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A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat
Neuropathic pain caused by nerve damage is a common and severe class of chronic pain. Disease-modifying clinical therapies are needed as current treatments typically provide only symptomatic relief; show varying clinical efficacy; and most have significant adverse effects. One approach is targeting...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478727/ https://www.ncbi.nlm.nih.gov/pubmed/28680400 http://dx.doi.org/10.3389/fphar.2017.00365 |
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author | Sidorova, Yulia A. Bespalov, Maxim M. Wong, Agnes W. Kambur, Oleg Jokinen, Viljami Lilius, Tuomas O. Suleymanova, Ilida Karelson, Gunnar Rauhala, Pekka V. Karelson, Mati Osborne, Peregrine B. Keast, Janet R. Kalso, Eija A. Saarma, Mart |
author_facet | Sidorova, Yulia A. Bespalov, Maxim M. Wong, Agnes W. Kambur, Oleg Jokinen, Viljami Lilius, Tuomas O. Suleymanova, Ilida Karelson, Gunnar Rauhala, Pekka V. Karelson, Mati Osborne, Peregrine B. Keast, Janet R. Kalso, Eija A. Saarma, Mart |
author_sort | Sidorova, Yulia A. |
collection | PubMed |
description | Neuropathic pain caused by nerve damage is a common and severe class of chronic pain. Disease-modifying clinical therapies are needed as current treatments typically provide only symptomatic relief; show varying clinical efficacy; and most have significant adverse effects. One approach is targeting either neurotrophic factors or their receptors that normalize sensory neuron function and stimulate regeneration after nerve damage. Two candidate targets are glial cell line-derived neurotrophic factor (GDNF) and artemin (ARTN), as these GDNF family ligands (GFLs) show efficacy in animal models of neuropathic pain (Boucher et al., 2000; Gardell et al., 2003; Wang et al., 2008, 2014). As these protein ligands have poor drug-like properties and are expensive to produce for clinical use, we screened 18,400 drug-like compounds to develop small molecules that act similarly to GFLs (GDNF mimetics). This screening identified BT13 as a compound that selectively targeted GFL receptor RET to activate downstream signaling cascades. BT13 was similar to NGF and ARTN in selectively promoting neurite outgrowth from the peptidergic class of adult sensory neurons in culture, but was opposite to ARTN in causing neurite elongation without affecting initiation. When administered after spinal nerve ligation in a rat model of neuropathic pain, 20 and 25 mg/kg of BT13 decreased mechanical hypersensitivity and normalized expression of sensory neuron markers in dorsal root ganglia. In control rats, BT13 had no effect on baseline mechanical or thermal sensitivity, motor coordination, or weight gain. Thus, small molecule BT13 selectively activates RET and offers opportunities for developing novel disease-modifying medications to treat neuropathic pain. |
format | Online Article Text |
id | pubmed-5478727 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-54787272017-07-05 A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat Sidorova, Yulia A. Bespalov, Maxim M. Wong, Agnes W. Kambur, Oleg Jokinen, Viljami Lilius, Tuomas O. Suleymanova, Ilida Karelson, Gunnar Rauhala, Pekka V. Karelson, Mati Osborne, Peregrine B. Keast, Janet R. Kalso, Eija A. Saarma, Mart Front Pharmacol Pharmacology Neuropathic pain caused by nerve damage is a common and severe class of chronic pain. Disease-modifying clinical therapies are needed as current treatments typically provide only symptomatic relief; show varying clinical efficacy; and most have significant adverse effects. One approach is targeting either neurotrophic factors or their receptors that normalize sensory neuron function and stimulate regeneration after nerve damage. Two candidate targets are glial cell line-derived neurotrophic factor (GDNF) and artemin (ARTN), as these GDNF family ligands (GFLs) show efficacy in animal models of neuropathic pain (Boucher et al., 2000; Gardell et al., 2003; Wang et al., 2008, 2014). As these protein ligands have poor drug-like properties and are expensive to produce for clinical use, we screened 18,400 drug-like compounds to develop small molecules that act similarly to GFLs (GDNF mimetics). This screening identified BT13 as a compound that selectively targeted GFL receptor RET to activate downstream signaling cascades. BT13 was similar to NGF and ARTN in selectively promoting neurite outgrowth from the peptidergic class of adult sensory neurons in culture, but was opposite to ARTN in causing neurite elongation without affecting initiation. When administered after spinal nerve ligation in a rat model of neuropathic pain, 20 and 25 mg/kg of BT13 decreased mechanical hypersensitivity and normalized expression of sensory neuron markers in dorsal root ganglia. In control rats, BT13 had no effect on baseline mechanical or thermal sensitivity, motor coordination, or weight gain. Thus, small molecule BT13 selectively activates RET and offers opportunities for developing novel disease-modifying medications to treat neuropathic pain. Frontiers Media S.A. 2017-06-21 /pmc/articles/PMC5478727/ /pubmed/28680400 http://dx.doi.org/10.3389/fphar.2017.00365 Text en Copyright © 2017 Sidorova, Bespalov, Wong, Kambur, Jokinen, Lilius, Suleymanova, Karelson, Rauhala, Karelson, Osborne, Keast, Kalso and Saarma. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Sidorova, Yulia A. Bespalov, Maxim M. Wong, Agnes W. Kambur, Oleg Jokinen, Viljami Lilius, Tuomas O. Suleymanova, Ilida Karelson, Gunnar Rauhala, Pekka V. Karelson, Mati Osborne, Peregrine B. Keast, Janet R. Kalso, Eija A. Saarma, Mart A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat |
title | A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat |
title_full | A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat |
title_fullStr | A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat |
title_full_unstemmed | A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat |
title_short | A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat |
title_sort | novel small molecule gdnf receptor ret agonist, bt13, promotes neurite growth from sensory neurons in vitro and attenuates experimental neuropathy in the rat |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478727/ https://www.ncbi.nlm.nih.gov/pubmed/28680400 http://dx.doi.org/10.3389/fphar.2017.00365 |
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