Brain, Vol. 126, No. 4, 1009-1011,
April 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg078
Book Review |
DEGENERATION AND REGENERATION IN THE NERVOUS SYSTEM
Department of Neuropathology, Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK
DEGENERATION AND REGENERATION IN THE NERVOUS SYSTEM
Edited by Norman R. Saunders and Katarzyna M. Dziegielewska
2000. Amsterdam: Harwood Academic Publishers
Price £39. pp. 348. ISBN 90-5823-022-8.
Repair of the damaged human central nervous system (CNS) remains a much sought after but still elusive goal of patients, clinicians and scientists. As noted by Douglas Brown, in the opening chapter of this book, patients and their families have been alternately excited by the prospect of cure and frustrated by the delays in achieving this. Clinicians have found themselves in an awkward position trying to bridge the gap between the expectations of patients, the enthusiasm of researchers, and the limitations of available treatment. This book comprises 14 reviews of different aspects of degeneration, regeneration and adaptation to injury in the nervous system, with an emphasis on interventions that promote the regrowth of damaged axons. Most of the reviews relate to degeneration and regeneration in the CNS but three of the chapters focus on the peripheral nervous system.
In the first chapter, Brown analyses the findings in several studies of high-dose methylprednisolone for the treatment of patients with acute spinal cord injury. The results of the US National Acute Spinal Cord Studies suggest that high-dose methylprednisolone may improve neurological outcome. However, methylprednisolone significantly increased the risk of severe sepsis, and several methodological problems, including the use of historical controls, limit the value of these trials as a guide to treatment. Brown also briefly considers other potential treatments for acute injury, such as GM-1 ganglioside and thyrotropin releasing hormone, and the possible role of the potassium channel-blocking agent 4-aminopyridine in patients with chronic spinal cord injury.
Saunders and Dziegielewska give a detailed account of studies demonstrating the enabling effect of embryonic spinal cord tissue in promoting (limited) axonal growth across transected neonatal spinal cord. Several of the studies have been complicated by a failure to distinguish unequivocally between the relative contributions of newly growing (‘late arriving’) and regenerating axons, but the use of retrogradely transported dyes to label neurons before and after cord transection suggests that some of the axonal growth does indeed represent regeneration. The importance of the immaturity of the spinal cord tissue in enabling such regeneration is emphasised by further studies that the authors of this chapter have conducted, on neonatal marsupials and fetal (E15) rats, in which regeneration that is more impressive, both structurally and functionally, than that in more mature animals has been demonstrated.
Anderson and Lieberman review a large number of studies involving the implantation of peripheral nerve into lesions in central nervous tissue. This chapter covers in some detail the relationship between the regenerative potential of different populations of neurons and their expression of a range of transcription factors, cell adhesion and recognition molecules, and growth cone proteins, such as GAP-43. Brief mention is also made of the regeneration inhibitor Nogo.
The inhibition of regeneration is considered in more detail by Fitch and Silver, in the next chapter. The focus is on the inhibitory effects of components of myelin and chondroitin sulphate proteoglycans on axonal regeneration. These effects are complex and vary for different populations of neurons. Towards the end of the chapter, the authors also review some of the complex effects on axonal regeneration of the inflammatory response to nervous system injury.
The complexity of the intrinsic neuronal and extrinsic glial and inflammatory determinants of axonal regeneration is highlighted in the chapter by Tetzlaff and Steeves, who compare the responses to axotomy of peripheral neurons with those of neurons in the CNS. The heterogeneity of different neuronal populations in their response to different neurotrophins and other growth factors is again emphasised. On the one hand this complexity seems to pose insurmountable barriers to achieving successful repair of the CNS in man. However, there is evidence of some redundancy in the mechanisms that promote and support regeneration, suggesting that it may not be necessary to overcome all potential inhibitory influences for axons to regenerate.
Beazley and Dunlop look at the inter-relationship between successful optic nerve regeneration and ganglion cell survival in different species. They identify a wide range of species-related differences in the responses of ganglion cells to axotomy, the extent of axonal sprouting and elongation, the responses of astrocytes and macrophages, and the effects on the blood–brain barrier. The authors also consider the possible role of NMDA antagonists, inhibitors of apoptosis, and trophic proteins such as NGF and BDNF in preventing ganglion cell death and promoting optic nerve regeneration.
The theme of the chapter by Conti and Selzer is the role of the cytoskeleton in the regeneration of axons within the CNS. Much of this chapter concerns the structure and functioning of the growth cone. This is clearly described and simply but effectively illustrated. Successful regeneration depends primarily on the transport and assembly of actin and microtubules rather than neurofilaments, which seem to play little part in axonal regrowth. However, neurofilaments are probably needed to ‘consolidate’ and sustain the structure of the axons after they have regenerated.
Mary Bunge provides an excellent review of the use of ‘bridges’ to promote axonal regeneration across sites of injury in the adult mammalian spinal cord. The chapter includes some introductory comments that give a clinical context to the book as a whole. She covers the use of peripheral nerve graphs, Schwann cell transplants, and olfactory ensheathing glia, and the growth-promoting effects of either co-administering methylprednisolone and neurotrophic factors or genetically modifying Schwann cells to secrete neurotrophic factors. Other types of transplant, such as genetically engineered fibroblasts, fetal CNS tissue and CNS-derived neural cell lines are also mentioned, although only briefly, towards the end of the chapter.
