GDNF Receptor Agonist Alleviates Motor Imbalance in Unilateral 6-Hydroxydopamine Model of Parkinson's Disease.

Autor:	Renko JM; Division of Pharmacology and Pharmacotherapy, University of Helsinki, Finland., Voutilainen MH; Division of Pharmacology and Pharmacotherapy, University of Helsinki, Finland.; Laboratory of Molecular Neuroscience, Institute of Biotechnology, University of Helsinki, Finland., Visnapuu T; Division of Pharmacology and Pharmacotherapy, University of Helsinki, Finland., Sidorova YA; Laboratory of Molecular Neuroscience, Institute of Biotechnology, University of Helsinki, Finland., Saarma M; Laboratory of Molecular Neuroscience, Institute of Biotechnology, University of Helsinki, Finland., Tuominen RK; Division of Pharmacology and Pharmacotherapy, University of Helsinki, Finland.
Jazyk:	angličtina
Zdroj:	Frontiers in neurology and neuroscience research [Front Neurol Neurosci Res] 2020 Nov 24; Vol. 1, pp. 100004.
Abstrakt:	Parkinson's disease (PD) is an incurable neurodegenerative disorder affecting up to 10 million people in the world. Diagnostic motor symptoms of PD appear as a result of progressive degeneration and death of nigrostriatal dopamine neurons. Current PD treatments only relieve symptoms without halting the progression of the disease, and their use is complicated by severe adverse effects emerging as the disease progresses. Therefore, there is an urgent need for new therapies for PD management. We developed a small molecule compound, BT13, targeting receptor tyrosine kinase RET. RET is the signalling receptor for a known survival factor for dopamine neurons called glial cell line-derived neurotrophic factor (GDNF). Previously we showed that BT13 prevents the death of cultured dopamine neurons, stimulates dopamine release and activates pro-survival signalling cascades in naïve rodent brain. In the present study, we evaluate the effects of BT13 on motor imbalance and nigrostriatal dopamine neurons in a unilateral 6-hydroxydopamine rat model of PD. We show that BT13 alleviates motor dysfunction in experimental animals. Further studies are needed to make a conclusion whether BT13 can protect the integrity of the nigrostriatal dopamine system since even the positive control, GDNF protein, was unable to produce a clear neuroprotective effect in the model used in the present work. In contrast to GDNF, BT13 is able to cross the blood-brain barrier, which together with the ability to reduce motor symptoms of the disease makes it a valuable lead for further development as a potential disease-modifying agent to treat PD. Competing Interests: Conflict of interests MS is an inventor in composition of matter patents of BT compounds US Patent, No 8,901,129 B2 and European Patent, No 2509953. MS is an inventor in patent application WO 2014041179 A1 on the treatment of peripheral neuropathy using GFRa3 type receptor agonists.
Databáze:	MEDLINE
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