uso de telefones celulares tornou-se generalizado nos últimos anos. Embora benéfico do ponto de vista da comunicação, os campos eletromagnéticos gerados por celulares pode causar alterações biológicas indesejáveis no corpo humano. Objetivo: Nesse estudo, o objetivo foi avaliar os efeitos do campo eletromagnético na frequência de 2.100 MHz, similar à modulação do Sistema Global para Comunicações Móveis, produzido por um gerador de campo eletromagnético, sobre o sistema auditivo de ratos usando os métodos eletrofisiológico, histopatológico e imunohistoquímico. Método: Foram incluídos no estudo catorze adultos ratos albinos Wistar. Os ratos foram divididos aleatoriamente em dois grupos de sete animais cada. O grupo de estudo foi exposto continuamente por 30 dias a um campo eletromagnético em 2100 MHz com um nível de sinal (potência) de 5,4 dBm (3,47 miliwatts) para simular o modo de conversação em um celular. O grupo controle não foi exposto ao campo eletromagnético acima mencionado. Após 30 dias, o potencial evocado auditivo de tronco encefálico de ambos os grupos foi gravado e os ratos foram sacrificados. Os núcleos cocleares foram avaliados pelos métodos histopatológico e imunohistoquímico. Resultados: Os registros do potencial evocado auditivo de tronco encefálico dos dois grupos não diferiram significativamente. A análise histopatológica mostrou aumento dos sinais de degeneração no grupo de estudo (p = 0,007). Além disso, a análise imuno-histoquímica revelou aumento do índice de apoptose no grupo de estudo em comparação com o grupo controle (p = 0,002). Conclusão: Os resultados confirmam que a exposição a longo prazo a um campo eletromagnético em 2100 MHz similar à modulação do sistema global para comunicações móveis causa um aumento na degeneração neuronal e apoptose no sistema auditivo.
Asunto(s)
Animales , Masculino , Ondas de Radio/efectos adversos , Núcleo Coclear/efectos de la radiación , Exposición a la Radiación/efectos adversos , Teléfono Celular , Campos Electromagnéticos/efectos adversos , Audición/efectos de la radiación , Valores de Referencia , Factores de Tiempo , Inmunohistoquímica , Factores de Riesgo , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de la radiación , Ratas Wistar , Apoptosis/efectos de la radiación , Núcleo Coclear/patología , Degeneración Nerviosa/etiologíaRESUMEN
The olfactory epithelium (OE) has the remarkable capability to constantly replace olfactory receptor neurons (ORNs) due to the presence of neural stem cells (NSCs). For this reason, the OE provides an excellent model to study neurogenesis and neuronal differentiation. In the present work, we induced neuronal degeneration in the OE of Xenopus laevis larvae by bilateral axotomy of the olfactory nerves. We found that axotomy induces specific- neuronal death through apoptosis between 24 and 48h post-injury. In concordance, there was a progressive decrease of the mature-ORN marker OMP until it was completely absent 72h post-injury. On the other hand, neurogenesis was evident 48h post-injury by an increase in the number of proliferating basal cells as well as NCAM-180- GAP-43+ immature neurons. Mature ORNs were replenished 21 days post-injury and the olfactory function was partially recovered, indicating that new ORNs were integrated into the olfactory bulb glomeruli. Throughout the regenerative process no changes in the expression pattern of the neurotrophin Brain Derivate Neurotrophic Factor were observed. Taken together, this work provides a sequential analysis of the neurodegenerative and subsequent regenerative processes that take place in the OE following axotomy. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1308-1320, 2017.
