Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3 Str., 05-110, Jabłonna, Poland.
Sci Rep. 2024 Jul 5;14(1):15506. doi: 10.1038/s41598-024-66094-x.
Relatively low levels of antioxidant enzymes coupled with high oxygen metabolism result in the formation of numerous oxidative DNA damages in the tissues of the central nervous system. Recently, kynurenic acid (KYNA), knowns for its neuroprotective properties, has gained increasing attention in this context. Therefore, our hypothesis assumed that increased KYNA levels in the brain would positively influence mRNA expression of selected enzymes of the base excision repair pathway as well as enhance their efficiency in excising damaged nucleobases in specific areas of the sheep brain. The study was conducted on adult anestrous sheep (n = 18), in which two different doses of KYNA (20 and 100 μg/day) were infused into the third brain ventricle for three days. Molecular and biochemical analysis included the hypothalamus (preoptic and mediol-basal areas), hippocampus (CA3 field) and amygdala (central amygdaloid nucleus), dissected from the brain of sheep euthanized immediately after the last infusion. The results revealed a significant increase P < 0.001) in the relative mRNA abundance of N-methylpurine DNA glycosylase (MPG) following administration of both dose of KYNA across all examined tissues. The transcription of thymine-DNA glycosylase (TDG) increased significantly (P < 0.001) in all tissues in response to the lower KYNA dose compared to the control group. Moreover, 8-oxoguanine (8-oxoG) DNA glycosylase (OGG1) mRNA levels were also higher in both animal groups (P < 0.001). In addition, in the hypothalamus, hippocampus and amygdala, AP endonuclease 1 (APE1) mRNA expression increased under both doses of KYNA. Moreover, the both dose of KYNA significantly stimulated the efficiency of 8-oxoG excision in hypothalamus and amygdala (P < 0.05-0.001). The lower and higher doses of KYNA significantly influenced the effectiveness of εA and εC in all structures (P < 0.01-0.001). In conclusion, the favorable effect of KYNA in the brain may include the protection of genetic material in nerve and glial cells by stimulating the expression and efficiency of BER pathway enzymes.
相对较低水平的抗氧化酶与高氧代谢相结合，导致中枢神经系统组织中形成大量氧化 DNA 损伤。最近，犬尿氨酸（KYNA）因其神经保护特性而受到越来越多的关注。因此，我们的假设是，大脑中 KYNA 水平的增加将积极影响碱基切除修复途径中选定酶的 mRNA 表达，并提高其在羊脑特定区域切除受损核碱基的效率。该研究在成年乏情绵羊（n = 18）中进行，其中将两种不同剂量的 KYNA（20 和 100μg/天）注入第三脑室，持续三天。分子和生化分析包括从最后一次输注后立即安乐死的绵羊大脑中分离出的下丘脑（视前区和中-基底区）、海马体（CA3 区）和杏仁核（中央杏仁核）。结果显示，两种剂量的 KYNA 给药后，所有检测组织中 N-甲基嘌呤 DNA 糖基化酶（MPG）的相对 mRNA 丰度均显著增加（P<0.001）。与对照组相比，较低剂量的 KYNA 使所有组织中的胸嘧啶-DNA 糖基化酶（TDG）转录显著增加（P<0.001）。此外，两种动物组的 8-氧鸟嘌呤（8-oxoG）DNA 糖基化酶（OGG1）mRNA 水平也较高（P<0.001）。此外，在下丘脑、海马体和杏仁核中，AP 内切酶 1（APE1）mRNA 表达在两种剂量的 KYNA 下均增加。此外，两种剂量的 KYNA 均显著刺激了下丘脑和杏仁核中 8-oxoG 切除的效率（P<0.05-0.001）。较低和较高剂量的 KYNA 显著影响了所有结构中 εA 和 εC 的有效性（P<0.01-0.001）。总之，KYNA 在大脑中的有益作用可能包括通过刺激 BER 途径酶的表达和效率来保护神经和神经胶质细胞中的遗传物质。
