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Brain Pathol ; 24(6): 557-67, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24576152


Mechanistic target of rapamycin complex 1 (mTORC1) is an intracellular kinase complex that regulates energy homeostasis and transcription. Modulation of mTORC1 has proven beneficial in experimental spinal cord injury, making this molecular target a candidate for therapeutic intervention in spinal cord injury. However, both inactivation and activation of mTORC1 have been reported beneficial for recovery. To obtain a more complete picture of mTORC1 activity, we aimed to characterize the spatiotemporal activation pattern of mTORC1 and identify activation in particular cell types after contusion spinal cord injury in rats. To be able to provide a spatial characterization of mTORC1 activation, we monitored activation of downstream target S6. We found robust mTORC1 activation both at the site of injury and in spinal segments rostral and caudal to the injury. There was constitutive mTORC1 activation in neurons that was biphasically reduced caudally after injury. We found biphasic mTORC1 activation in glial cells, primarily activated microglia/macrophages. Furthermore, we found mTORC1 activation in proliferating cells, suggesting this may be a function affected by mTORC1 modulation. Our results reveal potential windows of opportunity for therapeutic interference with mTORC1 signaling and immune cells as targets for inhibition of mTORC1 in spinal cord injury.

Macrófagos/metabolismo , Microglía/metabolismo , Complejos Multiproteicos/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Médula Espinal/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Proliferación Celular/fisiología , Modelos Animales de Enfermedad , Femenino , Inmunohistoquímica , Diana Mecanicista del Complejo 1 de la Rapamicina , Neuronas/metabolismo , Fosforilación , Ratas Sprague-Dawley , Proteínas Quinasas S6 Ribosómicas/metabolismo
J Neurotrauma ; 30(21): 1805-11, 2013 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-23879467


A number of different rodent experimental models of spinal cord injury have been used in an attempt to model the pathophysiology of human spinal cord injury. As a result, interlaboratory comparisons of the outcome measures can be difficult. Further complicating interexperiment comparisons is the fact that the rodent response to different experimental models is strain-dependent. Moreover, the literature is abundant with examples in which the same injury model and strain result in divergent functional outcomes. The objective of this research was to determine whether substrain differences influence functional outcome in experimental spinal cord injury. We induced mild contusion spinal cord injuries in three substrains of Sprague-Dawley rats purchased from three different European breeders (Scanbur, Charles River, and Harlan) and evaluated the impact of injury on spontaneous locomotor function, hypersensitivity to mechanical stimulation, and bladder function. We found that Harlan rats regained significantly more hindlimb function than Charles River and Scanbur rats. We also observed substrain differences in the recovery of the ability to empty the bladder and development of hypersensitivity to mechanical stimulation. The Harlan substrain did not show any signs of hypersensitivity in contrast to the Scanbur and Charles River substrains, which both showed transient reduction in paw withdrawal thresholds. Lastly, we found histological differences possibly explaining the observed behavioral differences. We conclude that in spite of being the same strain, there might be genetic differences that can influence outcome measures in experimental studies of spinal cord injury of Sprague-Dawley rats from different vendors.

Modelos Animales de Enfermedad , Hiperalgesia/fisiopatología , Actividad Motora/fisiología , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Animales , Femenino , Hiperalgesia/etiología , Inmunohistoquímica , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/patología
PLoS One ; 7(6): e38760, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22723886


We investigated whether imatinib (Gleevec®, Novartis), a tyrosine kinase inhibitor, could improve functional outcome in experimental spinal cord injury. Rats subjected to contusion spinal cord injury were treated orally with imatinib for 5 days beginning 30 minutes after injury. We found that imatinib significantly enhanced blood-spinal cord-barrier integrity, hindlimb locomotor function, sensorimotor integration, and bladder function, as well as attenuated astrogliosis and deposition of chondroitin sulfate proteoglycans, and increased tissue preservation. These improvements were associated with enhanced vascular integrity and reduced inflammation. Our results show that imatinib improves recovery in spinal cord injury by preserving axons and other spinal cord tissue components. The rapid time course of these beneficial effects suggests that the effects of imatinib are neuroprotective rather than neurorestorative. The positive effects on experimental spinal cord injury, obtained by oral delivery of a clinically used drug, makes imatinib an interesting candidate drug for clinical trials in spinal cord injury.

Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Recuperación de la Función/efectos de los fármacos , Traumatismos de la Médula Espinal/rehabilitación , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Benzamidas , Barrera Hematoencefálica/efectos de los fármacos , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Modelos Animales de Enfermedad , Femenino , Mesilato de Imatinib , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Ratones , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Piperazinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Ratas , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/metabolismo , Resultado del Tratamiento