Asunto(s)
Axotomía , Degeneración Nerviosa/etiología , Degeneración Nerviosa/patología , Mucosa Olfatoria/patología , Traumatismos del Nervio Olfatorio/patología , Regeneración/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Caspasa 3/metabolismo , Diferenciación Celular/fisiología , Proliferación Celular , Proteína GAP-43/metabolismo , Regulación de la Expresión Génica/fisiología , Queratina-2/metabolismo , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Proteína Marcadora Olfativa/metabolismo , Traumatismos del Nervio Olfatorio/etiología , Recuperación de la Función/fisiología , Olfato/fisiología , Factores de Tiempo , Xenopus laevisRESUMEN
BACKGROUND: The mammalian target of rapamycin (mTOR) is a kinase involved in a variety of physiological and pathological functions. However, the exact role of mTOR in excitotoxicity is poorly understood. Here, we investigated the effects of mTOR inhibition with rapamycin against neurodegeneration, and motor impairment, as well as inflammatory profile caused by an excitotoxic stimulus. METHODS: A single and unilateral striatal injection of quinolinic acid (QA) was used to induce excitotoxicity in mice. Rapamycin (250 nL of 0.2, 2, or 20 µM; intrastriatal route) was administered 15 min before QA injection. Forty-eight hours after QA administration, rotarod test was performed to evaluate motor coordination and balance. Fluoro-Jade C, Iba-1, and GFAP staining were used to evaluate neuronal cell death, microglia morphology, and astrocytes density, respectively, at this time point. Levels of cytokines and neurotrophic factors were measured by ELISA and Cytometric Bead Array 8 h after QA injection. Striatal synaptosomes were used to evaluate the release of glutamate. RESULTS: We first demonstrated that rapamycin prevented the motor impairment induced by QA. Moreover, mTOR inhibition also reduced the neurodegeneration and the production of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α induced by excitotoxic stimulus. The lowest dose of rapamycin also increased the production of IL-10 and prevented the reduction of astrocyte density induced by QA. By using an in vitro approach, we demonstrated that rapamycin differently alters the release of glutamate from striatal synaptosomes induced by QA, reducing or enhancing the release of this neurotransmitter at low or high concentrations, respectively. CONCLUSION: Taken together, these data demonstrated a protective effect of rapamycin against an excitotoxic stimulus. Therefore, this study provides new evidence of the detrimental role of mTOR in neurodegeneration, which might represent an important target for the treatment of neurodegenerative diseases.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Ácido Quinolínico/toxicidad , Sirolimus/farmacología , Sirolimus/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Cuerpo Estriado/fisiología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ácido Glutámico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos del Movimiento/tratamiento farmacológico , Trastornos del Movimiento/etiología , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/etiología , Neuroglía/efectos de los fármacos , Neuroglía/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Síndromes de Neurotoxicidad/complicaciones , Equilibrio Postural/efectos de los fármacos , Cloruro de Potasio/farmacología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Sinaptosomas/ultraestructuraRESUMEN
INTRODUCTION: The use of mobile phones has become widespread in recent years. Although beneficial from the communication viewpoint, the electromagnetic fields generated by mobile phones may cause unwanted biological changes in the human body. OBJECTIVE: In this study, we aimed to evaluate the effects of 2100MHz Global System for Mobile communication (GSM-like) electromagnetic field, generated by an electromagnetic fields generator, on the auditory system of rats by using electrophysiological, histopathologic and immunohistochemical methods. METHODS: Fourteen adult Wistar albino rats were included in the study. The rats were divided randomly into two groups of seven rats each. The study group was exposed continuously for 30days to a 2100MHz electromagnetic fields with a signal level (power) of 5.4dBm (3.47mW) to simulate the talk mode on a mobile phone. The control group was not exposed to the aforementioned electromagnetic fields. After 30days, the Auditory Brainstem Responses of both groups were recorded and the rats were sacrificed. The cochlear nuclei were evaluated by histopathologic and immunohistochemical methods. RESULTS: The Auditory Brainstem Responses records of the two groups did not differ significantly. The histopathologic analysis showed increased degeneration signs in the study group (p=0.007). In addition, immunohistochemical analysis revealed increased apoptotic index in the study group compared to that in the control group (p=0.002). CONCLUSION: The results support that long-term exposure to a GSM-like 2100MHz electromagnetic fields causes an increase in neuronal degeneration and apoptosis in the auditory system.
