Nerve growth factor (NGF) was discovered by Rita Levi-Montalcini, who revealed that mouse sarcomas transplanted into chicken embryos secrete a factor into the blood that induces sensory and sympathetic nerve growth (Levi-Montalcini 1952; Levi-Montalcini 1987). She was awarded the Nobel Prize in 1986 for this work (Abott 2009). NGF is indispensable for the prenatal growth of sensory and sympathetic nerves. Two NGF receptors have been identified, one with high affinity and the other with low affinity for NGF (Landreth and Shooter 1980); these were later named tropomyosin receptor kinase (Trk) A and p75 neurotrophin receptor (p75NTR), respectively. NGF was also identified as a key molecule in the development of basal forebrain cholinergic neurons (Chen et al. 1997). In adults, NGF plays an important role in the protection and survival of both peripheral and central nervous system neurons and in the generation of pain sensation (Marlin and Li 2015).
NGF is synthesized initially as a glycosylated precursor molecule called pro-NGF, which is cleaved intracellularly by furin and extracellularly by plasmin, thus generating mature NGF (Khan and Smith 2015). Pro-NGF binds to p75NTR and sortilin, and also to TrkA with relatively low affinity, promoting apoptosis in neurons to counter the effect of NGF (Bradshaw et al. 2015). The physiological roles of pro-NGF, however, are under investigation.
In addition to NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4/5 were discovered later as other neurotrophins that induce nerve growth.
NGF is composed of approximately 120 amino acids and is expressed in various cells, such as neurons, Schwann cells, epithelial cells, smooth muscle cells, fibroblasts, and immune cells (Bandtlow et al. 1987, Otten and Gadient 1995). In neural and nonneural tissues, NGF expression is high in the dorsal root ganglion, heart, and spleen and is relatively low in the sympathetic ganglia, brain, spinal cord, sciatic nerve, liver, muscle, kidney, and lung (Yamamoto et al. 1996). NGF binding to the extracellular domain of TrkA causes dimerization of TrkA, which is also expressed in various tissues, such as the dorsal root ganglion, sympathetic ganglia, and spleen, and to a lesser degree in the brain, spinal cord, kidney, and spleen (Yamamoto et al. 1996).
NGF and Pain
Congenital insensitivity to pain is a rare disorder in which patients do not sense pain. As NGF/TrkA signaling during the fetal period plays a pivotal role in the growth of nerve fibers that transmit pain sensations, a mutation in the gene encoding TrkA or NGF leads to a defect in the physiological actions of prenatal NGF and causes this type of hereditary sensory and autonomic neuropathy (Indo et al. 1996; Miranda et al. 2002; Einarsdottir et al. 2004).
On the other hand, NGF induces pain during adulthood (Hirose et al. 2016). NGF is secreted from immune cells with other inflammatory mediators in inflamed tissues (Basbaum et al. 2009). When tissue injury occurs, NGF binds to TrkA, phosphorylating sodium channels and transient receptor potential vanilloid 1 (TRPV1) at the sensory nerve endings, thus upregulating the expression of TRPV1, substance P, sodium channels, and calcitonin gene-related peptide. These changes induce peripheral sensitization and cause a hypersensitive reaction (hyperalgesia) in response to nociceptive pain (Khan and Smith 2015; Hirose et al. 2016). When peripheral nerve injury occurs, NGF is released from Schwann cells, satellite glial cells, and invading immune cells, increasing the expression of BDNF in both the dorsal root ganglion in the peripheral nerve and the spinal dorsal horn to induce central sensitization during neuropathic pain (Khan and Smith 2015). Therefore, analgesics that suppress NGF/TrkA signaling, such as anti-NGF antibody, are promising candidates for clinical use for the treatment of refractory pain (Hirose et al. 2016).
Chronic lower back pain, including both nociceptive and neuropathic pain, is one of the most common types of chronic pain, with a prevalence as high as 10–20%. Intervertebral disk degeneration is a major cause of chronic lower back pain. During degeneration, activated proteases, such as metalloproteinases, degrade the extracellular matrix of intervertebral disks, producing endogenous molecules that act as danger-associated patterns (DAMPs). The DAMPs activate toll-like receptors (TLRs) on intervertebral disk cells. Activated TLRs increase the expression of NGF and BDNF, which primarily induce aneural innervation of the disks and contribute to the development of chronic pain (Krock et al. 2016).
Potential Clinical Applications of NGF
Although inhibitory agents of NGF activity may be novel pain killers as mentioned above, clinical trials of NGF itself also have been performed to treat peripheral neuropathies, central nervous system diseases, and ocular and skin diseases. As dysregulation of NGF function occurs in peripheral neuropathies, recombinant human NGF (rhNGF) is expected to be useful for treating diabetic polyneuropathy, human immunodeficiency virus-associated peripheral neuropathy, and chemotherapy-induced peripheral neurotoxicity. Side effects of rhNGF such as hyperalgesia and arthralgias, however, have been observed (Aloe et al. 2012).
As NGF plays an important role in the development and survival of basal forebrain cholinergic neurons (Chen et al. 1997), NGF application, using gene therapy or intracerebroventricular infusion because of impermeability of NGF through the blood-brain barrier, was performed to treat Alzheimer’s disease (AD), Parkinson’s disease, and traumatic brain injury (Aloe et al. 2012). Although the healthy functions of basal forebrain cholinergic neurons depend on a supply of NGF that is cleaved from pro-NGF by plasmin, pro-NGF accumulates in the cerebral cortex due to impaired metabolism of NGF in AD. Therefore, correcting NGF metabolism may also be a potential therapeutic strategy for treating AD in the future (Iulita and Cuello 2014).
Keratinocytes produce NGF to regulate skin homeostasis. Topical mouse NGF (mNGF) has been used in clinical trials to treat skin ulcers. In the visual system, NGF modulates the principal functions of conjunctival epithelial and goblet cells, induces corneal epithelial cell proliferation and differentiation, and regulates the development and differentiation of the retina and optic nerve in addition to promoting the survival and recovery of retinal ganglion cells (Lambiase et al. 2011). mNGF in eye drops was used in clinical trials to treat neurotrophic keratitis, dry eye, and glaucoma (Aloe et al. 2012; Lambiase et al. 2011).
NGF is synthesized initially as pro-NGF, which is cleaved into NGF intracellularly and extracellularly. After the NGF dimer binds to the TrkA dimer at distal nerve endings, NGF/TrkA complexes are endocytosed and transported retrogradely to the soma. Activated TrkA induces activation of MAPK, PI3K, and PLC-γ pathways.
NGF is expressed not only in neural tissues but also in nonneural tissues. During the prenatal period, NGF plays a pivotal role in the growth of sensory and sympathetic nerves and the development of basal forebrain cholinergic neurons. After birth, the role of NGF is the protection and survival of peripheral and central nervous system neurons and the development and maintenance of nociceptive or neuropathic pain. NGF also regulates homeostasis in skin and ocular systems. Therefore, NGF/TrkA signaling inhibitors suppress pain caused by inflammation or nerve injury. On the other hand, NGF may be a useful therapeutic agent for peripheral neuropathies, central nervous system diseases, and ocular and skin diseases.
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