Neurotrophic factors and their receptors in human sensory neuropathies

Abstract

Neurotrophic factors may play key roles in pathophysiological mechanisms of human neuropathies. Nerve growth factor (NGF) is trophic to small-diameter sensory fibers and regulates nociception. This review focuses on sensory dysfunction and the potential of neurotrophic treatments. Genetic neuropathy. Mutations of the NGF high-affinity receptor tyrosine kinase A (Trk A) have been found in congenital insensitivity to pain and anhidrosis; these are likely to be partial loss-of-function mutations, as axon-reflex vasodilatation and sweating can be elicited albeit reduced, suggesting rhNGF could restore nociception in some patients. Leprous neuropathy. Decreased NGF in leprosy skin may explain cutaneous hypoalgesia even with inflammation and rhNGF may restore sensation, as spared nerve fibers show Trk A-staining. Diabetic neuropathy. NGF is depleted in early human diabetic neuropathy skin, in correlation with dysfunction of nociceptor fibers. We proposed rhNGF prophylaxis may prevent diabetic foot ulceration. Clinical trials have been disappointed, probably related to difficulty delivering adequate doses and need for multiple trophic factors. NGF and glial cell line-derived neurotrophic factor (GDNF) are both produced by basal keratinocytes and neurotrophin (NT-3) by suprabasal keratinocytes: relative mRNA expression was significantly lower in early diabetic neuropathy skin compared to controls, for NGF (P<0.02), BDNF (P<0.05), NT-3 (P<0.05), GDNF (<0.02), but not NT4/5, Trk A or p75 neurotrophin receptor (all P>0.05). Posttranslational modifications of mature and pro-NGF may also affect bioactivity and immunoreactivity. A 53 kD band that could correspond to a prepro-NGF-like molecule was reduced in diabetic skin. Traumatic neuropathy and pain. While NGF levels are acutely reduced in injured nerve trunks, neuropathic patients with chronic skin hyperalgesia and allodynia show marked local increases of NGF levels; here anti-NGF agents may provide analgesia. Physiological combinations of NGF, NT-3 and GDNF, to mimic a ‘surrogate target organ’, may provide a novel ‘homeostatic’ approach to prevent the development and ameliorate intractable neuropathic pain (e.g., at painful amputation stumps).

Introduction

A neurotrophic factor may be defined as a substance that plays a role in the development, maintenance or regeneration of the nervous system. Trophic factors act via their high-affinity receptors on specific nerve cells to influence their survival and gene expression. The classical neurotrophic factor, beta nerve growth factor (βNGF), is a protein normally produced by cells in the target organ, such as skin; NGF is taken up by sympathetic and small sensory fibers via a high-affinity tyrosine kinase A (TrkA) receptor and retrogradely transported to the cell body. NGF plays a key role in the survival and properties of sympathetic and sensory neurones (Levi-Montalcini, 1987) and in the development of human neuropathies (Anand et al., 1996). In addition, there is evidence that βNGF plays an important role in inflammatory processes (Levi-Montalcini, 1987; Otten et al., 1994; Levi-Montalcini et al., 1996), including inflammatory pain (McMahon et al., 1995; Woolf, 1996).

A number of factors trophic to sensory and autonomic fibers have been discovered, some of which belong to the NGF-superfamily, such as NT-3, while others do not, such as GDNF. There is a family of Trk genes and their products (TrkA-C) represent receptors for the NGF family–-NGF, BDNF, NT-3 and NT-4/5. Subpopulations of primary afferent fibers have differential expression of the trks, which correspond to their dependence on different neurotrophins. NGF is trophic to sympathetic and unmyelinated (including nociceptive) neurones (via TrkA), NT-3 (via TrkC) is trophic to large myelinated and small unmyelinated (proprioceptive, mechanosensitive) sensory fibers. The high affinity Trk receptors are coexpressed with the shared low-affinity neurotrophin receptor (p75^NTR). It is of interest that a target mutation of the gene coding for even the p75^NTR in the mouse leads to markedly decreased substance P (SP) and GRP innervation of footpad skin and to development of ulcers and mutilation of the feet (Lee et al., 1992).

Glial cell line-derived neurotrophic factor (GDNF) was isolated and cloned from the B49 glial cell line. It has been shown to have a broad range of neurotrophic actions both in vivo and in vitro. An age-dependent responsiveness to GDNF for sympathetic, parasympathetic, proprioceptive, small and large cutaneous sensory neurons and enteroceptive cells has been reported. The GDNF receptor is a multi-component receptor, consisting of a ligand-binding, cell surface glycosyl-phosphatidylinositol (GPI)-linked protein GDNFR-alpha and a transmembrane orphan tyrosine kinase, c-ret (Trupp et al., 1996). Binding of GDNF at the cell surface leads to phosphorylation of c-ret and initiation of the signaling cascade. C-ret and GDNF-deficient mice have been shown to suffer defects in the development of their sympathetic and enteric nervous system. A subset of nociceptors switch their dependency from NGF to GDNF for postnatal survival in the rodents; both NGF and GDNF are produced by basal keratinocytes in the skin.

Animal models show that neurotrophic factor deficiency may play a role in the development of common acquired peripheral neuropathies and exogenously administered neurotrophic factors may provide new treatments (see Lewin and Mendell, 1993; Brewster et al., 1994). Crushing or cutting a peripheral nerve leads to loss of target-derived NGF; although there is induction of NGF synthesis in Schwann cells at the site of the lesion and in the distal stump, the amount of NGF available to the dorsal root ganglion is insufficient to maintain substance P (SP) levels and NGF receptors are downregulated in injured fibers. In diabetic rats, NGF levels are decreased in peripheral nerves and their target organs (e.g., skin) and there is a defect of axonal transport of NGF and of Trk A expression.

We have described the first human neuropathy attributed to deficiency of a neurotrophic factor, NGF (Anand et al., 1991) and studied endogenous NGF levels in patients with nerve trauma (Anand et al., 1997), diabetes mellitus (Anand et al., 1996) and leprosy (Anand et al., 1994), the most common causes of human peripheral neuropathy world-wide. We have also reported regional changes of neurotrophic factor levels in patients with ALS/ motoneuron disease (Anand et al., 1995b). These studies aim to provide a rational basis for the clinical use of neurotrophic agents in peripheral neuropathy.