Asunto(s)
Teléfono Celular , Núcleo Coclear/efectos de la radiación , Campos Electromagnéticos/efectos adversos , Audición/efectos de la radiación , Exposición a la Radiación/efectos adversos , Ondas de Radio/efectos adversos , Animales , Apoptosis/efectos de la radiación , Núcleo Coclear/patología , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de la radiación , Inmunohistoquímica , Masculino , Degeneración Nerviosa/etiología , Ratas Wistar , Valores de Referencia , Factores de Riesgo , Factores de TiempoRESUMEN
OBJECTIVES: This study aimed to compare the effects of environmental enrichment in nourished (on a diet containing 16% protein) and malnourished (on a diet containing 6% protein) rats during the critical period of brain development, specifically focusing on the optic nerve. METHODS: By means of morphologic and morphometric assessment of the optic nerve, we analyzed the changes caused by diet and stimulation (environmental enrichment) on postnatal day 35, a time point ideal for such morphological analysis since developmental processes are considered complete at this age. RESULTS: Malnourished animals presented low body and brain weights and high body-to-brain weight ratio compared to well-nourished rats. Furthermore, malnourished animals showed morphological changes in the optic nerve such as edema and vacuolization characterized by increased interstitial space. The malnourished-stimulated group presented lesions characteristic of early protein malnutrition but were milder than lesions exhibited by malnourished-non-stimulated group. The morphometric analysis revealed no difference in glial cell density between groups, but there was significantly higher blood vessel density in the stimulated rats, independent of their nutritional condition. DISCUSSION: Our data indicate that protein malnutrition imposed during the critical period of brain development alters the cytoarchitecture of the optic nerve. In addition, we affirm that a 1-hour exposure to an enriched environment everyday was sufficient for tissue preservation in rats maintained on a low-protein diet. This protective effect might be related to angiogenesis, as confirmed by the increased vascular density observed in morphometric analyses.
Asunto(s)
Modelos Animales de Enfermedad , Lactancia , Fenómenos Fisiologicos Nutricionales Maternos , Degeneración Nerviosa/prevención & control , Tracto Óptico/irrigación sanguínea , Estimulación Luminosa , Deficiencia de Proteína/fisiopatología , Animales , Animales Recién Nacidos , Vasos Sanguíneos/patología , Vasos Sanguíneos/fisiopatología , Edema/etiología , Femenino , Masculino , Neovascularización Fisiológica , Degeneración Nerviosa/etiología , Nervio Óptico/irrigación sanguínea , Nervio Óptico/patología , Nervio Óptico/fisiopatología , Tracto Óptico/patología , Tracto Óptico/fisiopatología , Tamaño de los Órganos , Deficiencia de Proteína/patología , Distribución Aleatoria , Ratas Wistar , Vacuolas/patología , Aumento de PesoRESUMEN
We report a 37 years old male with a dermatomyositis treated with oral cyclophosphamide. He was admitted to the hospital due to a zone of skin necrosis with purulent exudate, located in the second left toe. A complete blood count showed a leukocyte count of 2,600 cells/mm³. A Chest CAT scan showed a pneumomediastinum with emphysema of adjacent soft tissue. Cyclophosphamide was discontinued and leukocyte count improved. The affected toe was amputated and a chest CAT scan showed a partial resolution of the pneumomediastinum. We discuss and review the pathogenesis, clinical presentation and management of pneumomediastinum and cutaneous necrosis in association with dermatomyositis.
