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1.
Cell ; 183(3): 786-801.e19, 2020 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-33125893

RESUMEN

Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunidad , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Nanotecnología , Acetilmuramil-Alanil-Isoglutamina/metabolismo , Animales , Conducta Animal , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Proliferación Celular/efectos de los fármacos , Colesterol/metabolismo , Femenino , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunidad/efectos de los fármacos , Inmunoterapia , Lipoproteínas HDL/metabolismo , Ratones Endogámicos C57BL , Primates , Distribución Tisular/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos
2.
Blood ; 140(26): 2844-2848, 2022 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-35960811

RESUMEN

Recombinant human tissue plasminogen activator (rh-tPA) is an important thrombolytic agent for treatment of acute ischemic stroke. It requires fibrin binding for plasminogen activation. In contrast, Microlyse, a novel thrombolytic agent, requires von Willebrand factor (VWF) binding for plasminogen activation. We compared rh-tPA with Microlyse, administered 20 minutes after inducing thrombosis, in 2 randomized blinded acute ischemic stroke mouse models. Thrombosis was induced in the middle cerebral artery with different experimental triggers. Where thrombin infusion generates fibrin-rich thrombi, topical FeCl3 application generates platelet-rich thrombi. In the fibrin-rich model, both rh-tPA and Microlyse increased cortical reperfusion (determined by laser speckle imaging) 10 minutes after therapy administration (35.8 ± 17.1%; P = .001 39.3 ± 13.1%; P < .0001; 15.6 ± 7.5%, respectively, vs vehicle). In addition, both thrombolytic agents reduced cerebral lesion volume (determined by magnetic resonance imaging) after 24 hours (18.9 ± 11.2 mm3; P = .033; 16.1 ± 13.9 mm3; P = .018; 26.6 ± 5.6 mm3, respectively, vs vehicle). In the platelet-rich model, neither rh-tPA nor Microlyse increased cortical reperfusion 10 minutes after therapy (7.6 ± 8.8%; P = .216; 16.3 ± 13.9%; P = .151; 10.1 ± 7.9%, respectively, vs vehicle). However, Microlyse, but not rh-tPA, decreased cerebral lesion volumes (13.9 ± 11.4 mm3; P < .001; 23.6 ± 11.1 mm3; P = .188; 30.3 ± 10.9 mm3, respectively, vs vehicle). These findings support broad applicability of Microlyse in ischemic stroke, irrespective of the thrombus composition.


Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Tromboembolia , Trombosis , Ratones , Humanos , Animales , Activador de Tejido Plasminógeno/farmacología , Activador de Tejido Plasminógeno/uso terapéutico , Fibrinolíticos/farmacología , Fibrinolíticos/uso terapéutico , Factor de von Willebrand/uso terapéutico , Fibrina/metabolismo , Terapia Trombolítica , Plasminógeno/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo
3.
Ecotoxicol Environ Saf ; 281: 116638, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38944013

RESUMEN

Studies have highlighted a possible link between air pollution and cerebral small vessel disease (CSVD) imaging markers. However, the exact association and effects of polygenic risk score (PRS) defined genetic susceptibility remains unclear. This cross-sectional study used data from the UK Biobank. Participants aged 40-69 years were recruited between the year 2006 and 2010. The annual average concentrations of NOX, NO2, PM2.5, PM2.5-10, PM2.5 absorbance, and PM10, were estimated, and joint exposure to multiple air pollutants was reflected in the air pollution index (APEX). Air pollutant exposure was classified into the low (T1), intermediate (T2), and high (T3) tertiles. Three CSVD markers were used: white matter hyper-intensity (WMH), mean diffusivity (MD), and fractional anisotropy (FA). The first principal components of the MD and FA measures in the 48 white matter tracts were analysed. The sample consisted of 44,470 participants from the UK Biobank. The median (T1-T3) concentrations of pollutants were as follows: NO2, 25.5 (22.4-28.7) µg/m3; NOx, 41.3 (36.2-46.7) µg/m3; PM10, 15.9 (15.4-16.4) µg/m3; PM2.5, 9.9 (9.5-10.3) µg/m3; PM2.5 absorbance, 1.1 (1.0-1.2) per metre; and PM2.5-10, 6.1 (5.9-6.3) µg/m3. Compared with the low group, the high group's APEX, NOX, and PM2.5 levels were associated with increased WMH volumes, and the estimates (95 %CI) were 0.024 (0.003, 0.044), 0.030 (0.010, 0.050), and 0.032 (0.011, 0.053), respectively, after adjusting for potential confounders. APEX, PM10, PM2.5 absorbance, and PM2.5-10 exposure in the high group were associated with increased FA values compared to that in the low group. Sex-specific analyses revealed associations only in females. Regarding the combined associations of air pollutant exposure and PRS-defined genetic susceptibility with CSVD markers, the associations of NO2, NOX, PM2.5, and PM2.5-10 with WMH were more profound in females with low PRS-defined genetic susceptibility, and the associations of PM10, PM2.5, and PM2.5 absorbance with FA were more profound in females with higher PRS-defined genetic susceptibility. Our study demonstrated that air pollutant exposure may be associated with CSVD imaging markers, with females being more susceptible, and that PRS-defined genetic susceptibility may modify the associations of air pollutants.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Enfermedades de los Pequeños Vasos Cerebrales , Exposición a Riesgos Ambientales , Predisposición Genética a la Enfermedad , Material Particulado , Humanos , Persona de Mediana Edad , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/inducido químicamente , Femenino , Masculino , Contaminantes Atmosféricos/toxicidad , Anciano , Estudios Transversales , Adulto , Contaminación del Aire/efectos adversos , Contaminación del Aire/estadística & datos numéricos , Reino Unido , Biomarcadores
4.
Stroke ; 54(8): 1962-1971, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37345546

