Targeting the Nerve Growth Factor (NGF) Pathway in Drug Discovery. Potential Applications to New Therapies for Chronic Pain

Abstract

The neurotrophin nerve growth factor (NGF) has been implicated as a key mediator of chronic pain. NGF binds the tropomysin receptor kinase A (TrkA) and p75, resulting in the activation of downstream signaling pathways that have been linked to pro-nociception. While anti-NGF antibodies have demonstrated analgesia both preclinically and in patients, the mechanism of action of these agents remains unclear. We describe ligands targeting NGF, its receptors, and downstream/related targets. This Perspective highlights large and small molecule approaches to targeting the NGF-TrkA pathway both extra- and intracellularly. In addition, we present a strategic framework for future drug discovery efforts in this pathway beyond the targeting of NGF or its receptors. While existing tools have greatly informed NGF-mediated signaling, ongoing and future pathway research may help focus new drug discovery efforts on key novel targets and mechanisms. This may result in highly differentiated therapeutics with greater efficacy and/or improved safety profiles.

A New Model of Sensorial Neuron-Like Cells for HTS of Novel Analgesics for Neuropathic Pain

“…The TrkA receptor interacts with NGF, which is very important in pain perception. 17 After measuring the global length of neurites, we observed that dibutyryl-cAMP plus forskolin yielded overall longer cell neurites. Thus, dibutyryl-cAMP and forskolin were finally selected as differentiation factors for further testing in the F11 cell line.…”

The NGFR100WMutation Specifically Impairs Nociception without Affecting Cognitive Performance in a Mouse Model of Hereditary Sensory and Autonomic Neuropathy Type V

“…Regulation of nociception and pain responses by NGF has long been a key area of research on this neurotrophin (Denk et al, 2017). This has spurred a significant translational interest for treating chronic pain conditions (Norman and McDermott, 2017). However, current understanding of these processes is still incomplete.…”

Anisotropic scaffolds for peripheral nerve and spinal cord regeneration

“…NGF, brain-derived neurotrophic factor (BDNF), neurotrophin 3/4/6 (NT-3/4/6), and glial cell line-derived neurotrophic factor (GDNF) are commonly used [ 77 , 78 ]. These neurotrophic factors exert their actions through specific transmembrane receptors, like tropomyosin receptor kinase (Trk) and p75 [ 79 ], which activate a cascade of downstream signaling pathways to promote physiological neuron responses [ 80 ]. In this review, we focus on the anisotropic scaffolds and provide a detailed overview of fabrication, in vitro and in vivo efficacy, and potential mechanisms.…”