Metformin and Sitagliptin Impact the Brain Kynurenine Pathway: Region-Specific Modulation of Neuroactive Metabolites in Non-Diabetic Male Rats

An excessive activation of the tryptophan-kynurenine (TRP-KYN) pathway, frequently observed in metabolic and inflammatory disorders, leads to disturbances in the balance between neurotoxic and neuroprotective metabolites. These alterations may contribute to neuronal dysfunction and cognitive impairment, highlighting the importance of modulating this pathway in the context of neuroprotection. Metformin, apart from the AMPK activation and its broad anti-inflammatory actions, has been indicated as a drug capable of influencing the synthesis of TRP metabolites, including the neuroprotective kynurenic acid (KYNA), whereas the effects of sitagliptin in this regard are not known. Here, the effects of sub-chronic metformin or sitagliptin treatment on the brain levels of kynurenines and on functional alterations within the TRP-KYN pathway were evaluated in vivo, in adult non-diabetic Wistar male rats. A 5-day treatment with metformin decreased cortical TRP and KYNA, hippocampal KYN, and cerebellar levels of all studied kynurenines, whereas in the striatum, KYNA level increased. In contrast, sitagliptin did not alter the formation of kynurenines in the examined structures. However, both of the tested drugs had a significant impact on TRP/L-KYN or L-KYN/KYNA ratios in different parts of the brain. These findings indicate a prominent region-specific effect of metformin on brain kynurenines. In conclusion, commonly used antidiabetic agents differ in their impact on central TRP metabolism, which may have significant implications for understanding their potential neuroprotective effects and role in cognitive impairment.