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Novel agonist of GDNF family ligand receptor RET for the treatment of experimental neuropathy

Maxim M. Bespalov, Yulia A. Sidorova, Ilida Suleymanova, James Thompson, Oleg Kambur, Viljami Jokinen, Tuomas Lilius, Gunnar Karelson, Laura Puusepp, Pekka Rauhala, Eija Kalso, Mati Karelson, Mart Saarma
doi: https://doi.org/10.1101/061820
Maxim M. Bespalov
aLaboratory of Molecular Neuroscience, Institute of Biotechnology, Viikinkaari 9, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland
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Yulia A. Sidorova
aLaboratory of Molecular Neuroscience, Institute of Biotechnology, Viikinkaari 9, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland
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Ilida Suleymanova
aLaboratory of Molecular Neuroscience, Institute of Biotechnology, Viikinkaari 9, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland
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James Thompson
bBiomedicum Helsinki High Throughput Center, Biomedicum Helsinki, Haartmaninkatu 8, FIN-00290, Helsinki, Finland
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Oleg Kambur
cDepartment of Pharmacology, Faculty of Medicine, Haartmaninkatu 8, University of Helsinki, 00014, Helsinki, Finland
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Viljami Jokinen
cDepartment of Pharmacology, Faculty of Medicine, Haartmaninkatu 8, University of Helsinki, 00014, Helsinki, Finland
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Tuomas Lilius
cDepartment of Pharmacology, Faculty of Medicine, Haartmaninkatu 8, University of Helsinki, 00014, Helsinki, Finland
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Gunnar Karelson
dGeneCode Ltd., Tatari 8, 10151 Tallinn, Estonia
eMolCode Ltd., Turu 2, 51014, Tartu, Estonia
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Laura Puusepp
fInstitute of Chemistry, Tartu University, Ravila 14a, 12618 Tartu, Estonia
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Pekka Rauhala
cDepartment of Pharmacology, Faculty of Medicine, Haartmaninkatu 8, University of Helsinki, 00014, Helsinki, Finland
gPain Clinic, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 2, P.O. Box 140, 00029 HUS, Helsinki, Finland
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Eija Kalso
cDepartment of Pharmacology, Faculty of Medicine, Haartmaninkatu 8, University of Helsinki, 00014, Helsinki, Finland
gPain Clinic, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 2, P.O. Box 140, 00029 HUS, Helsinki, Finland
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Mati Karelson
fInstitute of Chemistry, Tartu University, Ravila 14a, 12618 Tartu, Estonia
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Mart Saarma
aLaboratory of Molecular Neuroscience, Institute of Biotechnology, Viikinkaari 9, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland
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  • For correspondence: mart.saarma@helsinki.fi
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Abstract

Neuropathic pain is a chronic pain condition caused by lesion or disease affecting the somatosensory system. The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) alleviate symptoms of NP and stimulate regeneration of sensory neurons in vivo. Here we report the development of the compound BT18 that selectively activates GFLreceptors, alleviates pain and restores damaged dorsal root ganglion (DRG) neurons in rat models of NP.

Significance statement Neuropathic pain (NP) is a chronic syndrome caused by different diseases and lesions affecting nervous system. Earlier studies demonstrated that neurotrophic factors - the glial cell line-derived neurotrophic factor (GDNF) and artemin - could reverse the damage done by lesions in animal models of NP. We demonstrate for the first time that a small molecule can activate receptor of GDNF and artemin, it alleviates pain symptoms in vivo in two animal models of NP and restores to normal the molecular markers expressed in sensory neurons. This compound, termed BT18, can pave way for creating novel disease modifying therapies for NP.

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Posted July 04, 2016.
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Novel agonist of GDNF family ligand receptor RET for the treatment of experimental neuropathy
Maxim M. Bespalov, Yulia A. Sidorova, Ilida Suleymanova, James Thompson, Oleg Kambur, Viljami Jokinen, Tuomas Lilius, Gunnar Karelson, Laura Puusepp, Pekka Rauhala, Eija Kalso, Mati Karelson, Mart Saarma
bioRxiv 061820; doi: https://doi.org/10.1101/061820
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Novel agonist of GDNF family ligand receptor RET for the treatment of experimental neuropathy
Maxim M. Bespalov, Yulia A. Sidorova, Ilida Suleymanova, James Thompson, Oleg Kambur, Viljami Jokinen, Tuomas Lilius, Gunnar Karelson, Laura Puusepp, Pekka Rauhala, Eija Kalso, Mati Karelson, Mart Saarma
bioRxiv 061820; doi: https://doi.org/10.1101/061820

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