RESUMEN

BACKGROUND: Despite improvements in acute stroke therapies and rehabilitation strategies, many stroke patients are left with long-term upper limb motor impairment. We assessed whether an inhibitory repetitive transcranial magnetic stimulation treatment paradigm started within 3 weeks after stroke onset promotes upper limb motor recovery. METHODS: We performed a single-center randomized, sham-controlled clinical trial. Patients with ischemic stroke or intracerebral hemorrhage and unilateral upper limb motor impairment were randomized to 10 daily sessions of active or sham continuous theta-burst stimulation (cTBS) of the contralesional primary motor cortex combined with standard upper limb therapy, started within 3 weeks after stroke onset. The primary outcome was the change in the Action Research Arm Test score from baseline (pretreatment) at 3 months after stroke. Secondary outcomes included the score on the modified Rankin Scale at 3 months and the length of stay at the rehabilitation center. Statistical analyses were performed using mixed models for repeated measures. RESULTS: We enrolled 60 patients between April 2017 and February 2021, of whom 29 were randomized to active cTBS and 31 to sham cTBS. One patient randomized to active cTBS withdrew consent before the intervention and was excluded from the analyses. The mean difference in the change in Action Research Arm Test score from baseline at 3 months poststroke was 9.6 points ([95% CI, 1.2-17.9]; P=0.0244) in favor of active cTBS. Active cTBS was associated with better scores on the modified Rankin Scale at 3 months (OR, 0.2 [95% CI, 0.1-0.8]; P=0.0225) and with an 18 days shorter length of stay at the rehabilitation center than sham cTBS ([95% CI, 0.0-36.4]; P=0.0494). There were no serious adverse events. CONCLUSIONS: Ten daily sessions of cTBS of the contralesional primary motor cortex combined with upper limb training, started within 3 weeks after stroke onset, promote recovery of the upper limb, reduce disability and dependence and leads to earlier discharge from the rehabilitation center. REGISTRATION: URL: https://trialsearch.who.int/; Unique identifier: NTR6133.


Asunto(s)
Corteza Motora , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Humanos , Estimulación Magnética Transcraneal , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/complicaciones , Extremidad Superior , Resultado del Tratamiento , Recuperación de la Función/fisiología
5.
Stroke ; 53(5): 1473-1486, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35387495

RESUMEN

Maintaining blood-brain barrier (BBB) integrity is crucial for the homeostasis of the central nervous system. Structurally comprising the BBB, brain endothelial cells interact with pericytes, astrocytes, neurons, microglia, and perivascular macrophages in the neurovascular unit. Brain ischemia unleashes a profound neuroinflammatory response to remove the damaged tissue and prepare the brain for repair. However, the intense neuroinflammation occurring during the acute phase of stroke is associated with BBB breakdown, neuronal injury, and worse neurological outcomes. Here, we critically discuss the role of neuroinflammation in ischemic stroke pathology, focusing on the BBB and the interactions between central nervous system and peripheral immune responses. We highlight inflammation-driven injury mechanisms in stroke, including oxidative stress, increased MMP (matrix metalloproteinase) production, microglial activation, and infiltration of peripheral immune cells into the ischemic tissue. We provide an updated overview of imaging techniques for in vivo detection of BBB permeability, leukocyte infiltration, microglial activation, and upregulation of cell adhesion molecules following ischemic brain injury. We discuss the possibility of clinical implementation of imaging modalities to assess stroke-associated neuroinflammation with the potential to provide image-guided diagnosis and treatment. We summarize the results from several clinical studies evaluating the efficacy of anti-inflammatory interventions in stroke. Although convincing preclinical evidence suggests that neuroinflammation is a promising target for ischemic stroke, thus far, translating these results into the clinical setting has proved difficult. Due to the dual role of inflammation in the progression of ischemic damage, more research is needed to mechanistically understand when the neuroinflammatory response begins the transition from injury to repair. This could have important implications for ischemic stroke treatment by informing time- and context-specific therapeutic interventions.


Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Barrera Hematoencefálica/metabolismo , Células Endoteliales/metabolismo , Humanos , Inflamación/patología , Enfermedades Neuroinflamatorias , Accidente Cerebrovascular/metabolismo
6.
Stroke ; 53(4): 1411-1422, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35164533

RESUMEN

Translation of acute ischemic stroke research to the clinical setting remains limited over the last few decades with only one drug, recombinant tissue-type plasminogen activator, successfully completing the path from experimental study to clinical practice. To improve the selection of experimental treatments before testing in clinical studies, the use of large gyrencephalic animal models of acute ischemic stroke has been recommended. Currently, these models include, among others, dogs, swine, sheep, and nonhuman primates that closely emulate aspects of the human setting of brain ischemia and reperfusion. Species-specific characteristics, such as the cerebrovascular architecture or pathophysiology of thrombotic/ischemic processes, significantly influence the suitability of a model to address specific research questions. In this article, we review key characteristics of the main large animal models used in translational studies of acute ischemic stroke, regarding (1) anatomy and physiology of the cerebral vasculature, including brain morphology, coagulation characteristics, and immune function; (2) ischemic stroke modeling, including vessel occlusion approaches, reproducibility of infarct size, procedural complications, and functional outcome assessment; and (3) implementation aspects, including ethics, logistics, and costs. This review specifically aims to facilitate the selection of the appropriate large animal model for studies on acute ischemic stroke, based on specific research questions and large animal model characteristics.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Animales , Isquemia Encefálica/terapia , Modelos Animales de Enfermedad , Perros , Humanos , Reproducibilidad de los Resultados , Ovinos , Porcinos , Activador de Tejido Plasminógeno
7.
J Neurosci Res ; 100(5): 1182-1190, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-31769534

RESUMEN

Eating disorders and obesity form a major health problem in Western Society. To be able to provide adequate treatment and prevention, it is necessary to understand the neural mechanisms underlying the development of eating disorders and obesity. Specific brain networks have been shown to be involved in feeding behavior. We therefore hypothesized that functional connectivity in neural networks involved in feeding behavior is dependent on the status of homeostatic energy balance, thus on being hungry or satiated. To test our hypothesis, we measured functional connectivity and amplitudes of neural signals within neural networks in relation to food intake and sucrose tasting in rats. Therefore, 16 male Wistar rats, of which eight were food-restricted and eight were satiated, underwent resting-state functional magnetic resonance imaging (rs-fMRI) at 9.4 T. Subsequently, half of these animals underwent a sucrose tasting procedure followed by a second rs-fMRI scan. Functional connectivity and amplitude of low-frequency signal fluctuations were statistically analyzed in a linear mixed model. Although we did not detect a significant effect of food intake on functional connectivity before sucrose tasting, there was a trend toward interaction between group (satiated vs. hungry) and treatment (sucrose tasting). Functional connectivity between feeding-related regions tended to decrease stronger upon sucrose tasting in satiated rats as compared to food-restricted rats. Furthermore, rs-fMRI signal amplitudes decreased stronger upon sucrose tasting in satiated rats, as compared to food-restricted rats. These findings indicate that food intake and sucrose tasting can affect functional network organization, which may explain the specific patterns in feeding behavior.


Asunto(s)
Mapeo Encefálico , Sacarosa , Animales , Encéfalo , Mapeo Encefálico/métodos , Dieta , Ingestión de Alimentos , Imagen por Resonancia Magnética , Masculino , Obesidad , Ratas , Ratas Wistar , Sacarosa/farmacología
8.
Glia ; 69(3): 655-680, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33045105

RESUMEN

Encephalopathy of prematurity (EoP) is a common cause of long-term neurodevelopmental morbidity in extreme preterm infants. Diffuse white matter injury (dWMI) is currently the most commonly observed form of EoP. Impaired maturation of oligodendrocytes (OLs) is the main underlying pathophysiological mechanism. No therapies are currently available to combat dWMI. Intranasal application of mesenchymal stem cells (MSCs) is a promising therapeutic option to boost neuroregeneration after injury. Here, we developed a double-hit dWMI mouse model and investigated the therapeutic potential of intranasal MSC therapy. Postnatal systemic inflammation and hypoxia-ischemia led to transient deficits in cortical myelination and OL maturation, functional deficits and neuroinflammation. Intranasal MSCs migrated dispersedly into the injured brain and potently improved myelination and functional outcome, dampened cerebral inflammationand rescued OL maturation after dWMI. Cocultures of MSCs with primary microglia or OLs show that MSCs secrete factors that directly promote OL maturation and dampen neuroinflammation. We show that MSCs adapt their secretome after ex vivo exposure to dWMI milieu and identified several factors including IGF1, EGF, LIF, and IL11 that potently boost OL maturation. Additionally, we showed that MSC-treated dWMI brains express different levels of these beneficial secreted factors. In conclusion, the combination of postnatal systemic inflammation and hypoxia-ischemia leads to a pattern of developmental brain abnormalities that mimics the clinical situation. Intranasal delivery of MSCs, that secrete several beneficial factors in situ, is a promising strategy to restore myelination after dWMI and subsequently improve the neurodevelopmental outcome of extreme preterm infants in the future.


