Deficiency of neurotrophic factors and oxidative DNA damage are common causes of many neurodegenerative diseases. Recently, the importance of kynurenic acid (KYNA), an active metabolite of tryptophan, has increased as a neuroprotective molecule in the brain. Therefore, the present study tested the hypothesis that centrally acting KYNA would positively affect: (1) brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling and (2) selected base excision repair (BER) pathway enzymes activities in the hippocampal CA1 field in sheep. Both lower (20 μg in total) and higher (100 μg in total) doses of KYNA infused into the third brain ventricle differentially increased the abundance of BDNF and TrkB mRNA in the CA1 field; additionally, the higher dose increased BDNF tissue concentration. The lower dose of KYNA increased mRNA expression for 8-oxoguanine glycosylase (OGG1), N-methylpurine DNA glycosylase (MPG), and thymine DNA glycosylase and stimulated the repair of 1,N6-ethenodeoxyadenosine and 3,N4-ethenodeoxy-cytosine as determined by the excision efficiency of lesioned nucleobases. The higher dose increased the abundance of OGG1 and MPG transcripts, however, its stimulatory effect on repair activity was less pronounced in all cases compared to the lower dose. The increased level of AP-endonuclease mRNA expression was dose-dependent. In conclusion, the potential neurotrophic and neuroprotective effects of KYNA in brain cells may involve stimulation of the BDNF-TrkB and BER pathways.

Kynurenic acid (KYNA), a tryptophan metabolite, is believed to exert neuromodulatory and neuroprotective effects in the brain. This study aimed to examine KYNA’s capacity to modify gene expression and the activity of cellular antioxidant enzymes in specific structures of the sheep brain. Anestrous sheep were infused intracerebroventricularly with two KYNA doses—lower (4 × 5 μg/60 μL/30 min, KYNA20) and higher (4 × 25 μg/60 μL/30 min, KYNA100)—at 30 min intervals. The abundance of superoxide dismutase 2 (SOD2), catalase (CAT), and glutathione peroxidase 1 (GPx1) mRNA, as well as enzyme activities, were determined in the medial–basal hypothalamus (MBH), the preoptic (POA) area of the hypothalamus, and in the hippocampal CA1 field. Both doses of KYNA caused a decrease (p < 0.01) in the expression of SOD2 and CAT mRNA in all structures examined compared to the control group (except for CAT in the POA at the KYNA100 dose). Furthermore, lower levels of SOD2 mRNA (p < 0.05) and CAT mRNA (p < 0.01) were found in the MBH and POA and in the POA and CA, respectively, in sheep administered with the KYNA20 dose. Different stimulatory effects on GPx1 mRNA expression were observed for both doses (p < 0.05-p < 0.01). KYNA exerted stimulatory but dose-dependent effects on SOD2, CAT, and GPx1 activities (p < 0.05-p < 0.001) in all brain tissues examined. The results indicate that KYNA may influence the level of oxidative stress in individual brain structures in sheep by modulating the expression of genes and the activity of at least SOD2, CAT, and GPx1. The present findings also expand the general knowledge about the potential neuroprotective properties of KYNA in the central nervous system.

The prefrontal cortex (PCx) is involved in many higher-order cognitive processes, including decision making, reasoning, personality expression, and social cognition. These functions are associated with high energy demand and the production of harmful oxygen radicals. Recent studies indicate that kynurenic acid (KYNA) exerts neuroprotective effects, largely due to its anti-inflammatory and antioxidant properties. To further evaluate the antioxidant potential of this compound, we tested the hypothesis that increasing KYNA levels in the sheep cerebroventricular circulation would positively affect the mRNA expression and activity of selected antioxidant and DNA repair enzymes in the distal part of the brain, i.e., the PCx. Anestrous sheep were infused intracerebroventricularly with a series of two KYNA doses: lower (4 × 5 μg/60 μL/30 min) and higher (4 × 25 μg/60 μL/30 min) at 30 min intervals. The results demonstrated that KYNA exerted significant dose-dependent stimulatory effects on the activity of superoxide dismutase 2, catalase, and glutathione peroxidase 1 while inhibiting their transcription in a similar manner. In addition, KYNA was also found to dose-dependently activate the base excision repair pathway, as determined by the increased transcript levels of glycosylases: N-methylpurine DNA glycosylase, thymine-DNA glycosylase, 8-oxoguanine DNA glycosylase-1, and apurinic/apyrimidinic endonuclease 1. The excision efficiency of damaged nucleobases, such as εA, εC and 8-oxoG, by these enzymes was also increased in response to central KYNA infusion. These findings expand the knowledge on KYNA as a potential protective factor against oxidative stress in the central nervous system.

