NGF receptor TrkAd5: therapeutic agent and drug design target

Dawbarn, David; Fahey, Mark; Watson, Judy J.; Tyler, SJ; Shoemark, Debbie K.; Sessions, Richard B.; Zhang, R.; Brady, Leo; Willis, Christine L.; Allen, Shelley J

doi:10.1042/bst0340587

Cited by 13 publications

(7 citation statements)

References 16 publications

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“…MNAC13 is an anti-TrkA monoclonal antibody that exhibited similar potent analgesic effects in formalin-evoked pain licking responses in mice 29 . One experimental OA model 30 indicates comparable analgesic effects of an anti-NGF regimen using the TrkA domain 5 (TrkAd5) protein, a soluble receptor with high affinity to NGF 31 .…”

Section: Animal Studies – Pain and Effect Of Anti-ngf Regimensmentioning

confidence: 99%

Nerve growth factor: an update on the science and therapy

Seidel

Wise

Lane

2013

Osteoarthritis and Cartilage

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SUMMARY Objective Nerve growth factor (NGF) is a key regulator of nociceptive pain and thus appears to be an interesting target molecule for an innovative class of analgesic medication. We set out to review the principles of neurogenic inflammation and results of anti-NGF regimens in animal studies as well as clinical trials with patients with back pain and osteoarthritis (OA). Design We searched using Google Scholar Search and Pubmed as well as through conference reports for articles and abstracts related to NGF and clinical trials using anti-NGF regimens. We report on efficacy findings and adverse events (AEs) related to these agents in this review. Results We identified five full articles and eight abstract reports relating to anti-NGF agents studied for use in back pain and in OA. Conclusions Anti-NGF agents either alone or in combination with non-steroidal anti-inflammatory agents (NSAIDs) were more efficacious for the treatment of pain in a number of trials of knee and hip pain compared to NSAIDs alone. However, adverse effects that included rapidly progressive OA and joint replacement were more common in patients treated with anti-NGF and NSAIDs than either treatment alone. Anti-NGF treatment related neurologic symptoms including paresthesias, and potentially other types of adverse effects were usually transient but warrant additional investigation.

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Section: Animal Studies – Pain and Effect Of Anti-ngf Regimensmentioning

confidence: 99%

Nerve growth factor: an update on the science and therapy

Seidel

Wise

Lane

2013

Osteoarthritis and Cartilage

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“…Derivatives of these compounds have been described as candidates for clinical development. In addition small molecule mimetics of NGF or BDNF have also been suggested as Alzheimer therapeutics [180, 181]. Using in silico screening with a BDNF loop–domain pharmacophore, Longo and colleagues have identified small molecules with nanomolar neurotrophic activity at TrkB, which prevented neuronal degeneration and improved motor learning after traumatic brain injury in rats.…”

Section: Therapeutic Solutions Associated With Ngf and Bdnfmentioning

confidence: 99%

The Neurotrophins and Their Role in Alzheimers Disease

Allen

Watson²,

Dawbarn³

2011

145

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Besides being essential for correct development of the vertebrate nervous system the neurotrophins also play a vital role in adult neuron survival, maintenance and regeneration. In addition they are implicated in the pathogenesis of certain neurodegenerative diseases, and may even provide a therapeutic solution for some. In particular there have been a number of studies on the involvement of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in the development of Alzheimer’s disease. This disease is of growing concern as longevity increases worldwide, with little treatment available at the moment to alleviate the condition. Memory loss is one of the earliest symptoms associated with Alzheimer’s disease. The brain regions first affected by pathology include the hippocampus, and also the entorhinal cortex and basal cholinergic nuclei which project to the hippocampus; importantly, all these areas are required for memory formation. Both NGF and BDNF are affected early in the disease and this is thought to initiate a cascade of events which exacerbates pathology and leads to the symptoms of dementia. This review briefly describes the pathology, symptoms and molecular processes associated with Alzheimer’s disease; it discusses the involvement of the neurotrophins, particularly NGF and BDNF, and their receptors, with changes in BDNF considered particularly in the light of its importance in synaptic plasticity. In addition, the possibilities of neurotrophin-based therapeutics are evaluated.

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“…Withdrawal of NGF or pulsing MKs with K252a analogs after MKs are generated might improve the platelet yield by promoting thrombopoiesis. Besides K252a, new TrkA antagonists, such as ALE0540, RN624, REN1820 are under development and are expected to provide TrkA-specific targeting 90–92 . Given the clinical potential of our findings, further in-depth investigation of the NGF-TrkA axis in thrombopoiesis using in vivo models is warranted.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Tropomyosin Receptor Kinase A Signaling Negatively Regulates Megakaryopoiesis and induces Thrombopoiesis

Kizilyer¹,

Singh²,

Singh³

et al. 2019

Sci Rep

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Neurotrophin signaling modulates the differentiation and function of mature blood cells. The expression of neurotrophin receptors and ligands by hematopoietic and stromal cells of the bone marrow indicates that neurotrophins have the potential to regulate hematopoietic cell fate decisions. This study investigates the role of neurotrophins and Tropomyosin receptor kinases (Trk) in the development of megakaryocytes (MKs) and their progeny cells, platelets. Results indicate that primary human MKs and MK cells lines, DAMI, Meg-01 and MO7e express TrkA, the primary receptor for Nerve Growth Factor (NGF) signaling. Activation of TrkA by NGF enhances the expansion of human MK progenitors (MKPs) and, to some extent, MKs. Whereas, inhibition of TrkA receptor by K252a leads to a 50% reduction in the number of both MKPs and MKs and is associated with a 3-fold increase in the production of platelets. In order to further confirm the role of TrkA signaling in platelet production, TrkA deficient DAMI cells were generated using CRISPR-Cas9 technology. Comparative analysis of wild-type and TrkA-deficient Dami cells revealed that loss of TrkA signaling induced apoptosis of MKs and increased platelet production. Overall, these findings support a novel role for TrkA signaling in platelet production and highlight its potential as therapeutic target for Thrombocytopenia.

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NGF receptor TrkAd5: therapeutic agent and drug design target

Cited by 13 publications

References 16 publications

Nerve growth factor: an update on the science and therapy

Nerve growth factor: an update on the science and therapy

The Neurotrophins and Their Role in Alzheimers Disease

Inhibition of Tropomyosin Receptor Kinase A Signaling Negatively Regulates Megakaryopoiesis and induces Thrombopoiesis

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