Targeted metabolomics to assess positive effects of empagliflozin in a Parkinson's disease model – focused on the kynurenine pathway and oxidative stress
Abstract
Sodium-glucose cotransporter 2 inhibitors, such as empagliflozin (EMPA), have been increasingly investigated for their potential neuroprotective properties, but their overall metabolic impact in Parkinson’s disease (PD) remains incompletely understood. Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, we investigated the effect of EMPA on tryptophan (TRP) metabolism, neurotransmitter levels and antioxidant markers in the striatum. Targeted ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC–MS/MS) was used for metabolite quantification. Pairwise group differences were assessed using Welch’s two-sample t-test, with false discovery rate correction, and multivariate analyses were applied for exploratory pattern recognition. EMPA treatment significantly enhanced the neuroprotective arm of the kynurenine pathway (KP), increasing kynurenic acid (KA), anthranilic acid (AA), xanthurenic acid (XA) and the corresponding enzymatic activity ratios in MPTP-induced PD animals. The selective elevation of the KA/TRP ratio without a corresponding change in KYN/TRP suggests that EMPA acts specifically on the KAT-mediated neuroprotective branch, potentially through restoration of astrocytic redox state in the striatum, rather than through generalized modulation of IDO/TDO-driven TRP catabolism. In Sirtuin3 knock-out (S3KO) mice, EMPA reduced 3-hydroxykynurenine (3OHK) levels and the Oxidative Stress Index (3OHK/(KA + AA + XA)), and…
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