RESUMEN
Understanding the means by which microglia self-regulate the neuroinflammatory response helps modulating their reaction during neurodegeneration. In amyotrophic lateral sclerosis (ALS), classical NF-κB pathway is related to persistent microglia activation and motor neuron injury; however, mechanisms of negative control of NF-κB activity remain unexplored. One of the major players in the termination of classical NF-κB pathway is the ubiquitin-editing enzyme A20, which has recognized anti-inflammatory functions. Lately, microRNAs are emerging as potent fine-tuners of neuroinflammation and reported to be regulated in ALS, for instance, by purinergic P2X7 receptor activation. In this work, we uncover an interplay between miR-125b and A20 protein in the modulation of classical NF-κB signaling in microglia. In particular, we establish the existence of a pathological circuit in which termination of A20 function by miR-125b strengthens and prolongs the noxious P2X7 receptor-dependent activation of NF-κB in microglia, with deleterious consequences on motor neurons. We prove that, by restoring A20 levels, miR-125b inhibition then sustains motor neuron survival. These results introduce miR-125b as a key mediator of microglia dynamics in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/patología , MicroARNs/fisiología , Microglía/metabolismo , Superóxido Dismutasa/genética , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Muerte Celular , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismo , Expresión Génica , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BL , Microglía/inmunología , Neuronas Motoras/fisiología , Mutación Missense , Cultivo Primario de Células , Interferencia de ARN , Superóxido Dismutasa-1 , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND: Tako-tsubo cardiomyopathy (TTC), also known as "stress induced cardiomyopathy", is an acute cardiac condition characterized by transient myocardial dysfunction associated with a peculiar pattern of reversibile left ventricular ballooning that mimics myocardial infarction, but with normal coronary arteries. Tako-tsubo cardiomyopathy typically occurs in postmenopausal women and it is often triggered by physical or emotional stressful events. We report on a patient with Alzheimer's disease, who presented with TTC and an ischemic stroke.
Asunto(s)
Enfermedad de Alzheimer/patología , Infarto del Miocardio/patología , Accidente Cerebrovascular/patología , Cardiomiopatía de Takotsubo/patología , Anciano de 80 o más Años , Femenino , Humanos , Infarto del Miocardio/diagnóstico , Accidente Cerebrovascular/diagnóstico , Cardiomiopatía de Takotsubo/diagnósticoRESUMEN
The present study aims to assess the protective role of the antioxidant enzyme catalase (CAT) with relation to hydrogen peroxide (H(2)O(2)) degradation in oxygen plus water on electrophysiological and fluorescence changes induced by in vitro ischemia and on brain damage produced by transient in vivo ischemia. Neuroprotective effects of CAT were determined by means of electrophysiological recordings and confocal fluorescence microscopy in the hippocampal slice preparation. Ischemia was simulated in vitro by oxygen/glucose deprivation (OGD). In vivo ischemia was produced by transient middle cerebral artery occlusion (MCAo). A protection of the rat CA1 field excitatory postsynaptic potential (fEPSP) loss caused by a prolonged OGD (40 min) was observed after exogenous CAT (500 U/mL) bath-applied before a combined exposure to OGD and H(2)O(2) (3 mM). Of note, neither H(2)O(2) nor exogenous CAT alone had a protective action when OGD lasted for 40 min. The CAT-induced neuroprotection was confirmed in a transgenic mouse model over-expressing human CAT [Tg(CAT)]. In the presence of H(2)O(2), the hippocampus of Tg(CAT) showed an increased resistance against OGD compared to that of wild-type (WT) animals. Moreover, CAT treatment reduced for about 50 min fEPSP depression evoked by repeated applications of H(2)O(2) in normoxia. A lower sensitivity to H(2)O(2)-induced depression of fEPSPs was also indicated by the rightward shift of concentration-response curve in Tg(CAT) compared to WT mice. Noteworthy, Tg(CAT) mice had a reduced infarct size after MCAo. Our data suggest new strategies to reduce neuronal damage produced by transient brain ischemia through the manipulation of CAT enzyme.