Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats

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Renko , J-M , Mahato , A K , Visnapuu , T , Valkonen , K , Karelson , M , Voutilainen , M H , Saarma , M , Tuominen , R K & Sidorova , Y A 2021 , ' Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats ' , Journal of Parkinson's disease , vol. 11 , no. 3 , pp. 1023-1046 . https://doi.org/10.3233/JPD-202400

Title: Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats
Author: Renko, Juho-Matti; Mahato, Arun Kumar; Visnapuu, Tanel; Valkonen, Konsta; Karelson, Mati; Voutilainen, Merja H.; Saarma, Mart; Tuominen, Raimo K.; Sidorova, Yulia A.
Contributor: University of Helsinki, Regenerative pharmacology group
University of Helsinki, Institute of Biotechnology
University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Drug Research Program
University of Helsinki, Mart Saarma / Principal Investigator
University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Institute of Biotechnology
Date: 2021
Language: eng
Number of pages: 24
Belongs to series: Journal of Parkinson's disease
ISSN: 1877-7171
URI: http://hdl.handle.net/10138/333936
Abstract: 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.
Subject: BT44
RET agonist
glial cell line-derived neurotrophic factor
receptor tyrosine kinase RET
AKT pathway
MAPK pathway
rat 6-hydroxydopamine (6-OHDA) model
neuroprotection
Parkinson's disease
RECEPTOR TYROSINE KINASE
NEUROTROPHIC FACTOR
PARKINSONS-DISEASE
FUNCTIONAL RECOVERY
GDNF FAMILY
IN-VITRO
SUBSTANTIA-NIGRA
LESION MODEL
GENE-THERAPY
DOUBLE-BLIND
3112 Neurosciences
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