Novel RET agonist for the treatment of experimental neuropathies.
Hanna ViisanenUlpukka NuotioOleg KamburArun Kumar MahatoViljami JokinenTuomas LiliusWei LiHélder A SantosMati KarelsonPekka RauhalaEija KalsoYulia A SidorovaPublished in: Molecular pain (2021)
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.
Keyphrases
- neuropathic pain
- spinal cord
- spinal cord injury
- tyrosine kinase
- small molecule
- minimally invasive
- type diabetes
- cardiovascular disease
- poor prognosis
- endothelial cells
- binding protein
- metabolic syndrome
- skeletal muscle
- combination therapy
- depressive symptoms
- atrial fibrillation
- reactive oxygen species
- coronary artery disease
- long non coding rna
- weight loss
- cerebral ischemia
- high glucose
- cell cycle arrest