Identification of novel neurotrophic-like factors: a candidate for promoting nerve regeneration in neuropathy

Chemotactic axon guidance has an essential role in development and for re-innervation of target tissues after neuronal injury. We aimed to determine whether the low density lipoprotein receptorrelated protein 1 (LRP-1) and LRP-2 receptors mediate neurite chemoattraction, and to assess their therapeutic potential in a model of peripheral neuropathy. We found LRP-1 and LRP-2 on growth cones at the leading edge and on filopodia, suggesting that they are part of the environment-sensing machinery. E16-18 rat sensory neurons were used in a growth cone turning assay to test a range of LRP ligands for chemotactic effects in vitro; including metallothionein II (MTII), apolipoproteinE3, tissue plasminogen activator, alpha-2-macroglobulin (α2M), vitamin D and transthyretin. Neurites were attracted to MTII (+9.8°±1.7°, p<0.0001, cf. control -1.8°±1.1°), and repulsed from α2M (- 11.9°±3.4, P<0.01). MTII was screened for regenerative capability in a model of small-fibre neuropathy in rats. Ten age-matched rats had topical 8% capsaicin cream and placebo cream applied to contralateral areas on the lumbar dorsum. Treated areas were given 3x weekly intradermal injections of MTII or saline. Punch and epidermal roof biopsies were harvested weekly to monitor regeneration. At 14 days, regeneration was observed in saline treated capsaicin regions, compared to contralateral control skin, however MTII treated rats had complete regeneration by 7 days. The LRPMTII chemotactic system represents a novel, non-classical axon guidance system. MTII is a candidate disease-modifying agent for the injured nervous system.