Asunto(s)
Animales , Femenino , Ratas , Benzoxazinas/uso terapéutico , Cannabinoides/agonistas , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/patología , Morfolinas/uso terapéutico , Naftalenos/uso terapéutico , Neuronas/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Análisis de Varianza , /metabolismo , Caspasa 9/metabolismo , Recuento de Células/métodos , Sistema Nervioso Central/patología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/complicaciones , Macrófagos/efectos de los fármacos , Degeneración Nerviosa/etiología , Degeneración Nerviosa/prevención & control , Examen Neurológico , Poli(ADP-Ribosa) Polimerasas/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Linfocitos T/efectos de los fármacos , Factores de TiempoRESUMEN
Millions of children are exposed to concentrations of air pollutants, including fine particulate matter (PM2.5), above safety standards. In the Mexico City Metropolitan Area (MCMA) megacity, children show an early brain imbalance in oxidative stress, inflammation, innate and adaptive immune response-associated genes, and blood-brain barrier breakdown. We investigated serum and cerebrospinal fluid (CSF) antibodies to neural and tight junction proteins and environmental pollutants in 139 children ages 11.91 ± 4.2 y with high versus low air pollution exposures. We also measured metals in serum and CSF. MCMA children showed significantly higher serum actin IgG, occludin/zonulin 1 IgA, IgG, myelin oligodendrocyte glycoprotein IgG and IgM (p < 0.01), myelin basic protein IgA and IgG, S-100 IgG and IgM, and cerebellar IgG (p < 0.001). Serum IgG antibodies to formaldehyde, benzene, and bisphenol A, and concentrations of Ni and Cd were significantly higher in exposed children (p < 0.001). CSF MBP antibodies and nickel concentrations were higher in MCMA children (p = 0.03). Air pollution exposure damages epithelial and endothelial barriers and is a robust trigger of tight junction and neural antibodies. Cryptic 'self' tight junction antigens can trigger an autoimmune response potentially contributing to the neuroinflammatory and Alzheimer and Parkinson's pathology hallmarks present in megacity children. The major factor determining the impact of neural antibodies is the integrity of the blood-brain barrier. Defining the air pollution linkage of the brain/immune system interactions and damage to physical and immunological barriers with short and long term neural detrimental effects to children's brains ought to be of pressing importance for public health.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Inmunoglobulinas/metabolismo , Degeneración Nerviosa/etiología , Adolescente , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/metabolismo , Encéfalo/inmunología , Encéfalo/metabolismo , Niño , Exposición a Riesgos Ambientales , Femenino , Humanos , Masculino , México , Degeneración Nerviosa/inmunología , Degeneración Nerviosa/metabolismo , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/metabolismo , Uniones Estrechas/inmunología , Uniones Estrechas/metabolismoRESUMEN
Sedentary lifestyle leads to the accumulation of visceral fat. This is accompanied by the infiltration of immune cells with pro-inflammatory characteristics in adipose tissue, causing an increased release of cytokines and generating a low-grade inflammatory state. It has been associated with the development of insulin resistance, atherosclerosis, neurodegeneration, and development of tumors. Exercise can be used as a treatment to improve symptoms of many of these conditions because it promotes an anti-inflammatory effect. In this review we analyze the pro-inflammatory factors present in obesity and the induction of antiinflammatory factors that occur with exercise.
La vida sedentaria induce la acumulación de grasa visceral, que se acompaña de la infiltración de células inmunitarias con características proinflamatorias en el tejido adiposo, que ocasiona mayor liberación de citocinas y genera un estado inflamatorio de bajo grado, éste se ha asociado con resistencia a la insulina, aterosclerosis, neurodegeneración y tumores. El ejercicio físico puede indicarse como tratamiento para disminuir los síntomas de muchas afecciones porque promueve un estado antiinflamatorio. En esta revisión se analizarán los factores proinflamatorios que coexisten en la obesidad, y la inducción de factores antiinflamatorios que se originan con el ejercicio físico.
