Neural Plasticity And Neurotrophic Factors I: The Peripheral Nervous System
The peripheral nervous system (PNS) is capable of significant repair, to some extent independent of the age at which damage occurs. In contrast, the central nervous system (CNS) has always been thought of as being unable to repair itself, although there is now mounting evidence for considerable plasticity within it even in the adult state and that most, if not all areas of the CNS, are capable of some degree of reorganization (see Chapter 49).
Repair in the peripheral nervous system Injury to a peripheral nerve if severe enough will cause permanent damage with loss of sensation, loss of muscle bulk and weakness.
However, in many cases the nerve is able to repair itself, as the peripheral axon can regrow under the influence of the favourable environment of the Schwann cells. This is in contrast to the CNS where the neuroglial cells (astrocytes and oligodendrocytes) are generally inhibitory to axonal growth, even though most CNS neurones are capable of growing new axons.
When a peripheral nerve is damaged, the distal aspect of the axon is lost by the process of wallerian degeneration. Wallerian degeneration leads to the removal and recycling of both axonal and myelin-derived material, but leaves in place dividing Schwann cells inside the basal lamina tube that surrounds all nerve fibres. These columns of Schwann cells surrounded by basal lamina are known as endoneurial tubes, and provide the favourable substrate for axonal growth.
Following injury, the degenerating nerve fibre elicits an initial macrophage invasion and this in turn provides the mitogenic input to the Schwann cell. The regenerating axon starts to sprout within hours of injury and contacts the Schwann cell basal laminae on one side, and the Schwann cell membrane on the other. The Schwann cell basal lamina is especially important in the process of axonal sprouting as it contains a number of molecules that are powerful promoters of axonal outgrowth in vitro (e.g. laminin and fibronectin).
In addition to providing a substrate for axonal growth, Schwann cells also produce a number of neurotrophic factors, including nerve growth factor (NGF; see below). Thus, the Schwann cell provides a substrate along which the regenerating axon can grow, as well as providing a favourable humoral neurotrophic environment. It also helps direct the regenerating axon back to its appropriate target, by means of the endoneurial tube. Occasionally, the regrowth of the axons is inaccurate or incomplete so, for example, following damage to the third cranial nerve one can have aberrant regeneration such that there is elevation of the eyelid on looking down.
In contrast to axonal damage, the loss of the cell body (in the ventral horn or dorsal root ganglia) leads to an irreversible and permanent loss of axons in the peripheral nerve. Examples of such disorders include poliomyelitis and motor neurone disease (MND) with respect to the α-MN, and a number of inflammatory and paraneoplastic syndromes in the case of the dorsal root ganglia (see Chapters 60 and 62). In all these cases the loss of axons is secondary to the loss of the cell body and so no regeneration is possible. Attempts to rescue dying α-MN in MND via the peripheral delivery of neurotrophic factors have been made without much success to date (see Chapter 60).
The number of identified neurotrophic factors has expanded greatly since the original description of the first of these, NGF. These factors, many of which are also found to influence non- neural populations of cells, form discrete families that act through specific types of receptors. Many of these receptors are composed of subunits, one or some of which form common binding domains for a family of neurotrophic factors. For example, the neurotrophin family of neurotrophic factors and the trk receptors use a range of cytoplasmic tyrosine kinases as part of their signalling mechanism.
Many populations of neurones respond to neurotrophic factors experimentally both in vitro and in the lesioned animal. However, despite these encouraging results, administration of neurotrophic factors to patients in clinical trials of neurodegenerative disorders and neuropathies has met with only limited success. This argues against these disorders being the result of specific neurotrophic factor deficiencies (see Chapter 60). More recently, greater success has been achieved with the direct infusion of neurotrophic factors into the brain parenchyma rather than using the cerebrospinal fluid (CSF) or periphery, e.g. glial cell line derived neurotrophic factor (GDNF) in Parkinson’s disease (see Chapters 41 and 42).