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/enzimología , Catalasa/fisiología , Catalasa/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Animales , Encéfalo/enzimología , Encéfalo/patología , Isquemia Encefálica/patología , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Catalasa/biosíntesis , Infarto Cerebral/patología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Glucosa/deficiencia , Peróxido de Hidrógeno/farmacología , Hipoxia Encefálica/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Técnicas de Cultivo de Órganos , Oxidantes/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Superóxido Dismutasa/biosíntesis , Superóxido Dismutasa/genética , Superóxidos/metabolismo , Transmisión Sináptica/efectos de los fármacosRESUMEN
Although amyotrophic lateral sclerosis (ALS) has long been considered as a lower motor neuron (MN) disease, degeneration of upper MNs arising from a combination of mechanisms including insufficient growth factor signaling and enhanced extracellular glutamate levels is now well documented. The observation that these mechanisms are altered in presymptomatic superoxide dismutase (SOD1) mice, an ALS mouse model, suggests that defective primary motor cortex (M1) synaptic activity might precede the onset of motor disturbances. To examine this point, we assessed the composition of AMPAR and NMDAR subunits and of the alphaCa²(+)/calmodulin-dependent kinase autophosphorylation at threonine-286 in the triton insoluble fraction from the M1 in postnatal P80-P85 SOD1(G93A) and wild-type mice. We show that presymptomatic SOD1(G93A) exhibit a selective decrease of NR2A subunit expression and of the alphaCa²(+)/calmodulin-dependent kinase autophosphorylation at threonine-286 in the triton insoluble fraction of upper MNs synapses. These molecular alterations are associated with synaptic plasticity defects, and a reduction in upper MN dendritic outgrowth revealing that abnormal neuronal connectivity in the M1 region precedes the onset of motor symptoms. We suggest that the progressive disruption of M1 corticocortical connections resulting from the SOD1(G93A) mutation might extend to adjacent regions and promote development of cognitive/dementia alterations frequently associated with ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/fisiopatología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Neuronas Motoras/metabolismo , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/biosíntesis , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Western Blotting , Modelos Animales de Enfermedad , Potenciales Evocados , Técnica del Anticuerpo Fluorescente , Humanos , Ratones , Ratones Transgénicos , Microscopía Confocal , Neuronas Motoras/patología , Mutación , Fosforilación , Superóxido Dismutasa/genética , Superóxido Dismutasa-1 , Treonina/metabolismoRESUMEN
BACKGROUND: Scarce information is available on the usefulness of new prediction markers for identifying young ischemic stroke patients at highest risk of recurrence. METHODS: The predictive effect of traditional risk factors as well as of the 20210A variant of prothrombin gene, the 1691A variant of factor V gene, and the TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR) gene on the risk of recurrence was investigated in a hospital-based cohort study of 511 ischemic stroke patients younger than 45 years followed up for a mean of 43.4 months. Outcome measures were fatal/nonfatal myocardial infarction, ischemic stroke, or TIA. Risk prediction was assessed with the use of the concordance c (c index), and the Net Reclassification Improvement (NRI). RESULTS: The risk of recurrence increased with increasing number of traditional factors (hazard ratio [HR] 2.29, 95% confidence interval [CI] 1.57-3.35 for subjects with 1 factor: HR 5.25, 95% CI 2.45-11.2 for subjects with 2), as well as with that of predisposing genotypes (HR 1.96, 95% CI 1.33-2.89 for subjects carrying 1 at-risk genotype; HR 3.83, 95% CI 1.76-8.34 for those carrying 2). The c statistics increased significantly when the genotypes were included into a model with traditional risk factors (0.696 vs 0.635, test z = 2.41). The NRI was also significant (NRI = 0.172, test z = 2.17). CONCLUSIONS: Addition of common genetic variants to traditional risk factors may be an effective method for discriminating young stroke patients at different risk of future ischemic events.
