Nerve growth factor: from the early discoveries to the potential clinical use
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REVIEW
Open Access
Nerve growth factor: from the early discoveries to the potential clinical use Luigi Aloe1, Maria Luisa Rocco1, Patrizia Bianchi1 and Luigi Manni2*
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. Keywords: Nerve growth factor, Alzheimer’s disease, Parkinson’s disease, Peripheral neuropathies, Skin ulcers, Neurotrophic keratitis, Glaucoma, Hypoxic-ischemic brain injury, Optic glioma
Nerve growth factor Nerve growth factor (NGF) is the first discovered member of the neurotrophin family [1]. NGF is essential for the development and phenotypic maintenance of neurons in the peripheral nervous system (PNS) and for the functional integrity of cholinergic neurons in the central nervous system (CNS) (Figure 1) [2]. The amino acid and messenger RNA sequences of this neurotrophin have been classified and indicate that NGF is a highly conserved molecule that shares considerable homology within different species [3]. The mature, active form of NGF descend from proteolitic cleavage of a precursor form (ProNGF), that have important roles during development and in adult life, having both pro-apoptotic and neurotrophic properties [4,5]. NGF exerts its biological action by challenging the specific receptor tropomyosin kinase receptor A (TrkA), * Correspondence: [email protected] 2 Institute of Translational Pharmacology, National Research Council (CNR), via Fosso del Cavaliere 100, 00136, Rome, Italy Full list of author information is available at the end of the article
which is a typical tyrosine kinase receptor [6]. The major cytosolic/endosomal pathways activated by the TrkA are Ras-mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase
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