ABSTRACT
Multiple sclerosis (MS), especially in its progressive phase, involves early axonal and neuronal damage resulting from a combination of inflammatory mediators, demyelination, and loss of trophic support. During progressive disease stages, a microenvironment is created within the central nervous system (CNS) favoring the arrival and retention of inflammatory cells. Active demyelination and neurodegeneration have also been linked to microglia (MG) and astrocyte (AST)-activation in early lesions. While reactive MG can damage tissue, exacerbate deleterious effects, and contribute to neurodegeneration, it should be noted that activated MG possess neuroprotective functions as well, including debris phagocytosis and growth factor secretion. The progressive form of MS can be modeled by the prolonged administration to cuprizone (CPZ) in adult mice, as CPZ induces highly reproducible demyelination of different brain regions through oligodendrocyte (OLG) apoptosis, accompanied by MG and AST activation and axonal damage. Therefore, our goal was to evaluate the effects of a reduction in microglial activation through orally administered brain-penetrant colony-stimulating factor-1 receptor (CSF-1R) inhibitor BLZ945 (BLZ) on neurodegeneration and its correlation with demyelination, astroglial activation, and behavior in a chronic CPZ-induced demyelination model. Our results show that BLZ treatment successfully reduced the microglial population and myelin loss. However, no correlation was found between myelin preservation and neurodegeneration, as axonal degeneration was more prominent upon BLZ treatment. Concomitantly, BLZ failed to significantly offset CPZ-induced astroglial activation and behavioral alterations. These results should be taken into account when proposing the modulation of microglial activation in the design of therapies relevant for demyelinating diseases. Cover Image for this issue: https://doi.org/10.1111/jnc.15394.
Subject(s)
Demyelinating Diseases , Multiple Sclerosis , Animals , Colony-Stimulating Factors/adverse effects , Colony-Stimulating Factors/metabolism , Cuprizone/metabolism , Cuprizone/toxicity , Demyelinating Diseases/chemically induced , Demyelinating Diseases/drug therapy , Demyelinating Diseases/metabolism , Disease Models, Animal , Mice , Mice, Inbred C57BL , Microglia/metabolism , Multiple Sclerosis/metabolism , Myelin Sheath/metabolismABSTRACT
Previous work by our group has shown the pro-differentiating effects of apotransferrin (aTf) on oligodendroglial cells in vivo and in vitro. Further studies showed the remyelinating effect of aTf in animal demyelination models such as hypoxia/ischemia, where the intranasal administration of human aTf provided brain neuroprotection and reduced white matter damage, neuronal loss, and astrogliosis in different brain regions. These data led us to search for a less invasive and controlled technique to deliver aTf to the CNS. To such end, we isolated extracellular vesicles (EVs) from human and mouse plasma and different neuron and glia conditioned media and characterized them based on their quality, quantity, identity, and structural integrity by western blot, dynamic light scattering, and scanning electron microscopy. All sources yielded highly pure vesicles whose size and structures were in keeping with previous literary evidence. Given that, remarkably, EVs from all sources analyzed contained Tf receptor 1 (TfR1) in their composition, we employed two passive cargo-loading strategies which rendered successful EV loading with aTf, specifically through binding to TfR1. These results unveil EVs as potential nanovehicles of aTf to be delivered into the CNS parenchyma, and pave the way for further studies into their possible clinical application in the treatment of demyelinating diseases.
Subject(s)
Apoproteins/metabolism , Extracellular Vesicles/metabolism , Nanoparticles/metabolism , Receptors, Transferrin/metabolism , Transferrin/metabolism , Adult , Animals , Apoproteins/administration & dosage , Astrocytes/drug effects , Astrocytes/metabolism , Cell Line, Transformed , Cell Line, Tumor , Cells, Cultured , Female , Humans , Male , Mice , Nanoparticles/administration & dosage , Rats , Rats, Wistar , Receptors, Transferrin/administration & dosage , Transferrin/administration & dosageABSTRACT
Fueron estudiados 989 pacientes con linfoma. Tuvieron infiltración linfomatosa craneocerebral 53 casos (5.3%). Los principales factores de riesgo para esta complicación fueron: a. estado avanzado del linfoma (III o IV); b. las forma difusas histiocíticas, difusa pobremente diferenciada o celularidad mixta: c. el compromiso de la medula osea y de la quimioterapia sistémica previa. En el 32% de los casos la infiltración meníngea linfomatosa fué asintomática y representó hallazgos de autopsia. La tomografía cerebral fué de utilidad para detectar infiltraciones parenquimatosas focales, no así para las infiltraciones meníngeas. El tiempo medio de sobrevida en pacientes con infiltración meníngea linfomatosa fué de 4.3 meses, siguientes al uso combinado de terapia radiante a craneo total, quimioterápia sistémica y/o intratecal con methotrexate. Dos casos con linfoma cerebral primario no estuvieron asociados con inmunodeficiencia. Hemorragias intracraniales se observaron en 20 pacientes (2%), en relación con alteraciones plaquetarias. En 15 casos hubo infección del SNC (1.5%), causada por bacterias comunes o por agentes oportunistas. En 7 de esos casos el diagnóstico se hizo por autopsia. En 8 de 36 casos autopsiados (22%) se observaron desmielinización, microcalcificaciones, necrosis coagulativa o gliosis, sugestivas de complicaciones por los tratamientos efectuados
