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.

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

“…NGF and BDNF was evident following LV-hPGC-1α gene therapy and both exert neuroprotective properties in AD (18,19). In line with our findings was the report showing that exerciseinduced BDNF expression was mediated by PGC-1α regulation of Fndc5 gene expression (20).…”

Rita Levi-Montalcini: Presence in The Absence

“…Subsequent studies investigating the effect of NGF administration in rodent forebrain cholinergic neurons and behavior and memory performances led to the hypothesis that NGF may be useful in protecting these neurons that are known to degenerate in the brain of subjects affected b y Alzheimer's disease. While the therapeutic potential of NGF in the treatment of neurotrophic corneal ulcers, skin ulcers, glaucoma and Alzheimer's disease (6,(19)(20)(21) seems clearly demonstrated, the use of NGF as a drug is, to some extent limited due to its incompletely established pharmacokinetics and the high cost associated with the production of human recombinant NGF. These obstacles have also driven the scientific community toward the identification of small molecules (NGF mimetics) with drug-like properties.…”

Neuroprotective effects of geniposide on Alzheimer’s disease pathology

“…Nerve growth factor (NGF), a neurotrophin, plays a trophic role both during development and in adulthood and activates the tropomyosin kinase receptor A (TrkA)-Ras-ERK signaling pathway by interacting with the specific receptor TrkA (Patapoutian and Reichardt, 2001;Huang and Reichard, 2003;Aloe et al, 2012). Also, NGF elicits its neuritogenic effect through the activation of neuronal NOS (nNOS) followed by the activation of the NO-cGMP-PKG signaling pathway (Hartikka and Hefti, 1988).…”