Altered tryptophan metabolism in Parkinson's disease: a possible novel therapeutic approach

Abstract

Parkinson's disease (PD) is one of the most common disabling neurodegenerative diseases. Although several therapeutic approaches are available, there are two major unresolved issues: the lack of proved neuroprotective therapy and the treatment of L-dopa-induced motor complications. In the brain, 90% of the tryptophan is metabolized in the kynurenine pathway. Some of the intermediates, such as quinolinic acid and 3-hydroxy kynurenine, are neurotoxic, while others, such as kynurenic acid, are putative intrinsic neuroprotective compounds, mainly by acting as endogenous antagonists of ionotropic excitatory amino acid receptors. Alterations in the kynurenine pathway have been demonstrated in PD. Preclinical data suggest that intervention in the kynurenine pathway may result in neuroprotection and may alleviate L-dopa-induced dyskinesia. There are two alternative approaches for such intervention: the use of kynurenic acid analogues or pro-drugs, or modulation of the activities of the intrinsic enzymes of the pathway.