Asunto(s)
Ejercicio Físico , Inflamación/etiología , Obesidad/complicaciones , Conducta Sedentaria , Adipoquinas/metabolismo , Aterosclerosis/etiología , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Epinefrina/metabolismo , Ejercicio Físico/fisiología , Terapia por Ejercicio , Humanos , Hidrocortisona/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/prevención & control , Resistencia a la Insulina , Interleucina-6/metabolismo , Grasa Intraabdominal/metabolismo , Macrófagos/metabolismo , Contracción Muscular , Neoplasias/etiología , Neoplasias/inmunología , Neoplasias/metabolismo , Degeneración Nerviosa/etiología , Degeneración Nerviosa/inmunología , Degeneración Nerviosa/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , Estrés Oxidativo , Linfocitos T Reguladores/inmunología , Receptores Toll-Like/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
We reported that fish oil (FO) abolishes retrograde amnesia consistently following transient global cerebral ischemia (TGCI) in young rats, provided it covered the first days prior to and after ischemia. Here, we further evaluated whether FO given post-ischemia in older rats (15-18 months old) is equally effective in facilitating memory recovery. We also tested whether the antiamnesic effect of FO observed after TGCI can be reproduced after chronic cerebral hypoperfusion (CCH). FO (300 mg/kg docosahexaenoic acid [DHA]) was delivered orally 4h after TGCI and continued once per day for 9 days. In the CCH group, FO treatment began soon after the first stage of 4-VO/ICA and continued daily for 43 days. Two weeks after surgery, the animals were tested for retrograde memory performance across 5 weeks. Both TGCI and CCH caused persistent memory impairment and hippocampal and cortical neurodegeneration. TGCI-induced retrograde amnesia was reversed by FO, an effect that was sustained for at least 5 weeks after discontinuing treatment. In contrast, the memory deficit caused by CCH remained unchanged after FO treatment. Both hippocampal and cortical damage was not alleviated by FO. We conclude that the FO-mediated antiamnesic effect following TGCI can be extended to older rats, even when the treatment begins 4h postischemia. Such efficacy was not reproduced after CCH. Therefore, the present results support the notion that FO may have therapeutic utility in treating learning/memory dysfunction after acute/transient cerebral ischemia and suggest that such benefits may not apply when a state of chronic cerebrovascular insufficiency is present.
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Amnesia Retrógrada/tratamiento farmacológico , Aceites de Pescado/uso terapéutico , Ataque Isquémico Transitorio/complicaciones , Fármacos Neuroprotectores/uso terapéutico , Amnesia Retrógrada/etiología , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Ataque Isquémico Transitorio/mortalidad , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/etiología , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacosRESUMEN
A role of amyloid ß (Aß) peptide aggregation and deposition in Alzheimer's disease (AD) pathogenesis is widely accepted. Significantly, abnormalities induced by aggregated Aß have been linked to synaptic and neuritic degeneration, consistent with the "dying-back" pattern of degeneration that characterizes neurons affected in AD. However, molecular mechanisms underlying the toxic effect of aggregated Aß remain elusive. In the last 2 decades, a variety of aggregated Aß species have been identified and their toxic properties demonstrated in diverse experimental systems. Concurrently, specific Aß assemblies have been shown to interact and misregulate a growing number of molecular effectors with diverse physiological functions. Such pleiotropic effects of aggregated Aß posit a mayor challenge for the identification of the most cardinal Aß effectors relevant to AD pathology. In this review, we discuss recent experimental evidence implicating amyloid ß precursor protein (APP) as a molecular target for toxic Aß assemblies. Based on a significant body of pathologic observations and experimental evidence, we propose a novel pathologic feed-forward mechanism linking Aß aggregation to abnormalities in APP processing and function, which in turn would trigger the progressive loss of neuronal connectivity observed early in AD.
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Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Degeneración Nerviosa/etiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/farmacología , Precursor de Proteína beta-Amiloide/efectos de los fármacos , Adhesión Celular , Regulación de la Expresión Génica/fisiología , Humanos , Modelos Moleculares , Plasticidad NeuronalRESUMEN
Epilepsy affects 1 and 2 percent of the worldwide population, while temporal lobe epilepsy (TLE) covers 40 percent of all epilepsy cases. Controversy in defining epilepsy as a neurodegenerative disease exists because, no there is enough evidence to show seizures and status epilepticus (SE) as cause for irreversible neuronal damage. Epileptogenic insult at the beginning of the disease produces an acute and delayed neuronal death, resulting in gliosis, but also triggers compensatory processes such as angiogenesis, cell proliferation and reorganization of extracellular matrix as receptors, channels and drug transporter proteins. In neurogenesis and axonal regrowth, the age of onset is crucial for the formation of abnormal neurons and aberrant circuits as a result of seizures; approximately 30 percent begin in the temporal lobe. These disturbances continue in parallel or sequentially during the course of epilepsy, which implies a great challenge in the search of new treatments...
