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).
Neurotrophic factors
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).
