Potential Region-Specific Neuroprotective Effects of Kynurenine Administration in Healthy Rodents Using High-Resolution Mass Spectrometry

The tryptophan (TRP) metabolic pathway produces kynurenine (KYN) and serotonin (5-HT). These are important molecules in the central nervous system, as KYN plays a crucial role in neuroprotection, while 5-HT impacts mood and sleep patterns. The production of KYN is increased in response to inflammatory cytokines and cortisol release, which activates indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), respectively. These enzymes are responsible for converting TRP and KYN into neuroactive molecules including kynurenic acid (KA), quinolinic acid (QA), and 3-hydroxykynurenine (3HK). These metabolites play an important role in neuroprotection and have been linked to the development of several neurological disorders. Therefore, the aim of this study was to investigate the effect of exogenous KYN administration on the activity of the KYN pathway by measuring the brain tissue concentration of these metabolites and the mRNA expression of inflammatory markers, neurotrophic factors, IDO, and TDO. In the acute study, Sprague-Dawley rats (<i>n</i> = 25) received 100 mg/kg kynurenine (0.2 mL, ip) and were terminated at <i>t</i> = 0.5, 1, 2, 3, and 5 h post-KYN administration (<i>n</i> = 5/time point) while in the control group (<i>n</i> = 5) received saline (0.2 mL, ip) and were terminated at <i>t</i> = 1 h. In the chronic study, both KYN and control animals (<i>n</i> = 6 per group) received the same dose as the acute study for 14 days, once daily. Following the treatment period, animals were terminated by decapitation, and trunk blood was collected and separated into plasma, while the brain was surgically removed and dissected into the hippocampus, hypothalamus, midbrain, prefrontal cortex, striatum, cortex, and cerebellum. KYN metabolites were measured by liquid chromatography coupled to high-resolution mass spectrometry, while the mRNA expression of <i>IDO</i>, <i>TDO</i>, brain-derived neurotrophic factor (<i>BDNF</i>), cAMP response element-binding protein (<i>CREB</i>), and interleukin-6 (<i>IL-6</i>) was measured using RT-PCR. KYN and its metabolites were quantified at basal levels in plasma and seven brain regions to assess their distribution in the peripheral and central nervous system. The KA/3HK ratio increased in multiple brain regions, and the plasma KA/QA ratio increased significantly after acute and chronic KYN administration, suggesting peripheral neuroprotection. Reduced plasma and cerebellar KA/3HK ratios suggest region-specific neurotoxicity, whereas the hippocampus accumulates the most KYN and its metabolite KA, suggesting the potential neuroprotective effect of KYN administration in the hippocampus.