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1.
Neurobiol Dis ; 130: 104501, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31226301

RESUMEN

Diffusion tensor imaging (DTI) has been shown to detect white matter degeneration in multiple sclerosis (MS), a neurodegenerative autoimmune disease that presents with diffuse demyelination of the central nervous system. However, the utility of DTI in evaluating therapeutic remyelination has not yet been well-established. Here, we assessed the ability of DTI to distinguish between remyelination and neuroprotection following estrogen receptor ß ligand (Indazole chloride, IndCl) treatment, which has been previously shown to stimulate functional remyelination, in the cuprizone (CPZ) diet mouse model of MS. Adult C57BL/6 J male and female mice received a normal diet (control), demyelination-inducing CPZ diet (9wkDM), or CPZ diet followed by two weeks of a normal diet (i.e., remyelination period) with either IndCl (RM + IndCl) or vehicle (RM + Veh) injections. We evaluated tissue microstructure of the corpus callosum utilizing in vivo and ex vivo DTI and immunohistochemistry (IHC) for validation. Compared to control mice, the 9wkDM group showed decreased fractional anisotropy (FA), increased radial diffusivity (RD), and no changes in axial diffusivity (AD) both in vivo and ex vivo. Meanwhile, RM + IndCl groups showed increased FA and decreased RD ex vivo compared to the RM + Veh group, in accordance with the evidence of remyelination by IHC. In conclusion, the DTI technology used in the present study can identify some changes in myelination and is a valuable translational tool for evaluating MS pathophysiology and therapeutic efficacy.


Asunto(s)
Cuerpo Calloso/diagnóstico por imagen , Enfermedades Desmielinizantes/diagnóstico por imagen , Receptor beta de Estrógeno/agonistas , Indazoles/uso terapéutico , Esclerosis Múltiple/diagnóstico por imagen , Fármacos Neuroprotectores/uso terapéutico , Remielinización/efectos de los fármacos , Animales , Cuerpo Calloso/efectos de los fármacos , Cuprizona , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/tratamiento farmacológico , Imagen de Difusión Tensora , Modelos Animales de Enfermedad , Femenino , Indazoles/farmacología , Imagen por Resonancia Magnética , Masculino , Ratones , Esclerosis Múltiple/inducido químicamente , Esclerosis Múltiple/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología
2.
PLoS One ; 13(9): e0198464, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30248101

RESUMEN

Matrix metalloproteinases-2 and -9 (MMP-2/-9) are key tissue remodeling enzymes that have multiple overlapping activities critical for wound healing and tumor progression in vivo. To overcome issues of redundancy in studying their functions in vivo, we created MMP-2/-9 double knockout (DKO) mice in the C57BL/6 background to examine wound healing. We then bred the DKO mice into the polyomavirus middle T (PyVmT) model of breast cancer to analyze the role of these enzymes in tumorigenesis. Breeding analyses indicated that significantly fewer DKO mice were born than predicted by Mendelian genetics and weaned DKO mice were growth compromised compared with wild type (WT) cohorts. Epithelial wound healing was dramatically delayed in adult DKO mice and when the DKO was combined with the PyVmT oncogene, we found that the biologically related process of mammary tumorigenesis was inhibited in a site-specific manner. To further examine the role of MMP-2/-9 in tumor progression, tumor cells derived from WT or DKO PyVmT transgenic tumors were grown in WT or DKO mice. Ratiometric activatable cell penetrating peptides (RACPPs) previously used to image cancer based on MMP-2/-9 activity were used to understand differences in MMP activity in WT or knockout syngeneic tumors in WT and KO animals. Analysis of an MMP-2 selective RACPP in WT or DKO mice bearing WT and DKO PyVmT tumor cells indicated that the genotype of the tumor cells was more important than the host stromal genotype in promoting MMP-2/-9 activity in the tumors in this model system. Additional complexities were revealed as the recruitment of host macrophages by the tumor cells was found to be the source of the tumor MMP-2/-9 activity and it is evident that MMP-2/-9 from both host and tumor is required for maximum signal using RACPP imaging for detection. We conclude that in the PyVmT model, the majority of MMP-2/-9 activity in mammary tumors is associated with host macrophages recruited into the tumor rather than that produced by the tumor cells themselves. Thus therapies that target tumor-associated macrophage functions have the potential to slow tumor progression.


