Nerve growth factor: from the early discoveries to the potential clinical use

Abstract

The physiological role of the neurotrophin nerve growth factor (NGF) has been characterized, since its discovery in the 1950s, first in the sensory and autonomic nervous system, then in central nervous, endocrine and immune systems. NGF plays its trophic role both during development and in adulthood, ensuring the maintenance of phenotypic and functional characteristic of several populations of neurons as well as immune cells. From a translational standpoint, the action of NGF on cholinergic neurons of the basal forebrain and on sensory neurons in dorsal root ganglia first gained researcher's attention, in view of possible clinical use in Alzheimer's disease patients and in peripheral neuropathies respectively. The translational and clinical research on NGF have, since then, enlarged the spectrum of diseases that could benefit from NGF treatment, at the same time highlighting possible limitations in the use of the neurotrophin as a drug. In this review we give a comprehensive account for almost all of the clinical trials attempted until now by using NGF. A perspective on future development for translational research on NGF is also discussed, in view of recent proposals for innovative delivery strategies and/or for additional pathologies to be treated, such as ocular and skin diseases, gliomas, traumatic brain injuries, vascular and immune diseases.

Figure 1

NGF is produced by every peripheral tissue/organ that is innervated by sensory afferents and/or sympathetic efferents, as well as by central and peripheral nervous system and immune cells. The largest amount of the neurotrophin is produced in mice submaxillary glands, as revealed by immunofluorescence staining depicted in panel A, that are the source for murine NGF used in several clinical trials. When intravenously injected in rats (B), NGF levels quickly increases in the bloodstream, reaching a peak within 30 min and remaining above baseline levels up until 72 h. Peripheral NGF injection induces peculiar effects on immune circulating cells, such as the overexpression of its receptor TrkA on circulating lymphocytes (C) or degranulation of peritoneal mast cells (D). Radiolabelled, intra-cerebroventricular injected NGF is captured by TrkA-expressing neurons, such as cholinergic neurons in the basal forebrain complex (E).

Figure 2

The huge amount of research data produced since its discovery in the 1950s, first characterized the physiological role of the neurotrophin NGF in the regulation of development and phenotypic maintenance of peripheral nervous system (PNS). A similar role for central cholinergic neurons was described starting from the 1980s, while more recently NGF has been characterized as a survival, differentiative and trophic factors also for cells belonging to the immune system and the epithelial lineage. Basic and translational research based on such described NGF activities have then explored the possibility to develop NGF-based pharmacotherapies for peripheral neuropathies, brain degenerative and traumatic diseases, several kinds of epithelial derangements. A possible, yet unexplored field for clinical development of NGF as a drug, is based on its activity as immune-regulator, possibly involved in autoimmune and chronic inflammatory pathologies.