Asunto(s)
Isquemia Encefálica/epidemiología , Isquemia Encefálica/genética , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/epidemiología , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genética , Adolescente , Adulto , Distribución por Edad , Factores de Edad , Isquemia Encefálica/diagnóstico , Análisis Mutacional de ADN , Factor V/genética , Femenino , Pruebas Genéticas , Variación Genética , Genotipo , Humanos , Masculino , Tamizaje Masivo , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Protrombina/genética , Recurrencia , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Adulto JovenRESUMEN
Amyotrophic lateral sclerosis (ALS) is a fatal progressive neuropathy associated with the degeneration of spinal and brainstem motor neurons. Although ALS is essentially considered as a lower motor neuron disease, prefrontal cortex atrophy underlying executive function deficits have been extensively reported in ALS patients. Here, we examine whether prefrontal cortex neuronal abnormalities and related cognitive impairments are present in presymptomatic G93A Cu/Zn superoxide dismutase mice, a mouse model for familial ALS. Structural characteristics of prelimbic/infralimbic (PL/IL) medial prefrontal cortex (mPFC) neurons were studied in 3-month-old G93A and wild-type mice with the Golgi-Cox method, while mPFC-related cognitive operations were assessed using the conditioned fear extinction paradigm. Sholl analysis performed on the dendritic material showed a reduction in dendrite length and branch nodes on basal dendrites of PL/IL neurons in G93A mice. Spine density was also decreased on basal dendrite segments of branch order five. Consistent with the altered morphology of PL/IL cortical regions, G93A mice showed impaired extinction of conditioned fear. Our findings indicate that abnormal prefrontal cortex connectivity and function are appreciable before the onset of motor disturbances in this model.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/psicología , Trastornos del Conocimiento/genética , Extinción Psicológica/fisiología , Corteza Prefrontal/anomalías , Superóxido Dismutasa/genética , Esclerosis Amiotrófica Lateral/complicaciones , Animales , Forma de la Célula/genética , Trastornos del Conocimiento/enzimología , Trastornos del Conocimiento/fisiopatología , Condicionamiento Psicológico/fisiología , Espinas Dendríticas/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Miedo/fisiología , Predisposición Genética a la Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/genética , Malformaciones del Sistema Nervioso/enzimología , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/fisiopatología , Vías Nerviosas/anomalías , Vías Nerviosas/enzimología , Vías Nerviosas/fisiopatología , Corteza Prefrontal/enzimología , Corteza Prefrontal/fisiopatología , Células Piramidales/patología , Tinción con Nitrato de PlataRESUMEN
As there are a number of possible causes of syncope, differentiation between cardiovascular disease, neurogenic disease and other disorders is mandatory. Cerebral arteriovenous malformations (AVMs) are tangled anastomoses of blood vessels of varying calibre in which arteriovenous shunting occurs in a central nidus, which is the area towards which multiple feeding arteries converge and from which enlarged veins drain. We describe a clinical case of syncope caused by a large AVM discovered in a 66-year-old woman. The symptoms were probably related to an epileptogenic mechanism since the syncope disappeared following the administration of antiepileptic therapy. The anatomical, pathological and clinical aspects of AVMs are discussed.
Asunto(s)
Malformaciones Arteriovenosas Intracraneales/complicaciones , Síncope/etiología , Femenino , Humanos , Persona de Mediana Edad , RecurrenciaRESUMEN
In this hospital case series study we enrolled 394 consecutive ischemic stroke patients aged 14-47 years, all of whom were submitted to a diagnostic protocol. We evaluated the incidence of cerebral ischemia in young adults, as well as the risk factors and the etiopathogenesis of this pathology. Modified diagnostic criteria adopted from the TOAST and Baltimore-Washington Cooperative Young Stroke Study were used for the etiologic classification. The crude annual incidence rate was 8.8/100,000 (95% CI 7.7-9.9), which is in keeping with the rates reported in comparable registries. Risk factors were distributed as follows: smoking in 56% of patients, hypertension in 23%, dyslipidemia in 15%, migraine in 26%, and diabetes mellitus in 2%. Oral contraceptives were being taken by 38% of the women enrolled. The etiology of stroke in the patients was as follows: cardioembolism in 34%, atherothrombosis in 12%, non-atherosclerotic vasculopathies in 14% (including arterial dissection in 12%), other determined causes in 13%, lacunar stroke in 2.5%, migraine in 1%, and undetermined causes in 24%. Despite its biased sampling frame, this large hospital case series, in which risk factor distribution and etiopathogenesis were investigated, stresses the need for an adequate diagnostic approach in young ischemic patients.
