There is little axonal growth after central nervous system (CNS) injury in adult mammals. The administration of antibodies (IN-1) to neutralize the myelin-associated neurite growth inhibitory proteins leads to long-distance regrowth of a proportion of CNS axons after injury. Our aim was: to determine if spinal cord lesion in adult rats, followed by treatment with antibodies to neurite growth inhibitors, can lead to regeneration and anatomical plasticity of other spinally projecting pathways; to determine if the anatomical projections persist at long survival intervals; and to determine whether this fibre growth is associated with recovery of function. We report here that brain stem-spinal as well as corticospinal axons undergo regeneration and anatomical plasticity after application of IN-1 antibodies. There is a recovery of specific reflex and locomotor functions after spinal cord injury in these adult rats. Removal of the sensorimotor cortex in IN-1-treated rats 2-3 months later abolished the recovered contact-placing responses, suggesting that the recovery was dependent upon the regrowth of these pathways.
Although there is no spontaneous regeneration of mammalian spinal axons after injury, they can be enticed to grow if cAMP is elevated in the neuronal cell bodies before the spinal axons are cut. Prophylactic injection of cAMP, however, is useless as therapy for spinal injuries. We now show that the phosphodiesterase 4 (PDE4) inhibitor rolipram (which readily crosses the blood-brain barrier) overcomes inhibitors of regeneration in myelin in culture and promotes regeneration in vivo. Two weeks after a hemisection lesion at C3͞4, with embryonic spinal tissue implanted immediately at the lesion site, a 10-day delivery of rolipram results in considerable axon regrowth into the transplant and a significant improvement in motor function. Surprisingly, in rolipram-treated animals, there was also an attenuation of reactive gliosis. Hence, because rolipram promotes axon regeneration, attenuates the formation of the glial scar, and significantly enhances functional recovery, and because it is effective when delivered s.c., as well as post-injury, it is a strong candidate as a useful therapy subsequent to spinal cord injury.
Little axonal regeneration occurs after spinal cord injury in adult mammals. Regrowth of mature CNS axons can be induced, however, by altering the intrinsic capacity of the neurons for growth or by providing a permissive environment at the injury site. Fetal spinal cord transplants and neurotrophins were used to influence axonal regeneration in the adult rat after complete spinal cord transection at a midthoracic level. Transplants were placed into the lesion cavity either immediately after transection (acute injury) or after a 2-4 week delay (delayed or chronic transplants), and either vehicle or neurotrophic factors were administered exogenously via an implanted minipump. Host axons grew into the transplant in all groups. Surprisingly, regeneration from supraspinal pathways and recovery of motor function were dramatically increased when transplants and neurotrophins were delayed until 2-4 weeks after transection rather than applied acutely. Axonal growth back into the spinal cord below the lesion and transplants was seen only in the presence of neurotrophic factors. Furthermore, the restoration of anatomical connections across the injury site was associated with recovery of function with animals exhibiting plantar foot placement and weight-supported stepping. These findings suggest that the opportunity for intervention after spinal cord injury may be greater than originally envisioned and that CNS neurons with long-standing injuries can reinitiate growth, leading to improvement in motor function.
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