Gene Expression and Activity of Selected Antioxidant and DNA Repair Enzymes in the Prefrontal Cortex of Sheep as Affected by Kynurenic Acid

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.