Celebrating neural repair

Field: Neuroscience (Life Sciences)

The authors of this special collection of 11 manuscripts were invited to contribute to the Journal of Comparative Neurology after their scientific presentations at the 15th anniversary meeting of the American Society for Neural Therapy and Repair (ASNTR) held in May, 2008 in Clearwater Beach, Florida. These contributions represent work of society members who have advanced the field of neural repair through innovative approaches. This is a field of considerable interest to readers of the Journal of Comparative Neurology, and two of our Associate Editors focus on novel findings in nervous system regeneration and repair. This special issue features five manuscripts that reveal new approaches to protection and restoration of the nigrostriatal dopamine system, which is at risk in Parkinson's disease. Many studies, including clinical trials, have resulted in less than desired outcomes, and the current studies help to explain some present problems and offer potential solutions. Specifically, Nikkhah and colleagues demonstrate that the number of neurons that survive intracerebral grafting is important only if they are properly distributed throughout the intended target. Steece-Collier's laboratory presents strong evidence that prior levodopa treatment substantially reduces the behavioral and biochemical efficacy of neural grafts, which can be of profound importance for patient treatment. Dyskinesias that have occurred after grafting in humans may also be the result of a lack of afferent control of grafted neurons, and in this regard the laboratories of Redmond and Sladek have demonstrated the ability of glial-derived neurotrophic factor (GDNF), delivered through viral vectors, to promote neurite extension to the striatum from dopamine neurons grafted in the vicinity of the host substantia nigra in the non-human primate. Collier and colleagues add another interesting consideration for optimizing survival of dopamine neurons, i.e., essential synergies between implanted neural stem cells and the ability of the lesioned host brain to provide subventricular zone neurogenesis. They found preservation of the host dopamine system and propose that combination therapies may provide the best approach for neural protection and repair. Strömberg and colleagues show an unexpected benefit on survival of dopamine neurons when they are co-grafted with embryonic neurons of the noradrenergic locus coeruleus or when antioxidants such as blueberries are administered through the diet. The other six contributions focus on equally relevant questions and span a variety of neurological conditions that would benefit from cellular therapies. Sagen and colleagues highlight the importance of developing methods to produce γ-aminobutyric acid (GABA)-inhibitory neurons that could find numerous applications when neuronal communication would benefit from modulation by inhibitory neurons. Snyder and coworkers show the ability of neural stem cells to maintain long-term transgene expression following grafting, which is of critical importance when contemplating human interventions. The work presented by Hoffer's group addresses the ability of a novel factor derived from astrocytes of the mesencephalon to provide neuroprotection in an animal model of stroke. Stroke is also addressed by Low and associates, who provide an extensive overview of the potential for restoration of function in human ischemic disorders. The intriguing results presented by work from the laboratories of Garbuzova-Davis and Sanberg suggest that human umbilical cord-derived stem cells are capable of providing needed enzymes in a genetic childhood disorder for which no treatment currently exists. Finally, the keynote address for the 15th anniversary meeting by Howard Federoff describes novel therapeutics for neurodegenerative disorders that are characterized by protein misfoldings and the potential for vaccines to provide effective therapeutic options. This meeting celebrated two anniversaries; a comparatively modest 15th for ASNTR, which began as a hope and dream in 1994, and an impressive 100th for the first demonstration of graft-induced neural plasticity (Ranson,1909). That these two events have intertwined histories is perhaps providential. Walter S. Ranson, MD, PhD, first disseminated the results of his innovative experiment in the Quarterly Bulletin of Northwestern University Medical School, only 2 years after receiving his MD, and followed with a seminal paper in the Journal of Comparative Neurology in 1914 (Ranson,1914). It is fitting therefore that the Journal offered to help ASNTR celebrate its 15th anniversary with this special issue.1 Ranson's illustration of morphological change in transplanted spinal ganglion neurons. He carefully depicted the cells at 3 days and 17 days after transplantation using the art of drawing paraffin-embedded sections that had been stained with pyridine-silver to reveal the outlines of newly formed fibers. His fundamental observation is shown in his Figures 2 and 3, where newly formed, and abundant, fibers ramified throughout the grafted tissue. Although most neurons in the center of the grafted ganglion died, some of those located at the periphery survived and revealed evidence for regeneration of new fibers. Thus, they appeared to be multipolar soon after grafting. However, they later lost that characteristic and by 17 days again appeared to be unipolar, as shown in his Figure 5 (Fig. 2, 3 days; Fig. 3, 4 days; Fig. 4, 2 days; Fig. 5, 17 days). Reprinted from Ranson, 1909, with permission. This much is clear, in transplanted ganglia, simple unipolar spinal ganglion cells become transformed into complex multipolar cells, due to the sprouting of new processes from the cell body and axon, and these complex cells are very similar to, if not identical with, those found in varying number in normal ganglia. It is also clear that these now-formed processes can later disappear and the cell again can be transformed into the simple unipolar type. In this way it is demonstrated that the form of the spinal ganglion is not stable and fixed, but is capable of undergoing marked alteration in a short space of time. Just what the factors are that bring about such changes in form is here left unmentioned because we have no adequate means of forming a conception of them, and what theorizing that has been done on the subject has only tended to obscure the essential fact that the spinal ganglion cells may undergo striking changes in form. One can imagine the excitement Ranson must have experienced with the discovery that neurons (which even 50 years later were still being described in medical texts as part of a fixed, immutable structure of the brain) could take on altered shapes as a result of new environments. This occurred only 3 years after the heated debate by Santiago Ramón y Cajal and Camillo Golgi on the occasion of their Nobel Prize lectures (Grant,2007). Golgi described the nervous system as a connected syncytium of neurons, which would be difficult to reconcile with the concept of plasticity. In this context, the work of Ranson not only provided a classic demonstration supporting the Neuron Doctrine that Cajal proclaimed, but also opened up the entirely new field of neural transplants, which ASNTR and the Journal celebrate with this issue. We look forward to harnessing the ability of neurons and glia to adapt in our attempts to restore function.