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Neurotrophic Factors
Published in Martin Berry, Ann Logan, CNS Injuries: Cellular Responses and Pharmacological Strategies, 2019
Developing neurons become dependent for their survival on neurotrophic factors, typically ∼10- to 30-kDa proteins which originate from their neural surroundings and/or innervation territory.1,2 The prototypical nerve growth factor (NGF) was recognized for its ability to promote survival, neurite outgrowth, and expression of transmitter-synthesizing enzymes of developing peripheral neurons.1 Neurotrophic factors, which typically promote the growth (cell size or neurite length) of neurons, have been distinguished from growth factors, i.e., factors that promote growth or proliferation of a cell population. This distinction is not always clear since many growth factors also have survival-promoting activity for neurons. Moreover, neurotrophic factors are not exclusively directed towards the nervous system since they have actions for nonneural cells. Nor are they exclusively “trophic”, since they have other types of activities including the induction of proliferation of certain cells.3,4 Neurotrophic factors generally have many types of actions on several types of neurons which may limit their ability to affect only injured neurons or certain repair processes.
Advances in Osteoarthritis of the Hip
Published in K. Mohan Iyer, Hip Joint in Adults: Advances and Developments, 2018
Pratham Surya, Sriram Srinivasan, Dipen K. Menon
Pharmacological manipulation of nerve growth factor (NGF) is another potential target area that is under trial. NGF is overexpressed in joint tissues and believed to have a role in the progression of OA. Tanezumab is a molecule that can inhibit NGF and its receptors. Tanezumab treatment has produced remarkable results in early clinical trials, providing hope for OA patients. Nitric oxide is a highly reactive cytotoxic free radical that is implicated in tissue injury, including cartilage. Inhibition of nitric oxide synthesis (nitric oxide synthase) is a therapeutic strategy in altering the course of OA. Synovitis is a common feature in OA. A mediator called bradykinin is released in synovitis. An antagonist of bradykinin is being developed. A recent phase 2 study showed its effectiveness in OA patients when compared with a placebo [22].
Growth Factors
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
It is known that nerve growth factor regulates the intracellular phosphorylation of several proteins. Hama, Huang and Guroff (1986) investigated the effect of protein kinase C on the nerve growth factor-sensitive phosphorylation of a 100 kDa protein substrate known as NsplOO. Treatment of PC12 cells with either nerve growth factor or a phorbol ester that increases protein kinase C activity caused a decrease in the phosphorylation of NsplOO. The activity of protein kinase C was increased by the nerve growth factor treatment. These and other results suggested that the binding of nerve growth factor to its receptor on PC12 cells causes an increase in the activity of protein kinase C and the phosphorylation of NsplOO kinase, which in turn lowers the ability of this kinase to phosphorylate NsplOO.
Neurotrophic keratopathy: current challenges and future prospects
Published in Annals of Medicine, 2022
Erin NaPier, Matthew Camacho, Timothy F. McDevitt, Adam R. Sweeney
Stage 3 is an advanced form of NK and can be difficult to treat. Several medical and surgical approaches can be used. A new medical option for treatment is directed at replacing nerve growth factor (NGF) with topical instillation. On the surface of the eye, NGF is involved in the survival and healing of sensory and sympathetic neurons and immune responses [4,31]. A topical formulation of recombinant human NGF, cenegermin (Oxervate; Dompé Farmaceutici SpA, Milan, Italy), has become readily available in the USA in the last decade. A multi-center, randomized, double-masked trial demonstrated that patients treated with cenegermin topical drops had higher rates of corneal healing at 8 weeks in patients with NK and non-healing corneal defects compared to the vehicle control group [32]. Patients receiving cenegermin had a faster rate of corneal healing and slower disease progression. Additionally, cenegermin patients had a lower rate of disease recurrence in the 48 weeks following the completion of treatment [32,33]. This study was not able to demonstrate statistical benefit in corneal sensitivity and visual acuity.
A novel anti-NGF PEGylated Fab’ provides analgesia with lower risk of adverse effects
Published in mAbs, 2023
Yukari Koya, Hirotsugu Tanaka, Eiji Yoshimi, Nobuaki Takeshita, Shuji Morita, Hiroki Morio, Kanako Mori, Hiroshi Fushiki, Masazumi Kamohara
Nerve growth factor (NGF) plays important roles in the growth, maintenance, and survival of target neurons.5 It is also considered a key modulator of pain perception in several chronic pain conditions, including OA.6–9 The physiological actions of NGF are mediated via the high-affinity tyrosine kinase receptor tropomyosin receptor kinase A (TrkA) and low-affinity NGF receptor p75.10 Anti-NGF antibodies have been shown to significantly improve pain and physical function in pre-clinical animal models and patients with clinical chronic pain conditions.11 However, anti-NGF therapeutic antibodies are associated with several safety concerns. First, when the antibodies are administered to women of childbearing potential, they could have adverse effects on fetal and postnatal development. The mutation in the NGF gene or TrkA gene in patients causes congenital insensitivity to pain.12,13 In addition, studies using NGF and TrkA-deficient mice have demonstrated that deletion of NGF inhibits the development of embryonic sensory and sympathetic neurons.14,15 These reports suggest that NGF/TrkA signaling is essential for the early stages of neural development. This concern is pertinent as many female patients of childbearing age have NGF-related diseases such as chronic low back pain.16–18 Second, anti-NGF therapeutic antibodies can increase the risk of developing rapidly progressive osteoarthritis (RPOA). Clinical trials have shown an association with higher doses of tanezumab, a humanized anti-NGF IgG, alone or with non-steroidal anti-inflammatory drugs, although the underlying molecular mechanism remains unknown.11,19
Comparative safety review of current treatment options for chronic low back pain and unmet needs: a narrative review
Published in Expert Opinion on Drug Safety, 2021
Filip Jovanovic, Iulia Pirvulescu, Emilija Knezevic, Kenneth D. Candido, Nebojsa Nick Knezevic
Nerve growth factor is a neurotrophic protein that plays an irreplaceable role in differentiation, function, and survival of sympathetic and sensory afferent neurons [86]. The ability of NGF to promote neuronal growth into the poorly innervated intervertebral disc stresses its role in disc degeneration and pain perception [87]. A monoclonal antibody against NGF, tanezumab, was studied in a long-term RCT in which 6 participants treated with tanezumab reported osteonecrosis, an SAE that required total joint replacement [88]. Such reports were later subsequently reviewed and disputed by an independent adjudication committee.