2. Academic Validation
  3. Novel RET agonist for the treatment of experimental neuropathies

Novel RET agonist for the treatment of experimental neuropathies

  • Mol Pain. 2020 Jan-Dec;16:1744806920950866. doi: 10.1177/1744806920950866.
Hanna Viisanen 1 2,  Ulpukka Nuotio 3,  Oleg Kambur 1,  Arun Kumar Mahato 3,  Viljami Jokinen 1,  Tuomas Lilius 1 2,  Wei Li 3 4,  Hélder A Santos 4 5,  Mati Karelson 6,  Pekka Rauhala 1 2,  Eija Kalso 1 7,  Yulia A Sidorova 3 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • 2 Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • 3 Laboratory of Molecular Neuroscience, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • 4 Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Helsinki, Finland.
  • 5 Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
  • 6 Institute of Chemistry, Tartu University, Tartu, Estonia.
  • 7 Department of Anaesthesiology, Intensive Care Medicine and Pain Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
PMID: 32811276 DOI: 10.1177/1744806920950866
Abstract

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) alleviate symptoms of experimental neuropathy, protect and stimulate regeneration of sensory neurons in animal models of neuropathic pain, and restore their functional activity. However, clinical development of GFL proteins is complicated by their poor pharmacokinetic properties and multiple effects mediated by several receptors. Previously, we have identified a small molecule that selectively activates the major signal transduction unit of the GFL receptor complex, receptor tyrosine kinase RET, as an alternative to GFLs, for the treatment of neuropathic pain. We then introduced a series of chemical changes to improve the biological activity of these compounds and tested an optimized compound named BT44 in a panel of biological assays. BT44 efficiently and selectively stimulated the GFL receptor RET and activated the intracellular mitogene-activated protein kinase/extracellular signal-regulated kinase pathway in immortalized cells. In cultured sensory neurons, BT44 stimulated neurite outgrowth with an efficacy comparable to that of GFLs. BT44 alleviated mechanical hypersensitivity in surgery- and diabetes-induced rat models of neuropathic pain. In addition, BT44 normalized, to a certain degree, the expression of nociception-related neuronal markers which were altered by spinal nerve ligation, the neuropathy model used in this study. Our results suggest that the GFL mimetic BT44 is a promising new lead for the development of novel disease-modifying agents for the treatment of neuropathy and neuropathic pain.

Keywords

GDNF family ligands; Glial cell line-derived neurotrophic factor; RET agonist; artemin; diabetes mellitus; diabetic neuropathy; neuropathic pain; neuropathy; receptor tyrosine kinase RET; spinal nerve ligation.

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