Alan Harvey continues the theme of ‘bridges’ but with an emphasis on the use of synthetic polymers to construct the bridges, with or without co-implantation of Schwann cells, astrocytes, olfactory ensheathing glia or trophic factors. My impression on reading this chapter was that most of these studies on the use of polymer or hybrid structures as conduits for axonal regeneration have been informative but disappointing. However, some interesting results have been reported after the incorporation of matrix components such as collagen IV into methacrylate polymers, and very recent reports (not included in this review) suggest a role for the incorporation of chondroitinases. Harvey suggests that in future these approaches may be combined with the application of external chemical or electromagnetic gradients to promote axonal regrowth.
A well-written chapter on neural stem cells follows, by Bartlett, Brooker, Faux, Turnley and Kilpatrick. Although the field has progressed since this chapter was written, it remains an excellent account of the history of this rapidly moving field of research and of the basic molecular and developmental signals that determine whether neural stem cells differentiate into astrocytes, oligodendrocytes or neurons.
The next three chapters move away from the CNS to cover some aspects of degeneration and regeneration in the peripheral nervous system. The first of these is an account of the possible roles of the low-affinity neurotrophin receptor, p75, in nerve regeneration, by Ferguson, Lu, Zhou and Rush. This receptor has, to some extent, long been a molecule in search of a function. Potential functions include the modulation of binding of neurotrophins to trk receptors, the retrograde transport of neurotrophins, and the transduction of pro-apoptotic signals. Recent research (not covered in this book) suggests that p75 can form a complex with Nogo receptor to mediate the negative neurotropic effects of myelin-associated glycoprotein on axonal growth. As noted by the authors, the functions of p75 probably vary in different neuronal populations so that, for example, p75 transcripts increase in facial motor neurons after crush injury to the facial nerve but neuronal levels of p75 decline after transection of sensory or sympathetic nerves.
Mark Bisby continues the discussion of regeneration in the peripheral nervous system, with a summary of some of the associated biochemical events, including the up-regulation of GAP-43, 
-tubulin and neurodap-1, and the activation of c-jun protein kinase. He summarises several studies concerned with the guidance of the growth cone, the inhibitory effect of myelin debris and the tropic and trophic actions of the distal nerve stump, BDNF and other mediators. In considering the role of the Schwann cell in promoting axonal regeneration, Bisby concentrates on the function of neuregulins, which stimulate Schwann cell proliferation, migration and the secretion of neurotrophic and neurotropic factors. He also briefly alludes to Reg-2, which is produced by motor neurons after axotomy and which stimulates Schwann cell proliferation.
There follows an excellent account by Hughes and Perry on the role of macrophages in degeneration and regeneration in the peripheral nervous system. This review leans heavily on evidence from mouse models, especially C57BL/Wld, a mutant showing delayed wallerian degeneration, that the authors have studied in detail. They summarise evidence indicating that axonal degeneration is an active process, involving calcium-activated proteases, that Schwann cell proliferation is probably initiated by specific chemical signals rather than solely by loss of axonal contact and is promoted in an autocrine fashion by Schwann cell production of neuregulins, and that myelin degradation is initially independent of macrophages but requires macrophages from about one week. The leukocyte response to peripheral nerve injury is unusual in that it is almost exclusively mediated by macrophages. The responsible signals have not been identified. Hughes and Perry briefly summarise the processes involved in the phagocytosis of myelin, both opsonin-dependent and opsonin-independent, and consider the possible role of macrophages in promoting axonal degeneration, either directly, through the release of cytokines, or indirectly as a result of removal of myelin debris.
The last chapter is a review by Kitchener and Wilson of changes in somatosensory organisation that occur after injury to the nervous system. The authors provide a comprehensive overview of the plasticity of low threshold somatosensory representations at the level of the dorsal horn, dorsal column nuclei, ventroposterior nucleus of the thalamus and cerebral cortex. Sensitive tracing techniques have revealed more extensive synaptic ramifications at each of these levels than would be anticipated on the basis of the mapping of functional afferent inputs. These observations suggest that the plasticity demonstrated by functional expansion of afferent projections is due, at least in part, to the unmasking of pre-existing synaptic connections.
I found this to be a well-edited book. The structure is reasonably consistent between chapters, and the different reviews are appropriately cross-referenced with surprisingly little duplication of content. Most of the authors have made effective use of lists of key points, that summarise the main findings and limitations of the studies on which these reviews are based. Some of the information is slightly dated: the book was published in 2000, the introduction is dated June 1999 and the latest references are from 1998. In consequence, some interesting and very pertinent recent information is missing. For example, Nogo is described only in passing, with no reference to Nogo receptor and Nogo receptor antagonists; there is no mention of the work of Clifford Woolf and colleagues on combining peripheral and central injuries to promote the central regeneration of primary sensory neurons, of the role of CAP-23 in axonal regrowth, of chondoitinase-mediated promotion of regeneration, or the burgeoning field of Edg receptors and their role in Schwann cell proliferation, migration and differentiation.
However, I do not think that these minor caveats should detract from the strength of this book as an excellent compilation of well-structured reviews. This inexpensive, well-referenced book deserves a wide readership within the basic and clinical neuroscience communities. It may encourage more of our young scientists to develop a research interest in nervous system repair and provide those already active in the field with new perspectives and ideas for tackling this challenging clinical problem.
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