Pharmacological validation of TDO as a target for Parkinson’s disease

• DOI: 10.1111/febs.15721
• Publication Date: 2021-01-20T15:03:52Z
• Authors: Paula Perez‐Pardo; Yvonne Grobben; Nicole Willemsen‐...; Mitch Hartog; Michaela Tutone; Michelle Muller; Youri Adolfs; Ronald Jeroen Pas...; Diep Vu‐Pham; Antoon M. van Doo...; Freek van Cauter; Joeri de Wit; Jan Gerard Sterre...; Joost C.M. Uitdehaag; Jos de Man; Rogier C. Buijsman; Guido J.R. Zaman; Aletta D. Kraneveld
• Keywords: Rotenone

Parkinson’s disease patients suffer from both motor and nonmotor impairments. There is currently no cure for disease, the most commonly used treatment, levodopa, only functions as a temporary relief of symptoms. Inhibition expression 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 potential therapeutic strategy brain‐penetrable, small molecule inhibitor was developed, referred NTRC 3531‐0. This compound potently inhibits human mouse biochemical cell‐based assays selective over IDO1, an evolutionary unrelated that catalyzes same reaction. In mice, 3531‐0 increased plasma brain L‐tryptophan levels after oral administration, demonstrating activity vivo The effect on symptoms evaluated rotenone‐induced model. A structurally dissimilar inhibitor, LM10, parallel. Both inhibitors had beneficial effects cognitive dysfunction well dopaminergic cell loss neuroinflammation substantia nigra Moreover, improved intestinal transit enhanced colon length, which indicates reduction dysfunction. Consistent with this, mice treated showed decreased glial fibrillary acidic protein, marker enteric cells, accumulation plexus Our data support decrease motor, cognitive, gastrointestinal disease.