Browsing by Subject "RET agonist"

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  • Kotliarova, Anastasiia; Sidorova, Yulia A. (2021)
    Well-known effects of neurotrophic factors are related to supporting the survival and functioning of various neuronal populations in the body. However, these proteins seem to also play less well-documented roles in glial cells, thus, influencing neuroinflammation. This article summarizes available data on the effects of glial cell line derived neurotrophic factor (GDNF) family ligands (GFLs), proteins providing trophic support to dopaminergic, sensory, motor and many other neuronal populations, in non-neuronal cells contributing to the development and maintenance of neuropathic pain. The paper also contains our own limited data describing the effects of small molecules targeting GFL receptors on the expression of the satellite glial marker IBA1 in dorsal root ganglia of rats with surgery- and diabetes-induced neuropathy. In our experiments activation of GFLs receptors with either GFLs or small molecule agonists downregulated the expression of IBA1 in this tissue of experimental animals. While it can be a secondary effect due to a supportive role of GFLs in neuronal cells, growing body of evidence indicates that GFL receptors are expressed in glial and peripheral immune system cells. Thus, targeting GFL receptors with either proteins or small molecules may directly suppress the activation of glial and immune system cells and, therefore, reduce neuroinflammation. As neuroinflammation is considered to be an important contributor to the process of neurodegeneration these data further support research efforts to modulate the activity of GFL receptors in order to develop disease-modifying treatments for neurodegenerative disorders and neuropathic pain that target both neuronal and glial cells.
  • Mahato, Arun Kumar; Sidorova, Yulia A. (2020)
    Rearranged during transfection (RET), in complex with glial cell line-derived (GDNF) family receptor alpha (GFR alpha), is the canonical signaling receptor for GDNF family ligands (GFLs) expressed in both central and peripheral parts of the nervous system and also in non-neuronal tissues. RET-dependent signaling elicited by GFLs has an important role in the development, maintenance and survival of dopamine and sensory neurons. Both Parkinson's disease and neuropathic pain are devastating disorders without an available cure, and at the moment are only treated symptomatically. GFLs have been studied extensively in animal models of Parkinson's disease and neuropathic pain with remarkable outcomes. However, clinical trials with recombinant or viral vector-encoded GFL proteins have produced inconclusive results. GFL proteins are not drug-like; they have poor pharmacokinetic properties and activate multiple receptors. Targeting RET and/or GFR alpha with small molecules may resolve the problems associated with using GFLs as drugs and can result in the development of therapeutics for disease-modifying treatments against Parkinson's disease and neuropathic pain.
  • Renko, Juho-Matti; Mahato, Arun Kumar; Visnapuu, Tanel; Valkonen, Konsta; Karelson, Mati; Voutilainen, Merja H.; Saarma, Mart; Tuominen, Raimo K.; Sidorova, Yulia A. (2021)
    Background: Parkinson's disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF's receptor, the transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo. Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons fromMPP+-induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and seemed to protect dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying, therapy for PD.
  • Viisanen, Hanna; Nuotio, Ulpukka; Kambur, Oleg; Mahato, Arun Kumar; Jokinen, Viljami; Lilius, Tuomas; Li, Wei; Santos, Hélder A; Karelson, Mati; Rauhala, Pekka; Kalso, Eija; Sidorova, Yulia A (2020)
    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.
  • Mahato, Arun Kumar; Sidorova, Yulia A. (2020)
    Rearranged during transfection (RET) is the tyrosine kinase receptor that under normal circumstances interacts with ligand at the cell surface and mediates various essential roles in a variety of cellular processes such as proliferation, differentiation, survival, migration, and metabolism. RET plays a pivotal role in the development of both peripheral and central nervous systems. RET is expressed from early stages of embryogenesis and remains expressed throughout all life stages. Mutations either activating or inhibiting RET result in several aggressive diseases, namely cancer and Hirschsprung disease. However, the physiological ligand-dependent activation of RET receptor is important for the survival and maintenance of several neuronal populations, appetite, and weight gain control, thus providing an opportunity for the development of disease-modifying therapeutics against neurodegeneration and obesity. In this review, we describe the structure of RET, its signaling, and its role in both normal conditions as well as in several disorders. We highlight the differences in the signaling and outcomes of constitutive and ligand-induced RET activation. Finally, we review the data on recently developed small molecular weight RET agonists and their potential for the treatment of various diseases.
  • Sidorova, Yulia A.; Saarma, Mart (2020)
    Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are able to promote the survival of multiple neuronal populations in the body and, therefore, hold considerable promise for disease-modifying treatments of diseases and conditions caused by neurodegeneration. Available data reveal the potential of GFLs for the therapy of Parkinson's disease, neuropathic pain and diseases caused by retinal degeneration but, also, amyotrophic lateral sclerosis and, possibly, Alzheimer's disease. Despite promising data collected in preclinical models, clinical translation of GFLs is yet to be conducted. The main reasons for the limited success of GFLs clinical development are the poor pharmacological characteristics of GFL proteins, such as the inability of GFLs to cross tissue barriers, poor diffusion in tissues, biphasic dose-response and activation of several receptors in the organism in different cell types, along with ethical limitations on patients' selection in clinical trials. The development of small molecules selectively targeting particular GFL receptors with improved pharmacokinetic properties can overcome many of the difficulties and limitations associated with the clinical use of GFL proteins. The current review lists several strategies to target the GFL receptor complex with drug-like molecules, discusses their advantages, provides an overview of available chemical scaffolds and peptides able to activate GFL receptors and describes the effects of these molecules in cultured cells and animal models.