La epilepsia es una enfermedad que afecta entre el 1 al 2 por ciento de la población mundial, siendo la epilepsia del lóbulo temporal (ELT) la que abarca el 40 por ciento de todos los casos de epilepsia. La controversia en definir a la epilepsia como una enfermedad neurodegenerativa, se debe a que no hay pruebas suficientes que demuestren como las convulsiones y el estado de mal epiléptico (SE) provocan un daño neuronal irreversible. El insulto epileptógenico presente al inicio de la enfermedad genera la muerte neuronal aguda y tardía, para dar lugar a la gliosis; pero también se desencadenan procesos compensatorios como la angiogénesis, la proliferación celular y una reorganización tanto de la matriz extracelular como de los receptores, canales y proteínas transportadoras de fármacos. En el caso de la neurogénesis y recrecimiento axonal, la edad de inicio es determinante para la formación de neuronas anormales y circuitos aberrantes como consecuencia de las convulsiones, dónde aproximadamente un 30 por ciento comienzan en el lóbulo temporal. Estas alteraciones se continúan en paralelo o de forma secuencia! durante la evolución de la epilepsia, lo que implica un gran desafío en la búsqueda de nuevos tratamientos...
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Humanos , Epilepsia del Lóbulo Temporal/complicaciones , Epilepsia del Lóbulo Temporal/fisiopatología , Degeneración Nerviosa/etiología , Degeneración Nerviosa/fisiopatología , Gliosis , Inflamación , Neovascularización PatológicaRESUMEN
Status epilepticus (SE) when occurred during brain development can cause short- and long-term consequences, which are frequently associated with NMDA-mediated glutamatergic excitotoxicity. In the present work, we investigated the putative neuroprotective role of ketamine, an NMDA receptor antagonist, on early life SE-induced acute neuronal death and long-term behavioral abnormalities. Male Wistar rats (16 postnatal days) were induced to SE by LiCl-pilocarpine i.p. administration (3 mEq/kg; 60 mg/kg, respectively). Fifteen or 60min after pilocarpine injection, animals received a ketamine administration (22.5mg/kg i.p.). Neuronal degeneration was assessed 24h after SE induction. Another subset of animals was destined to behavioral tasks in adulthood (75-80 postnatal days). Fluoro-Jade C labeling revealed a marked neuronal death on CA1 hippocampal subfield, habenula, thalamus and amygdala in SE animals. Ketamine post-SE onset treatment prevented neuronal death in all regions assessed. In the elevated plus maze, SE induced an increase in anxiety-like behaviors whereas ketamine administration during seizures was able to prevent this alteration. Ketamine administration in non-SE animals resulted in high anxiety levels. There were no observed differences among groups in the open field task in all parameters analyzed. Our results suggest that ketamine post-SE onset treatment was effective in preventing acute and long-standing alterations caused by SE early in life, which indicates a putative role of glutamatergic system on SE-induced brain damage as well as long-lasting behavioral consequences.
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Ansiedad/prevención & control , Ketamina/farmacología , Degeneración Nerviosa/prevención & control , Fármacos Neuroprotectores/farmacología , Estado Epiléptico/tratamiento farmacológico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Convulsivantes/toxicidad , Masculino , Degeneración Nerviosa/etiología , Pilocarpina/toxicidad , Ratas , Ratas Wistar , Estado Epiléptico/patología , Estado Epiléptico/psicologíaRESUMEN
Temporal lobe epilepsy (TLE) is the most common type of human epilepsy and has been related with extensive loss of hippocampal pyramidal and dentate hilar neurons and gliosis. Many characteristics of TLE are reproduced in the pilocarpine model of epilepsy in mice. This study analyzed the neuronal damage, assessed with Fluoro-Jade (FJB) and cresyl violet, and gliosis, investigated with glial fibrilary acidic protein (GFAP) immunohistochemistry, occurring in the hippocampal formation of mice at 3, 6, 12 and 24h, 1 and 3 weeks after the pilocarpine-induced status-epilepticus (SE) onset. The maximum neuronal damage score and the FJB-positive neurons peak were found in the hilus of dentate gyrus 3 and 12 h after SE onset (P<0.05), respectively. At 1 week after SE onset, the greatest neuronal damage score was detected in the CA1 pyramidal cell layer and the greatest numbers of FJB-positive neurons were found both in the CA1 and CA3 pyramidal cell layers (P<0.05). The molecular, CA3 and CA1 pyramidal cell layers expressed highest presence of GFAP immunoreaction at 1 and 3 weeks after SE onset (P<0.05). Our findings show that, depending on the affected area, neuronal death and gliosis can occur within few hours or weeks after SE onset. Our results corroborate previous studies and characterize short time points of temporal evolution of neuropathological changes after the onset of pilocarpine-induced SE in mice and evidences that additional studies of this temporal evolution may be useful to the comprehension of the cellular mechanisms underlying epileptogenesis.