Kynurenic acid (KYNA), a tryptophan metabolite, is believed to exert neuromodulatory and neuroprotective effects in the brain. The study aimed to examine the KYNA’s capacity to modify gene expression and the activity of cellular antioxidant enzymes in specific structures of the sheep brain. Anestrous sheep were infused intracerebroventricularly with two KYNA doses: lower (4×5 μg/60 μL/30 min, KYNA20) and higher (4×25 μg/60 μL/30 min, KYNA100) at 30min intervals. The abundance of superoxide dismutase (SOD2), catalase (CAT) and glutathione peroxidase (GPx1) mRNA, as well as enzyme activities (µM/µg of protein), were determined in the hypothalamic medial-basal (MBH) and preoptic (POA) areas, and in the hippocampal CA1 field. Both doses of KYNA caused a decrease (P<0.01) in the expression of SOD2 and CAT mRNA in all structures examined compared to the control group (except for CAT in the POA at the KYNA100 dose). Furthermore, lower levels of SOD2 mRNA (P<0.05) and CAT mRNA (P<0.01) were found in the MBH and POA and in the POA and CA, respectively, in sheep administered with the KYNA20 dose. Different stimulatory effects on GPx1 mRNA expression were observed for both doses (P<0.05-P<0.01). KYNA exerted stimulatory, but dose-dependent effects on SOD2, CAT and GPx1 activities (P<0.05-P<0.01) in all brain tissues examined. The results indicate that KYNA may influence the level of oxidative stress in individual brain structures in sheep by modulating the expression of genes and activity of at least SOD2, CAT and GPx1. The present findings also expand the general knowledge about the potential neuroprotective properties of KYNA in the central nervous system.

Fluctuations in kynurenic acid (KYNA) and brain-derived neurotrophic factor (BDNF) levels in the brain reflect its neurological status. The aim of the study was to investigate the effect of transiently elevated KYNA concentrations in the cerebroventricular circulation on the expression of BDNF and its high-affinity tropomyosin-related kinase receptor B (TrkB) in specific structures of the sheep brain. Intracerebroventricularly cannulated anestrous sheep were subjected to a series of four 30 min infusions of KYNA: 4 × 5 μg/60 μL/30 min (KYNA20, n = 6) and 4 × 25 μg/60 μL/30 min (KYNA100, n = 6) or a control infusion (n = 6), at 30 min intervals. Sections of the hippocampal CA3 field, amygdala (AMG), prefrontal cortex (PCx), and the hypothalamic medial-basal (MBH) and preoptic (POA) areas were dissected from the brain immediately after the experiment. The highest concentration of BDNF protein was found in the CA3 field (p < 0.001), which was 8-fold higher than in the AMG and 12-fold higher than that in the PCx (MBH and POA were not analyzed). The most pronounced BDNF mRNA expression was observed in the MBH, followed by the PCx, POA, AMG and CA3, while the highest abundance of TrkB mRNA was recorded in the AMG, followed by the MBH, PCx, CA3, and POA. KYNA increased (p < 0.05–p < 0.01) BDNF protein levels and the expression of its gene in the brain structures were examined, with the effect varying by dose and brain region. KYNA, particularly at the KYNA100 dose, also increased (p < 0.01) TrkB gene expression, except for the AMG, where the lower KYNA20 dose was more effective (p < 0.01). These findings suggest a positive relationship between KYNA levels in the cerebroventricular circulation and BDNF–TrkB expression in specific brain regions in a sheep model. This indicates that a transient increase in the CSF KYNA concentration can potentially restore BDNF production, for which deficiency underlies numerous neurological disorders.