I. A Nobel Discovery:
The first member of the neurotrophin family, Nerve Growth Factor (NGF), was discovered by Rita Levi-Montalcini in 1953 which led to her receiving the Nobel Prize in 1986.1,2 In her seminal study, Levi-Montalcini grafted a piece of mouse sarcoma tissue onto chick embryos whose wing buds had been removed.3,4 Despite the absence of wing buds, the chicken embryo nearby sensory and sympathetic ganglia grew due to the release of a soluble factor from the adjacent tumor tissue.1,3 Further investigation by biochemist Stanley Cohen, led to isolation of the growth-promoting soluble factor and its official designation as NGF.
II. NGF Signaling Pathway:
Decades following Levi-Montalcini’s discovery, research established NGF essential for the development of the peripheral nervous system (PNS) and functional integrity within the central nervous system (CNS).4 Within the peripheral nervous system, NGF dynamically controls neurotransmitters and neuropeptides synthesis and phenotypic maintenance of neurons.5 In the central nervous system (CNS), the greatest amount of NGF is produced in the cortex, the hippo-campus and in the pituitary gland. Basal forebrain cholinergic neurons (BFCNs) rely on NGF for their maintenance and survival within the basal forebrain complex (BFC); thereby, influencing attention, arousal, motivation, memory and consciousness. 1,3,6,7 NGF is also a direct anti-amyloidogenic factor.8,9
NGF biological transduction is carried out by the specific receptor tropomyosin kinase receptor A (TrkA) and/or the p75 Neutrophin Receptor (p75NTR).10 Once activated by NGF, TrkA promotes downstream signaling via Ras-mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K), and Phospholipase C (PLC) –γ which regulate various cellular functions and fates.11,12 In the absence of TrkA, NGF stimulates cellular apoptosis by binding to p75NTR at a lower and non-selective affinity and transduces through Jun kinase, NF-kB, and ceramine production.10,13,14
III. NGF Pathophysiology and Therapeutic Capability:
The cholinergic neurons profoundly degenerate in Alzheimer’s disease (AD) and contribute to cognitive decline.15,16 Therefore, NGF is indicated as a potential preventative and/or therapeutic factor for neurodegenerative disorders. NGF as a therapeutic candidate extends beyond its BFCN regulation. Restoring proNGF/NGF homeostasis represents a strategy to combat early neurodegeneration and to provide neuroprotection in neurodegenerative conditions through anti-amyloidogenic action and management within astrocyte and microglia cells.17,18
Within neurodegenerative disorders, the greatest challenge in the systemic delivery of NGF resides in its inability to cross the blood–brain barrier (BBB).19 The second limit delineates NGF intrinsic property of being one of the key molecules for mediating inﬂammatory pain and neuropathic pain in the PNS; thereby, increasing pain sensitivity.20–22 A potential approach to overcome such limitations is represented by gene therapy which increase the expression of NGF.4 The olfactory pathway is a promising, non-invasive route for drug delivery to the brain, which has potential for the treatment of neurodegenerative diseases.23,24 Finally, another investigated route to deliver NGF to the brain in a safe and effective manner is the topical administration of NGF on ocular surface.25
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