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Gliosis/etiología , Hipocampo/patología , Degeneración Nerviosa/etiología , Estado Epiléptico/patología , Análisis de Varianza , Animales , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Fluoresceínas , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Masculino , Ratones , Trastornos del Movimiento/etiología , Agonistas Muscarínicos/toxicidad , Compuestos Orgánicos , Pilocarpina/toxicidad , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Células Piramidales/patología , Estado Epiléptico/inducido químicamente , Factores de TiempoRESUMEN
VEGF (vascular endothelial growth factor) prevents neuronal death in different models of ALS (amyotrophic lateral sclerosis), but few studies have addressed the efficacy of VEGF to protect motor neurons after the onset of symptoms, a critical point when considering VEGF as a potential therapeutic target for ALS. We studied the capability of VEGF to protect motor neurons after an excitotoxic challenge in two models of spinal neurodegeneration in rats induced by AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) administered either chronically with osmotic minipumps or acutely by microdialysis. VEGF was administered through osmotic minipumps in the chronic model or injected intracerebroventricularly in the acute model, and its effects were assessed by immunohistochemical and histological analyses and motor performance tests. In the chronic model, VEGF stopped the progression of the paralysis and protected motor neurons when administered after AMPA before the onset of the motor symptoms, whereas no protection was observed when administered after the onset. VEGF was also protective in the acute model, but with a short time window, since the protection was effective when administered 1 h but not 2 h after AMPA. Our results indicate that while VEGF has an indubitable neuroprotective effect, its therapeutic potential for halting or delaying the progression of motor neuron loss in ALS would likely have a short effective time frame.
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Neuronas Motoras/efectos de los fármacos , Enfermedades de la Médula Espinal/patología , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Análisis de Varianza , Animales , Factor Neurotrófico Derivado del Encéfalo/administración & dosificación , Muerte Celular/efectos de los fármacos , Colina O-Acetiltransferasa/metabolismo , Modelos Animales de Enfermedad , Vías de Administración de Medicamentos , Esquema de Medicación , Sistemas de Liberación de Medicamentos , Agonistas de Aminoácidos Excitadores/toxicidad , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Microdiálisis , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neuronas Motoras/metabolismo , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/etiología , Parálisis/etiología , Parálisis/prevención & control , Ratas , Ratas Wistar , Enfermedades de la Médula Espinal/inducido químicamente , Enfermedades de la Médula Espinal/complicaciones , Enfermedades de la Médula Espinal/tratamiento farmacológico , Factores de Tiempo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/toxicidadRESUMEN
Permanent, stepwise occlusion of the vertebral arteries (VAs) and internal carotid arteries (ICAs) following the sequence VAâICAâICA, with an interstage interval (ISI, â) of 7 days, has been investigated as a four-vessel occlusion (4-VO)/ICA model of chronic cerebral hypoperfusion. This model has the advantage of not causing retinal damage. In young rats, however, 4-VO/ICA with an ISI of 7 days fails to cause behavioral sequelae. We hypothesized that such a long ISI would allow the brain to efficiently compensate for cerebral hypoperfusion, preventing the occurrence of cognitive impairment and neurodegeneration. The present study evaluated whether brain neurodegeneration and learning/memory deficits can be expressed by reducing the length of the ISI and whether aging influences the outcome. Young, male Wistar rats were subjected to 4-VO/ICA with different ISIs (5, 4, 3 or 2 days). An ISI of 4 days was used in middle-aged rats. Ninety days after 4-VO/ICA, the rats were tested for learning/memory impairment in a modified radial maze and then examined for neurodegeneration of the hippocampus and cerebral cortex. Regardless of the ISI, young rats were not cognitively impaired, although hippocampal damage was evident. Learning/memory deficits and hippocampal and cortical neurodegeneration occurred in middle-aged rats. The data indicate that 4-VO/ICA has no impact on the capacity of young rats to learn the radial maze task, despite 51% hippocampal cell death. Such resistance is lost in middle-aged animals, for which the most extensive neurodegeneration observed in both the hippocampus and cerebral cortex may be responsible.