Asunto(s)
Lesiones Encefálicas , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Animales , Humanos , Hipoxia , Recién Nacido , Recien Nacido Prematuro , Inflamación , Ratones , Enfermedades Neuroinflamatorias , Secretoma
9.
Stroke ; 52(12): e788-e791, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34674544

RESUMEN

BACKGROUND AND PURPOSE: Brain imaging has become central in the management of acute ischemic stroke. Detection of parenchymal injury and perfusion enables characterization of the extent of ischemic damage, which guides treatment decision-making. Additional assessment of secondary events, such as inflammation, which may particularly arise after recanalization, may improve diagnosis and (supplementary) treatment selection. Therefore, we developed and tested a molecular magnetic resonance imaging (MRI) approach for in vivo detection of vascular inflammation after transient middle cerebral artery occlusion in rats. METHODS: Molecular MRI of VCAM-1 (vascular cell adhesion molecule-1) expression was performed with a targeted contrast agent, in addition to MR angiography, and diffusion-, T2- and perfusion-weighted MRI, from 1 hour until 96 hours after transient middle cerebral artery occlusion in rats. RESULTS: VCAM-1 expression, detected with susceptibility-weighted MRI, was significantly enhanced at 6 hours after recanalization as compared with 1-hour postrecanalization, coinciding with a transient decline in perfusion after initial hyperperfusion. VCAM-1 levels declined after 24 hours, but remained elevated, particularly in lesion borderzones. CONCLUSIONS: The implementation of molecular MRI of vascular inflammation into imaging protocols after acute ischemic stroke could provide complementary information that may guide treatment decision-making before and after recanalization therapy.


Asunto(s)
Infarto de la Arteria Cerebral Media/patología , Imagen por Resonancia Magnética/métodos , Enfermedades Neuroinflamatorias/patología , Vasculitis/patología , Animales , Modelos Animales de Enfermedad , Procedimientos Endovasculares , Infarto de la Arteria Cerebral Media/cirugía , Masculino , Ratas , Ratas Sprague-Dawley , Trombectomía
10.
J Neurosci Res ; 99(5): 1377-1389, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33511664

RESUMEN

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique implicated as a promising adjunct therapy to improve motor function through the neuromodulation of brain networks. Particularly bilateral tDCS, which affects both hemispheres, may yield stronger effects on motor learning than unilateral stimulation. Therefore, the aim of this exploratory study was to develop an experimental model for simultaneous magnetic resonance imaging (MRI) and bilateral tDCS in rats, to measure instant and resultant effects of tDCS on network activity and connectivity. Naïve, male Sprague-Dawley rats were divided into a tDCS (n = 7) and sham stimulation group (n = 6). Functional MRI data were collected during concurrent bilateral tDCS over the sensorimotor cortex, while resting-state functional MRI and perfusion MRI were acquired directly before and after stimulation. Bilateral tDCS induced a hemodynamic activation response, reflected by a bilateral increase in blood oxygenation level-dependent signal in different cortical areas, including the sensorimotor regions. Resting-state functional connectivity within the cortical sensorimotor network decreased after a first stimulation session but increased after a second session, suggesting an interaction between multiple tDCS sessions. Perfusion MRI revealed no significant changes in cerebral blood flow after tDCS. Our exploratory study demonstrates successful application of an MRI-compatible bilateral tDCS setup in an animal model. Our results indicate that bilateral tDCS can locally modulate neuronal activity and connectivity, which may underlie its therapeutic potential.


Asunto(s)
Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiología , Corteza Sensoriomotora/diagnóstico por imagen , Corteza Sensoriomotora/fisiología , Estimulación Transcraneal de Corriente Directa/métodos , Animales , Corteza Cerebral/fisiología , Imagen por Resonancia Magnética/métodos , Masculino , Red Nerviosa/irrigación sanguínea , Ratas , Ratas Sprague-Dawley , Corteza Sensoriomotora/irrigación sanguínea
11.
Int J Eat Disord ; 54(7): 1116-1126, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-32671875

