中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (2): 308-309.doi: 10.4103/1673-5374.290897

• 观点:退行性病与再生 • 上一篇    下一篇

研究犬尿氨酸代谢产物在抗神经退行性疾病药物开发中的潜力

  

  • 出版日期:2021-02-15 发布日期:2020-12-03

Potential of kynurenine metabolites in drug development against neurodegenerative diseases

Lenka Kubicova, Vladimir Chobot*   

  1. Division of Molecular Systems Biology, Department of Ecogenomics and Systems Biology, Faculty of Life Sciences, University of Vienna, Vienna, Austria
  • Online:2021-02-15 Published:2020-12-03
  • Contact: Vladimir Chobot, PhD,vladimir.chobot@univie.ac.at.
  • Supported by:
    This work was funded by Austrian Science Fund (FWF), grant No. P 24630-B21 (to VC).

摘要: https://orcid.org/0000-0003-0029-1453(Vladimir Chobot)

Abstract: Reactive oxygen species (ROS) and kynurenines: Kynurenines represent a relatively heterogenous group of tryptophan metabolites (Figure 1A). The amino acid tryptophan is metabolized in the humans by the kynurenine or serotonin pathway. For a long time, the kynurenine pathway was assumed primarily to constitute the source for nicotinamide-adenine dinucleotide phosphate, one of the most utilized redox active enzyme cofactors. However, in the last years, various kynurenines were identified as important endogenous neuroactive agents. For example, quinolinic (QUIN) and kynurenic acid (KYNA) interact with the excitatory N-methyl-D-aspartate (NMDA) receptors. Additionally, KYNA can bind to α7-nicotinic receptors in high concentrations. Furthermore, several kynurenines showed apparent effects on the immune system and inflammation that is often associated with degeneration processes (Schwarcz and Stone, 2017). Since kynurenine metabolites may influence ROS concentrations, they can affect redox signal cascades by interfering with redox homeodynamic equilibrium. Within the tissue, ROS can participate in various physiological and pathological processes, such as maturation, reproduction, inflammation, and, under specific conditions, programmed cell death by ferroptosis. The function of the ferroptosis in organisms is still far from being satisfactorily understood. In this context, the accumulation of iron can contribute to the development of neurodegenerative pathogenesis in damaged brains. The senile plaques of patients suffering from Alzheimer’s disease, accumulate iron up to a concentration of about 0.9 mM, three times more than in healthy controls (0.3 mM). Usually, iron is stored in complexes with storage proteins, such as transferrin and ferritin, or occurs as cofactors of various enzymes as heme and nonheme coordination complexes. If iron coordinates other molecules than the mentioned ones, it is called “poorly liganded” iron that can catalyze uncontrolled production of highly cytotoxic hydroxyl radicals via the Fenton reaction (Kell, 2010). Again, hydroxyl radicals can increase levels of “poorly liganded” iron by oxidative destruction of the iron storage proteins.