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Isquemia Encefálica/complicaciones , Corteza Cerebral/patología , Trastornos del Conocimiento/etiología , Degeneración Nerviosa/etiología , Factores de Edad , Animales , Conducta Animal/fisiología , Isquemia Encefálica/patología , Muerte Celular , Trastornos del Conocimiento/patología , Hipocampo/patología , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/etiología , Trastornos de la Memoria/patología , Degeneración Nerviosa/patología , Neuronas/patología , Ratas , Ratas WistarRESUMEN
Aiming at a better understanding of the role of A(2A) in temporal lobe epilepsy (TLE), we characterized the effects of the A(2A) antagonist SCH58261 (7-(2-phenylethyl)-5-amino-2(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) on seizures and neuroprotection in the pilocarpine model. The effects of SCH58261 were further analyzed in combination with the A(1) agonist R-Pia (R(-)-N(6)-(2)-phenylisopropyl adenosine). Eight groups were studied: pilocarpine (Pilo), SCH+Pilo, R-Pia+Pilo, R-Pia+SCH+Pilo, Saline, SCH+Saline, R-Pia+Saline, and R-Pia+SCH+Saline. The administration of SCH58261, R-Pia, and R-Pia+SCH58261 prior to pilocarpine increased the latency to SE, and decreased either the incidence of or rate of mortality from SE compared with controls. Administration of R-Pia and R-Pia+SCH58261 prior to pilocarpine reduced the number of Fluoro-Jade B-stained cells in the hippocampus and piriform cortex when compared with control. This study showed that pretreatment with R-Pia and SCH58261 reduces seizure occurrence, although only R-Pia has neuroprotective properties. Further studies are needed to clarify the neuroprotective role of A(2A) in TLE.
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Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A2A/metabolismo , Estado Epiléptico/metabolismo , Adenosina/farmacología , Análisis de Varianza , Animales , Encéfalo/patología , Recuento de Células , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Fluoresceínas , Masculino , Degeneración Nerviosa/etiología , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Compuestos Orgánicos/metabolismo , Fenilisopropiladenosina/farmacología , Fenilisopropiladenosina/uso terapéutico , Pilocarpina/toxicidad , Pirimidinas/uso terapéutico , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/patología , Triazoles/uso terapéuticoRESUMEN
Recent research data have shown that systemic administration of pyruvate and oxaloacetate causes an increased brain-to-blood glutamate efflux. Since increased release of glutamate during epileptic seizures can lead to excitotoxicity and neuronal cell death, we tested the hypothesis that glutamate scavenging mediated by pyruvate and oxaloacetate systemic administration could have a neuroprotective effect in rats subjected to status epilepticus (SE). SE was induced by a single dose of pilocarpine (350mg/kgi.p.). Thirty minutes after SE onset, a single dose of pyruvate (250mg/kgi.p.), oxaloacetate (1.4mg/kgi.p.), or both substances was administrated. Acute neuronal loss in hippocampal regions CA1 and hilus was quantitatively determined five hours after SE onset, using the optical fractionator method for stereological cell counting. Apoptotic cascade in the hippocampus was also investigated seven days after SE using caspase-1 and -3 activity assays. SE-induced neuronal loss in CA1 was completely prevented in rats treated with pyruvate plus oxaloacetate. The SE-induced caspase-1 activation was significantly reduced when rats were treated with oxaloacetate or pyruvate plus oxaloacetate. The treatment with pyruvate and oxaloacetate caused a neuroprotective effect in rats subjected to pilocarpine-induced SE.