RESUMEN

Satiation is influenced by a variety of signals including gastric distention and oro-sensory stimulation. Here we developed a high-field (9.4 T) functional magnetic resonance imaging (fMRI) protocol to test how oro-sensory stimulation and gastric distention, as induced with a block-design paradigm, affect brain activation under different states of energy balance in rats. Repeated tasting of sucrose induced positive and negative fMRI responses in the ventral tegmental area and septum, respectively, and gradual neural activation in the anterior insula and the brain stem nucleus of the solitary tract (NTS), as revealed using a two-level generalized linear model-based analysis. These unique findings align with comparable human experiments, and are now for the first time identified in rats, thereby allowing for comparison between species. Gastric distention induced more extensive brain activation, involving the insular cortex and NTS. Our findings are largely in line with human studies that have shown that the NTS is involved in processing both visceral information and taste, and anterior insula in processing sweet taste oro-sensory signals. Gastric distention and sucrose tasting induced responses in mesolimbic areas, to our knowledge not previously detected in humans, which may reflect the rewarding effects of a full stomach and sweet taste, thereby giving more insight into the processing of sensory signals leading to satiation. The similarities of these data to human neuroimaging data demonstrate the translational value of the approach and offer a new avenue to deepen our understanding of the process of satiation in healthy people and those with eating disorders.


Asunto(s)
Encéfalo , Gusto , Animales , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Humanos , Imagen por Resonancia Magnética , Ratas , Saciedad , Percepción del Gusto
12.
PLoS Biol ; 15(5): e1002605, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28549068

RESUMEN

In the vertebrate nervous system, myelination of axons for rapid impulse propagation requires the synthesis of large amounts of lipids and proteins by oligodendrocytes and Schwann cells. Myelin membranes are thought to be cell-autonomously assembled by these axon-associated glial cells. Here, we report the surprising finding that in normal brain development, a substantial fraction of the lipids incorporated into central nervous system (CNS) myelin are contributed by astrocytes. The oligodendrocyte-specific inactivation of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), an essential coactivator of the transcription factor SREBP and thus of lipid biosynthesis, resulted in significantly retarded CNS myelination; however, myelin appeared normal at 3 months of age. Importantly, embryonic deletion of the same gene in astrocytes, or in astrocytes and oligodendrocytes, caused a persistent hypomyelination, as did deletion from astrocytes during postnatal development. Moreover, when astroglial lipid synthesis was inhibited, oligodendrocytes began incorporating circulating lipids into myelin membranes. Indeed, a lipid-enriched diet was sufficient to rescue hypomyelination in these conditional mouse mutants. We conclude that lipid synthesis by oligodendrocytes is heavily supplemented by astrocytes in vivo and that horizontal lipid flux is a major feature of normal brain development and myelination.


Asunto(s)
Astrocitos/metabolismo , Enfermedades Desmielinizantes/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metabolismo de los Lípidos , Proteínas de la Membrana/metabolismo , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Animales , Astrocitos/patología , Astrocitos/ultraestructura , Biomarcadores/metabolismo , Cruzamientos Genéticos , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/prevención & control , Dieta Alta en Grasa , Acido Graso Sintasa Tipo I/metabolismo , Eliminación de Gen , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Mutación , Vaina de Mielina/patología , Vaina de Mielina/ultraestructura , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/patología , Oligodendroglía/ultraestructura , Especificidad de Órganos , Procesamiento Proteico-Postraduccional , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética
13.
BMC Neurol ; 20(1): 365, 2020 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-33023487

RESUMEN

BACKGROUND: Transcranial magnetic stimulation (TMS) treatments have shown promise in improving arm recovery in stroke patients. Currently, little is known about patients' experiences with repetitive TMS treatment, and this lack of knowledge may affect optimal implementation in clinical practice. The aim of this explorative study was to gain insight in the perceived effects and experiences of the design and delivery of a rTMS treatment for upper limb recovery from the perspectives of stroke patients. METHODS: This qualitative study was conducted as part of a randomized controlled trial (RCT) in a specialized rehabilitation center. Data were collected through face-to-face semi-structured interviews with 13 stroke patients who completed a 10-day rTMS intervention for upper limb recovery. The interviews were recorded, transcribed verbatim and analyzed using thematic analysis. RESULTS: The major themes that emerged from the patients' feedback were the following: positive experiences of the treatment (experienced physical effects, comfort, therapeutic relationship, receiving information, learning about the brain, no burden of added rTMS treatment session, no unpleasant aspects), concerns (effects of stimulation of the brain, equipment, logistics), general experience of recovery, experienced psychological effects (grateful, sense of purpose, recovery as extra motivation to exercise, disappointment and hope of group allocation), and motivation to participate (personal benefit and cognitions, altruism). Important components related to the positive experience of the design and delivery of the treatment included comfort (i.e. moment of relaxation) and the sensation of a painless treatment without side-effects. Key concerns included uncertainty and anxiety about possible negative consequences and group allocation. CONCLUSIONS: This study demonstrates that rTMS is well accepted by stroke patients with an upper limb paresis. Besides the expectation of a therapeutic benefit, the patients reported various psychological effects. Positive experiences, such as the provision of a short moment of relaxation each day, could have practical implications for clinical stroke rehabilitation settings aimed at improving patient satisfaction. Explanation about and feedback from routine motor recovery progression monitoring at fixed times post-stroke is also valued by patients. Negative emotions may be limited or avoided by transparent and recurrent information delivery in future trials.


