A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat

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Sidorova , Y A , Bespalov , M M , Wong , A W , Kambur , O , Jokinen , V , Lilius , T O , Suleymanova , I , Karelson , G , Rauhala , P V , Karelson , M , Osborne , P B , Keast , J R , Kalso , E A & Saarma , M 2017 , ' A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat ' , Frontiers in Pharmacology , vol. 8 , 365 . https://doi.org/10.3389/fphar.2017.00365

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
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
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Research Programs Unit
University of Helsinki, Department of Pharmacology
University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Institute of Biotechnology
University of Helsinki, Medicum
University of Helsinki, Eija Kalso / Principal Investigator
University of Helsinki, Institute of Biotechnology
Date: 2017-06-21
Language: eng
Number of pages: 18
Belongs to series: Frontiers in Pharmacology
ISSN: 1663-9812
URI: http://hdl.handle.net/10138/231861
Abstract: 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.
Subject: neuropathic pain
glial cell line-derived neurotrophic factor (GDNF)
GDNF family ligands (GFLs)
artemin (ARTN)
small molecule RET agonist
GFL mimetic
GDNF family receptor alpha (GFR alpha)
receptor tyrosine kinase RET
SPINAL NERVE LIGATION
NEUROTROPHIC FACTOR
SYSTEMIC ARTEMIN
FAMILY LIGANDS
DRG NEURONS
C-RET
PAIN
INJURY
NGF
SUBPOPULATIONS
317 Pharmacy
1182 Biochemistry, cell and molecular biology
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