Asunto(s)
Biomarcadores , Esclerosis Múltiple Crónica Progresiva , Humanos , Biomarcadores/sangre , Esclerosis Múltiple Crónica Progresiva/sangre , Esclerosis Múltiple Crónica Progresiva/inmunología , Moléculas de Adhesión Celular/sangre , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Femenino , Progresión de la Enfermedad , MasculinoRESUMEN
Low neuronal cAMP levels in adults and a further decline following traumatic central nervous system (CNS) injury has been associated with the limited ability of neurons to regenerate. An approach to increase neuronal cAMP levels post injury is electrical stimulation. Stimulation as a tool to promote neuronal growth has largely been studied in the peripheral nervous system or in spared fibers of the CNS and this research suggests that a single session of electrical stimulation is sufficient to initiate a long-lasting axonal growth program. Here, we sought to promote plasticity and growth of the injured corticospinal tract with electrical cortical stimulation immediately after its spinal injury. Moreover, given the importance of rehabilitative motor training in the clinical setting and in translating plasticity into functional recovery, we applied training as a standard treatment to all rats (i.e., with or without electrical stimulation). Our findings show that electrical cortical stimulation did improve recovery in forelimb function compared to the recovery in unstimulated animals. This recovery is likely linked to increased corticospinal tract plasticity as evidenced by a significant increase in sprouting of collaterals above the lesion site, but not to increased regenerative growth through the lesion itself.
Asunto(s)
Corteza Cerebral , Terapia por Estimulación Eléctrica/métodos , Traumatismos de la Médula Espinal/rehabilitación , Animales , Axones , AMP Cíclico/metabolismo , Femenino , Miembro Anterior , Fuerza de la Mano , Fibras Nerviosas/patología , Regeneración Nerviosa , Neuritas , Plasticidad Neuronal , Tractos Piramidales/crecimiento & desarrollo , Ratas , Ratas Endogámicas Lew , Recuperación de la Función , Traumatismos de la Médula Espinal/metabolismoRESUMEN
The reticulospinal tract (RtST) descends from the reticular formation and terminates in the spinal cord. The RtST drives the initiation of locomotion and postural control. RtST axons form new contacts with propriospinal interneurons (PrINs) after incomplete spinal cord injury (SCI); however, it is unclear if injured or uninjured axons make these connections. We completely transected all traced RtST axons in rats using a staggered model, where a hemisection SCI at vertebra T10 is followed by a contralateral hemisection at vertebra T7. In one group of the animals, the T7 SCI was performed 2 weeks after the T10 SCI (delayed; dSTAG), and in another group, the T10 and T7 SCIs were concomitant (cSTAG). dSTAG animals had significantly more RtST-PrIN contacts in the grey matter compared to cSTAG animals (p < 0.05). These results were accompanied by enhanced locomotor recovery with dSTAG animals significantly outperforming cSTAG animals (BBB test; p < 0.05). This difference suggests that activity in neuronal networks below the first SCI may contribute to enhanced recovery, because dSTAG rats recovered locomotor ability before the second hemisection. In conclusion, our findings support the hypothesis that the injured RtST forms new connections and is a key player in the recovery of locomotion post-SCI.
Asunto(s)
Axones/patología , Interneuronas/patología , Locomoción , Regeneración Nerviosa , Traumatismos de la Médula Espinal/fisiopatología , Animales , Femenino , Técnicas de Trazados de Vías Neuroanatómicas , Ratas Endogámicas Lew , Recuperación de la Función , Traumatismos de la Médula Espinal/patología , Vértebras TorácicasRESUMEN
A major goal of Schwann cell (SC) transplantation for spinal cord injury (SCI) is to fill the injury site to create a bridge for regenerating axons. However, transplantation of peripheral nerve SCs requires an invasive biopsy, which may result in nerve damage and donor site morbidity. SCs derived from multipotent stem cells found in skin dermis (SKP-SCs) are a promising alternative. Regardless of source, loss of grafted SCs post-grafting is an issue in studies of regeneration, with survival rates ranging from â¼1 to 20% after ≥6 weeks in rodent models of SCI. Immune rejection has been implicated in these low survival rates. Therefore, our aim was to explore the role of the immune response on grafted SKP-SC survival in Fischer rats with a spinal hemisection injury. We compared SKP-SC survival 6 weeks post-transplantation in: (I) cyclosporine-immunosuppressed rats (n=8), (II) immunocompetent rats (n=9), and (III) rats of a different sub-strain than the SKP-SC donor rats (n=7). SKP-SC survival was similar in all groups, suggesting immune rejection was not a main factor in SKP-SC loss observed in this study. SKP-SCs were consistently found on laminin expressed at the injury site, indicating detachment-mediated apoptosis (i.e., anoikis) might play a major role in grafted cell loss.
Asunto(s)
Ciclosporina/farmacocinética , Regeneración Nerviosa/fisiología , Células de Schwann/citología , Traumatismos de la Médula Espinal/terapia , Animales , Ciclosporina/farmacología , Modelos Animales de Enfermedad , Femenino , Nervios Periféricos/citología , Ratas Endogámicas F344 , Recuperación de la Función/fisiología , Células de Schwann/efectos de los fármacos , Médula Espinal/patología , Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/patologíaRESUMEN
Injured neurons in the adult mammalian central nervous system (CNS) have a very limited capacity for axonal regeneration and neurite outgrowth. This inability to grow new axons or to regrow injured axons is due to the presence of molecules that inhibit axonal growth, and age related changes in the neuron's innate growth capabilities. Available levels of cAMP are thought to have an important role in linking both of these factors. Elevated levels of cAMP in the developing nervous system are important for the guidance and stability of growth cones. As the nervous system matures, cAMP levels decline and the growth promoting effects of cAMP diminish. It has frequently been demonstrated that increasing neuronal cAMP can enhance neurite growth and regeneration. Some methods used to increase cAMP include administration of cAMP agonists, conditioning lesions, or electrical stimulation. Furthermore, it has been proposed that multiple stages of cAMP induced growth exist, one directly caused by its downstream effector Protein Kinase A (PKA) and one caused by the eventual upregulation of gene transcription. Although the role cAMP in promoting axon growth is well accepted, the downstream pathways that mediate cAMP-mediated axonal growth are less clear. This is partly because various key studies that explored the link between PKA and axonal outgrowth relied on the PKA inhibitors KT5720 and H89. More recent studies have shown that both of these drugs are less specific than initially thought and can inhibit a number of other signalling molecules including the Exchange Protein Activated by cAMP (EPAC). Consequently, it has recently been shown that a number of intracellular signalling pathways previously attributed to PKA can now be attributed solely to activation of EPAC specific pathways, or the simultaneous co-activation of PKA and EPAC specific pathways. These new studies open the door to new potential treatments for repairing the injured spinal cord.