Asunto(s)
Satisfacción del Paciente , Recuperación de la Función , Rehabilitación de Accidente Cerebrovascular/métodos , Estimulación Magnética Transcraneal/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paresia/etiología , Paresia/rehabilitación , Accidente Cerebrovascular/complicaciones , Extremidad Superior
14.
Neuromodulation ; 23(3): 324-334, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31353780

RESUMEN

BACKGROUND: Rodent models are fundamental in unraveling cellular and molecular mechanisms of transcranial magnetic stimulation (TMS)-induced effects on the brain. However, proper translation of human TMS protocols to animal models have been restricted by the lack of rodent-specific focal TMS coils. OBJECTIVE: We aimed to improve TMS focalization in rodent brain with a novel small, cooled, and rodent-specific TMS coil. METHODS: A rodent-specific 25-mm figure-of-eight TMS coil was developed. Stimulation focalization was simulated in silico for the rodent coil and a commercial human 50-mm figure-of-eight TMS coil. Both coils were also compared in vivo by electromyography measurements of brachialis motor evoked potential (MEP) responses to TMS at different brain sites in anesthetized rats (n = 6). Focalization was determined from the coils' level of stimulation laterality. Differences in MEPs were statistically analyzed with repeated-measures, within-subjects, ANOVA. RESULTS: In silico simulation results deemed the human coil insufficient for unilateral stimulation of the rat motor cortex, whereas lateralized electrical field induction was projected attainable with the rodent coil. Cortical, in vivo MEP amplitude measurements from multiple points in each hemisphere, revealed unilateral activation of the contralateral brachialis muscle, in absence of ipsilateral brachialis activation, with both coils. CONCLUSION: Computer simulations motivated the design of a smaller rodent-specific TMS coil, but came short in explaining the capability of a larger commercial human coil to induce unilateral MEPs in vivo. Lateralized TMS, as demonstrated for both TMS coils, corroborates their use in translational rodent studies, to elucidate mechanisms of action of therapeutic TMS protocols.


Asunto(s)
Simulación por Computador , Diseño de Equipo/métodos , Modelos Animales , Estimulación Magnética Transcraneal/instrumentación , Animales , Potenciales Evocados Motores/fisiología , Masculino , Ratas , Ratas Sprague-Dawley
15.
Pain Pract ; 20(5): 510-521, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32124540

RESUMEN

OBJECTIVES: To assess the supraspinal working mechanisms of the burst spinal cord stimulation (SCS) mode, we used functional magnetic resonance imaging (fMRI) in chronic neuropathic rats. We hypothesized that active recharge burst SCS would induce a more profound blood oxygenation level-dependent (BOLD) signal increase in areas associated with cognitive-emotional aspects of pain, as compared to tonic SCS. METHODS: Sprague Dawley rats (n = 17) underwent a unilateral partial sciatic nerve ligation, which resulted in chronic neuropathic pain. Quadripolar SCS electrodes were epidurally positioned on top of the dorsal columns at Th13. Isoflurane-anesthetized (1.5%) rats received either tonic SCS (n = 8) or burst SCS (n = 9) at 66% of motor threshold. BOLD fMRI was conducted before, during, and after SCS using a 9.4-T horizontal bore scanner. RESULTS: Overall, both tonic and burst SCS induced a significant increase of BOLD signal levels in areas associated with the location and intensity of pain, and areas associated with cognitive-emotional aspects of pain. Additionally, burst SCS significantly increased BOLD signal levels in the raphe nuclei, nucleus accumbens, and caudate putamen. Tonic SCS did not induce a significant increase in BOLD signal levels in these areas. CONCLUSIONS: In conclusion, active recharge burst and tonic SCS have different effects on the intensity and localization of SCS-induced activation responses in the brain. This work demonstrates that active recharge burst is another waveform that can engage brain areas associated with cognitive-emotional aspects of pain as well as areas associated with location and intensity of pain. Previous studies showing similar engagement used only passive recharge burst.


Asunto(s)
Encéfalo/fisiopatología , Neuralgia/fisiopatología , Estimulación de la Médula Espinal/métodos , Animales , Imagen por Resonancia Magnética , Masculino , Ratas , Ratas Sprague-Dawley , Nervio Ciático/lesiones , Médula Espinal/fisiopatología
16.
Neurobiol Dis ; 126: 23-35, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30086387

