Tryptophan 2,3-dioxygenase, a novel therapeutic target for Parkinson's disease

Alterations in the activity of tryptophan 2,3-dioxygenase (TDO) cause imbalances in the levels of serotonin and other neuroactive metabolites which can contribute to motor, psychiatric, gastrointestinal, and other dysfunctions often seen in Parkinson's disease (PD). TDO is a key enzyme of tryptophan metabolism at the entry of the kynurenine pathway (KP) which moderates production of neuroactive compounds primarily outside the central nervous system (CNS). Recent data from experimental models indicate that TDO modulation could have beneficial effects on PD symptoms not targeted by traditional dopamine substitution therapies.

Based on data available in PubMed and ClinicalTrials databases up until 1 August 2021, we summarize current knowledge of KP alterations in relation to PD. We overview effects of TDO inhibition in preclinical models of neurodegeneration and discuss findings of the impact of enzyme inhibition on motor, memory and gastrointestinal dysfunctions, and neuronal cell loss.

TDO inhibition potentially alleviates motor and non-motor dysfunctions of PD. However, data suggesting harmful effects of long-term TDO inhibition raise concerns. To exploit possibilities of TDO inhibitory treatment, development of further selective TDO inhibitor compounds with good bioavailability features and models adequately replicating PD symptoms of systemic origin should be prioritized.