Asunto(s)
Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Adolescente , Adulto , Factores de Edad , Femenino , Humanos , Incidencia , Masculino , Factores de Riesgo , Ciudad de Roma/epidemiología , Factores Sexuales , Accidente Cerebrovascular/clasificaciónAsunto(s)
Disección de la Arteria Carótida Interna/diagnóstico por imagen , Accidente Cerebrovascular/etiología , Disección de la Arteria Carótida Interna/complicaciones , Disección de la Arteria Carótida Interna/patología , Lateralidad Funcional , Humanos , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Radiografía , Rotura Espontánea/complicaciones , Rotura Espontánea/diagnóstico por imagen , Rotura Espontánea/patología , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/patologíaRESUMEN
There are many evidences implicating glutamatergic toxicity as a contributory factor in the selective neuronal injury occurring in amyotrophic lateral sclerosis (ALS). This neurodegenerative disorder is characterized by the progressive loss of motor neurons, whose pathogenesis is thought to involve Ca(2+) influx mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate receptors (AMPARs). In the present study we report alterations in the AMPARs function in a transgenic mouse-model of the human SOD1(G93A) familial ALS. Compared with those expressed in motor neurons carrying the human wild type gene, AMPAR-gated channels expressed in motor neurons carrying the human mutant gene exhibited modified permeability, altered agonist cooperativity between the sites involved in the process of channel opening and were responsible for slower spontaneous synaptic events. These observations demonstrate that the SOD1(G93A) mutation induces changes in AMPAR functions which may underlie the increased vulnerability of motor neurons to glutamatergic excitotoxicity in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Neuronas Motoras/metabolismo , Mutación , Receptores AMPA/metabolismo , Médula Espinal/metabolismo , Superóxido Dismutasa/metabolismo , Alanina/genética , Esclerosis Amiotrófica Lateral/enzimología , Animales , Técnicas de Cultivo de Célula , Modelos Animales de Enfermedad , Electrofisiología , Glicina/genética , Inmunohistoquímica , Ratones , Ratones Transgénicos , Neuronas Motoras/enzimología , Técnicas de Placa-Clamp , Médula Espinal/enzimología , Superóxido Dismutasa/genética , Regulación hacia ArribaRESUMEN
Ischemic stroke in young adults is rare (5%-10% of all ischemic strokes) and, in absence of other risk factors, may be associated with migraine. We describe the case of a 34-year-old woman, with a history of migraine without aura, who presented a sudden onset of headache with Horner's syndrome, and in whom neuroimaging showed evidence compatible with fibromuscular dysplasia (FMD) and arterial dissection of the extracranial internal carotid artery (ICA) and the carotid siphon. In our opinion, in young women with a long history of migraine, a careful study of the extracranial and intracranial arteries would be useful, although the cost/benefit ratio does not at present justify such a procedure. Our aim in the future is, therefore, to study a larger sample of migraine patients in order to find those patients who are most at risk of arterial dissection and who should, consequently, be carefully studied.
Asunto(s)
Disección de la Arteria Carótida Interna/complicaciones , Síndrome de Horner/etiología , Migraña sin Aura/complicaciones , Adulto , Femenino , Humanos , Angiografía por Resonancia Magnética , Accidente Cerebrovascular/etiologíaRESUMEN
Over the last few years, many authors have described the possibility of using transcranial Doppler to demonstrate the passage of microemboli in the cerebral arteries. We report the case of a 44-year-old woman with thrombotic diathesis and thrombocytosis who was admitted twice within a short period of time (one and a half months) to a neurological department because of multiple cerebral infarctions. On the occasion of the second admission, a colour-Doppler examination of the epiaortic vessels, which had previously been negative, showed a carotid lesion due to a mural thrombus and, on the same side as the carotid lesion, transcranial Doppler detected short-duration, high-intensity signals in the middle and anterior cerebral arteries, an expression of the passage of microemboli. As already described by other authors in similar clinical situations, our case confirms that transcranial Doppler can identify the passage of microemboli in the circle of Willis.