RESUMEN

Neural network changes during aging may contribute to vulnerability and resilience to brain lesions in age-related neurological disorders, such as stroke. However, the relationship between age-related neural network features and stroke outcome is unknown. Therefore, we assessed structural and functional network status in young adult and aged rat brain, and measured the effects of simulated stroke lesions. Eleven rats underwent diffusion-weighted MRI and resting-state functional MRI at young adult age (post-natal day 88) and old age (between post-natal day 760 and 880). Structural and functional brain network features were calculated from graph-based network analysis. We performed three lesion simulations based on the brain injury pattern in frequently applied rodent stroke models, i.e. a small cortical lesion, a subcortical lesion, or a large cortical plus subcortical lesion, for which we computationally removed the involved network regions. Global network characteristics, i.e. integration and segregation, were not significantly different between the two age groups. However, we detected local differences in structural and functional networks between young adult and old rats, mainly reflected by shifts of hub regions. Stroke lesion simulations induced significant global and local network changes, characterized by lower efficiency and shifts of hub regions in structural and functional networks, which was most evident after a large cortical plus subcortical lesion. Functional and structural hub region shifts after lesion simulations differed between young adult and aged rats. Our lesion simulation study demonstrates that age-dependent brain network status affects structural and functional network reorganization after stroke, particularly involving hub shifts, which may influence functional outcome. Computational lesion studies offer a cheap and simple alternative to empirical studies and can complement or guide more complicated experimental studies in animal models and patients.


Asunto(s)
Encéfalo/fisiopatología , Modelos Neurológicos , Red Nerviosa/fisiopatología , Accidente Cerebrovascular/fisiopatología , Factores de Edad , Animales , Masculino , Ratas , Ratas Wistar
17.
Glia ; 66(1): 78-93, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28925578

RESUMEN

Diffuse white matter injury (WMI) is a serious problem in extremely preterm infants, and is associated with adverse neurodevelopmental outcome, including cognitive impairments and an increased risk of autism-spectrum disorders. Important risk factors include fetal or perinatal inflammatory insults and fluctuating cerebral oxygenation. However, the exact mechanisms underlying diffuse WMI are not fully understood and no treatment options are currently available. The use of clinically relevant animal models is crucial to advance knowledge on the pathophysiology of diffuse WMI, allowing the definition of novel therapeutic targets. In the present study, we developed a multiple-hit animal model of diffuse WMI by combining fetal inflammation and postnatal hypoxia in rats. We characterized the effects on white matter development and functional outcome by immunohistochemistry, MRI and behavioral paradigms. Combined fetal inflammation and postnatal hypoxia resulted in delayed cortical myelination, microglia activation and astrogliosis at P18, together with long-term changes in oligodendrocyte maturation as observed in 10 week old animals. Furthermore, rats with WMI showed impaired motor performance, increased anxiety and signs of autism-like behavior, i.e. reduced social play behavior and increased repetitive grooming. In conclusion, the combination of fetal inflammation and postnatal hypoxia in rats induces a pattern of brain injury and functional impairments that closely resembles the clinical situation of diffuse WMI. This animal model provides the opportunity to elucidate pathophysiological mechanisms underlying WMI, and can be used to develop novel treatment options for diffuse WMI in preterm infants.


Asunto(s)
Trastorno Autístico/etiología , Hipoxia/complicaciones , Leucoencefalopatías/complicaciones , Vaina de Mielina/patología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Animales , Animales Recién Nacidos , Ansiedad/etiología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/fisiología , Gliosis/etiología , Aseo Animal/efectos de los fármacos , Aseo Animal/fisiología , Hipoxia/diagnóstico por imagen , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/etiología , Lipopolisacáridos/toxicidad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/diagnóstico por imagen , Ratas , Ratas Wistar , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología
18.
Acta Neuropathol ; 135(3): 311-336, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29411111

RESUMEN

The adult quiescent blood-brain barrier (BBB), a structure organised by endothelial cells through interactions with pericytes, astrocytes, neurons and microglia in the neurovascular unit, is highly regulated but fragile at the same time. In the past decade, there has been considerable progress in understanding not only the molecular pathways involved in BBB development, but also BBB breakdown in neurological diseases. Specifically, the Wnt/ß-catenin, retinoic acid and sonic hedgehog pathways moved into the focus of BBB research. Moreover, angiopoietin/Tie2 signalling that is linked to angiogenic processes has gained attention in the BBB field. Blood vessels play an essential role in initiation and progression of many diseases, including inflammation outside the central nervous system (CNS). Therefore, the potential influence of CNS blood vessels in neurological diseases associated with BBB alterations or neuroinflammation has become a major focus of current research to understand their contribution to pathogenesis. Moreover, the BBB remains a major obstacle to pharmaceutical intervention in the CNS. The complications may either be expressed by inadequate therapeutic delivery like in brain tumours, or by poor delivery of the drug across the BBB and ineffective bioavailability. In this review, we initially describe the cellular and molecular components that contribute to the steady state of the healthy BBB. We then discuss BBB alterations in ischaemic stroke, primary and metastatic brain tumour, chronic inflammation and Alzheimer's disease. Throughout the review, we highlight common mechanisms of BBB abnormalities among these diseases, in particular the contribution of neuroinflammation to BBB dysfunction and disease progression, and emphasise unique aspects of BBB alteration in certain diseases such as brain tumours. Moreover, this review highlights novel strategies to monitor BBB function by non-invasive imaging techniques focussing on ischaemic stroke, as well as novel ways to modulate BBB permeability and function to promote treatment of brain tumours, inflammation and Alzheimer's disease. In conclusion, a deep understanding of signals that maintain the healthy BBB and promote fluctuations in BBB permeability in disease states will be key to elucidate disease mechanisms and to identify potential targets for diagnostics and therapeutic modulation of the BBB.


