Pharmacological validation of TDO as a target for Parkinson's disease.

Autor: Perez-Pardo P; Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands., Grobben Y; Netherlands Translational Research Center B.V, Oss, The Netherlands., Willemsen-Seegers N; Netherlands Translational Research Center B.V, Oss, The Netherlands., Hartog M; Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands., Tutone M; Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands., Muller M; Netherlands Translational Research Center B.V, Oss, The Netherlands., Adolfs Y; Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Pasterkamp RJ; Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Vu-Pham D; Netherlands Translational Research Center B.V, Oss, The Netherlands., van Doornmalen AM; Netherlands Translational Research Center B.V, Oss, The Netherlands., van Cauter F; Netherlands Translational Research Center B.V, Oss, The Netherlands., de Wit J; Netherlands Translational Research Center B.V, Oss, The Netherlands., Gerard Sterrenburg J; Netherlands Translational Research Center B.V, Oss, The Netherlands., Uitdehaag JCM; Netherlands Translational Research Center B.V, Oss, The Netherlands., de Man J; Netherlands Translational Research Center B.V, Oss, The Netherlands., Buijsman RC; Netherlands Translational Research Center B.V, Oss, The Netherlands., Zaman GJR; Netherlands Translational Research Center B.V, Oss, The Netherlands., Kraneveld AD; Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2021 Jul; Vol. 288 (14), pp. 4311-4331. Date of Electronic Publication: 2021 Feb 18.
DOI: 10.1111/febs.15721
Abstrakt: Parkinson's disease patients suffer from both motor and nonmotor impairments. There is currently no cure for Parkinson's disease, and the most commonly used treatment, levodopa, only functions as a temporary relief of motor symptoms. Inhibition of the expression of the L-tryptophan-catabolizing enzyme tryptophan 2,3-dioxygenase (TDO) has been shown to inhibit aging-related α-synuclein toxicity in Caenorhabditis elegans. To evaluate TDO inhibition as a potential therapeutic strategy for Parkinson's disease, a brain-penetrable, small molecule TDO inhibitor was developed, referred to as NTRC 3531-0. This compound potently inhibits human and mouse TDO in biochemical and cell-based assays and is selective over IDO1, an evolutionary unrelated enzyme that catalyzes the same reaction. In mice, NTRC 3531-0 increased plasma and brain L-tryptophan levels after oral administration, demonstrating inhibition of TDO activity in vivo. The effect on Parkinson's disease symptoms was evaluated in a rotenone-induced Parkinson's disease mouse model. A structurally dissimilar TDO inhibitor, LM10, was evaluated in parallel. Both inhibitors had beneficial effects on rotenone-induced motor and cognitive dysfunction as well as rotenone-induced dopaminergic cell loss and neuroinflammation in the substantia nigra. Moreover, both inhibitors improved intestinal transit and enhanced colon length, which indicates a reduction of the rotenone-induced intestinal dysfunction. Consistent with this, mice treated with TDO inhibitor showed decreased expression of rotenone-induced glial fibrillary acidic protein, which is a marker of enteric glial cells, and decreased α-synuclein accumulation in the enteric plexus. Our data support TDO inhibition as a potential therapeutic strategy to decrease motor, cognitive, and gastrointestinal symptoms in Parkinson's disease.
(© 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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