Asunto(s)
Carcinogénesis/metabolismo , Péptidos de Penetración Celular/metabolismo , Neoplasias Mamarias Animales/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Cicatrización de Heridas , Animales , Carcinogénesis/genética , Carcinogénesis/patología , Línea Celular Tumoral , Femenino , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/patología , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos
3.
J Neurosci Methods ; 284: 71-84, 2017 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-28396177

RESUMEN

BACKGROUND: While many groups use experimental autoimmune encephalomyelitis (EAE) as a model to uncover therapeutic targets and understand the pathology underlying multiple sclerosis (MS), EAE protocol variability introduces discrepancies in central nervous system (CNS) pathogenesis and clinical disease, limiting the comparability between studies and slowing much-needed translational research. OPTIMIZED METHOD: Here we describe a detailed, reliable protocol for chronic EAE induction in C57BL/6 mice utilizing two injections of myelin oligodendrocyte glycoprotein (35-55) peptide mixed with complete Freund's adjuvant and paired with pertussis toxin. RESULTS: The active MOG35-55-EAE protocol presented here induces ascending paralysis in 80-100% of immunized mice. We observe: (1) consistent T cell immune activation, (2) robust CNS infiltration by peripheral immune cells, and (3) perivascular demyelinating lesions concurrent with axon damage in the spinal cord and various brain regions, including the optic nerve, cortex, hippocampus, internal capsule, and cerebellum. COMPARISON WITH EXISTING METHOD(S): Lack of detailed protocols, combined with variability between laboratories, make EAE results difficult to compare and hinder the use of this model for therapeutic development. We provide the most detailed active MOG35-55-EAE protocol to date. With this protocol, we observe high disease incidence and a consistent, reliable disease course. The resulting pathology is MS-like and includes optic neuritis, perivascular mononuclear infiltration, CNS axon demyelination, and axon damage in both infiltrating lesions and otherwise normal-appearing white matter. CONCLUSIONS: By providing a detailed active MOG35-55-EAE protocol that yields consistent and robust pathology, we aim to foster comparability between pre-clinical studies and facilitate the discovery of MS therapeutics.


Asunto(s)
Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Adyuvante de Freund , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Glicoproteína Mielina-Oligodendrócito , Animales , Combinación de Medicamentos , Encefalomielitis Autoinmune Experimental/inducido químicamente , Femenino , Humanos , Estudios Longitudinales , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inducido químicamente , Fragmentos de Péptidos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Resultado del Tratamiento
4.
Neuroscience ; 346: 409-422, 2017 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-28153692

RESUMEN

Multiple sclerosis (MS) patients are three to six times more likely to develop epilepsy compared to the rest of the population. Seizures are more common in patients with early onset or progressive forms of the disease and prognosticate rapid progression to disability and death. Gray matter atrophy, hippocampal lesions, interneuron loss, and elevated juxtacortical lesion burden have been identified in MS patients with seizures; however, translational studies aimed at elucidating the pathophysiological processes underlying MS epileptogenesis are limited. Here, we report that cuprizone-mediated chronically demyelinated (9-12weeks) mice exhibit marked changes to dorsal hippocampal electroencephalography (EEG) and evidence of overt seizure activity. Immunohistochemical (IHC) analyses within the hippocampal CA1 region revealed extensive demyelination, loss of parvalbumin (PV+) interneurons, widespread gliosis, and changes in aquaporin-4 (AQP4) expression. Our results suggest that chronically demyelinated mice are a valuable model with which we may begin to understand the mechanisms underlying demyelination-induced seizures.


Asunto(s)
Enfermedades Desmielinizantes/fisiopatología , Hipocampo/fisiopatología , Esclerosis Múltiple/fisiopatología , Convulsiones/fisiopatología , Animales , Acuaporina 4/metabolismo , Cuprizona/administración & dosificación , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Electroencefalografía , Gliosis/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/metabolismo , Esclerosis Múltiple/inducido químicamente , Esclerosis Múltiple/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Convulsiones/inducido químicamente , Convulsiones/patología
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