Asunto(s)
Barrera Hematoencefálica/citología , Barrera Hematoencefálica/patología , Animales , Barrera Hematoencefálica/diagnóstico por imagen , Barrera Hematoencefálica/metabolismo , Humanos
19.
Pharm Res ; 35(4): 88, 2018 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-29520577

RESUMEN

PURPOSE: The aim of this study was to determine the potential of magnetic resonance imaging to evaluate the biodistribution of exogenous iron within 24 h after one single injection of Venofer® (iron sucrose). METHODS: Venofer® was evaluated in vitro for its ability to generate contrast in MR images. Subsequently, iron disposition was assessed in rats with MRI, in vivo up to 3 h and post mortem at 24 h after injection of Venofer®, at doses of 10- and 40 mg/kg body weight (n = 2 × 4), or saline (n = 4). RESULTS: Within 10-20 min after injection of Venofer®, transverse relaxation rates (R2) clearly increased, representative of a local increase in iron concentration, in liver, spleen and kidney, including the kidney medulla and cortex. In liver and spleen R2 values remained elevated up to 3 h post injection, while the initial R2 increase in the kidney was followed by gradual decrease towards baseline levels. Bone marrow and muscle tissue did not show significant increases in R2 values. Whole-body post mortem MRI showed most prominent iron accumulation in the liver and spleen at 24 h post injection, which corroborated the in vivo results. CONCLUSIONS: MR imaging is a powerful imaging modality for non-invasive assessment of iron distribution in organs. It is recommended to use this whole-body imaging approach complementary to other techniques that allow quantification of iron disposition at a (sub)cellular level.


Asunto(s)
Sacarato de Óxido Férrico/farmacocinética , Hematínicos/farmacocinética , Imagen por Resonancia Magnética , Imagen de Cuerpo Entero , Animales , Evaluación Preclínica de Medicamentos/métodos , Sacarato de Óxido Férrico/administración & dosificación , Semivida , Hematínicos/administración & dosificación , Inyecciones Intravenosas , Riñón/diagnóstico por imagen , Riñón/metabolismo , Hígado/diagnóstico por imagen , Hígado/metabolismo , Masculino , Modelos Animales , Ratas , Ratas Sprague-Dawley , Bazo/diagnóstico por imagen , Bazo/metabolismo , Distribución Tisular
20.
Z Kinder Jugendpsychiatr Psychother ; 46(3): 246-263, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-28922069

RESUMEN

OBJECTIVE: Research has implicated glutamatergic projections between the various frontal subregions in the pathogenesis of compulsivity and impulsivity. Reducing striatal glutamate release, or antagonising the action of glutamate at its receptors, may therefore represent viable treatment strategies. Several glutamatergic agents with regulatory approval for other indications are available and may be of potential benefit in the treatment of compulsivity/impulsivity in psychiatric disorders in paediatric patients. METHOD: This review was performed according to PRISMA guidelines and evaluates available scientific literature concerning the use of glutamatergic agents in these patients, in order to determine their reported effectiveness/efficacy and tolerability/safety. RESULTS: Out of a total of 1,426 publications, 21 trials examining six glutamatergic substances in patients with obsessive-compulsive disorder, autism spectrum disorders, and attention deficit/hyperactivity disorder were included. CONCLUSIONS: Trial designs as well as results were heterogeneous and thus comparability was limited. Available data support the hypothesis that glutamatergic agents are of potential value in the treatment of compulsivity/impulsivity in children and adolescents. Based on the data reviewed, memantine and N-acetylcysteine suggest the best risk-benefit profile for future trials. Riluzole should primarily be further investigated in adults. Clinical research of this nature is a key element of the TACTICS Consortium project funded by the European Union (FP7).


Asunto(s)
Encéfalo/efectos de los fármacos , Fármacos actuantes sobre Aminoácidos Excitadores/uso terapéutico , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Acetilcisteína/efectos adversos , Acetilcisteína/uso terapéutico , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno del Espectro Autista/tratamiento farmacológico , Niño , Cuerpo Estriado/efectos de los fármacos , Fármacos actuantes sobre Aminoácidos Excitadores/efectos adversos , Ácido Glutámico/metabolismo , Humanos , Memantina/efectos adversos , Memantina/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Glutamato/efectos de los fármacos , Medición de Riesgo , Resultado del Tratamiento
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