Enhancing Recovery after Cervical Spinal Injury in Primates

In a recent publication in Nature Medicine (12: 790–792, 2006), Freund et al., provide important information regarding the factors, which may inhibit or enhance functional recovery after spinal cord lesions. Any process of organogenesis or CNS repair must have an interplay of forces that encourage the growth and development of neurocomponents, as well as, modify and direct those components in order to provide a coherent final product and avoid neoplasia. Indeed, one of the major developments in the study of plasticity after injury is the understanding that neurite growth inhibitors such as, Nogo-A may limit and direct growth. While their function in regulation may be valuable, they may indeed restrict adult regenerative capacity by limiting neurite sprouting and growth. Several studies in lower animals have suggested that in neutralizing these, we can encourage sprouting. Questions remain whether such function takes place in higher level animals such as primates, whether it can happen in adults and whether it has any functional significance needs to be answered. For this reason, the authors have taken these experiments to primates and specifically ask to see whether the beneficial function of sprouting takes place in the adult primate. In addition, does it have functional significance and can we, in any way, assess the concern that disinhibited gene sprouting may have pathological or dysesthetic consequences?

Specifically, the researchers looked at both function and anatomic recovery after possible spinal cord injuries in animals treated with specific antibodies to block neurite growth inhibitors. These studies were done previously in non-primate rats and suggest that one of the reasons that transected nerve fibers in the spinal cord to not spontaneously regrow is the effect of such inhibitors of myelin-associated neurite growth, such as Nogo-A. Therefore, studies have suggested that neutralizing Nogo-A may be a therapeutic approach. These studies are further validated in the author's adult primate models. The significance of these studies is the use of adult primates and the ability to monitor not only functional recovery of hand function, but also evidence of pathological sprouting, which could theoretically cause dysfunction or pain. None was seen in this study. The authors look at dexterous movement in the fingers after spinal cord injury, reasoning correctly that deficits in manual dexterity are of considerable importance after partial corticospinal tract injuries. They further validate their studies by labeling corticospinal axons with an antegrade tracer Biotinylated Dextran Amine (BDA) in the motor cortex, and studying for sprouting of corticospinal fibers caudal to the lesion. Both cases suggest improvements with quicker recovery. More complete recovery and more sprouting of axons were seen in the animals treated with the Nogo-A specific antibody. This is an important finding in that it extends previous studies in rats to adult primates and also utilizes functional testing of manual dexterity not possible in other models. In addition, these animals did not show evidence of dysesthetic pain, reassuringly suggesting an absence of pathological sprouting, which could theoretically have resulted in further dysfunction. The study suggests one more step in the process of CNS repair and some rather nice models for us to test such hypothesis.

ROBERT J. DEMPSEY, M.D.

NATIONAL INSTITUTES OF HEALTH NEWS