Kynurenines, the products of tryptophan oxidative degradation, are involved in multiple neuropathologies, such as Huntington's chorea, Parkinson's disease, senile dementia, etc. The major cause for hydroxykynurenines's neurotoxicity is the oxidative stress induced by the reactive oxygen species (ROS), the by-products of L-3-hydroxykynurenine (L-3HOK) and 3-hydroxyanthranilic acid (3HAA) oxidative self-dimerization. 2-aminophenol (2AP), a structural precursor of L-3HOK and 3HAA, undergoes the oxidative conjugation to form 2-aminophenoxazinone. There are several modes of 2AP dimerization, including both enzymatic and non-enzymatic stages. In this study, the free energies for 2AP, L-3HOK and 3HAA dimerization stages have been calculated at B3LYP/6-311G(d,p)//6-311+(O)+G(d) level, both in the gas phase and in heptane or water solution. For the intermediates, ionization potentials and electron affinities were calculated, as well as free energy and kinetics of molecular oxygen interaction with several non-enzymatically formed dimers. H-atom donating power of the intermediates increases upon the progress of the oxidation, making possible generation of hydroperoxyl radical or hydrogen peroxide from O₂ at the last stages. Among the dimerization intermediates, 2-aminophenoxazinole derivatives have the lowest ionization potential and can reduce O₂ to superoxide anion. The rate for O-H homolytic bond dissociation is significantly higher than that for C-H bond in non-enzymatic quinoneimine conjugate. However, the last reaction passes irreversibly, reducing O₂ to hydroperoxyl radical. The inorganic ferrous iron and the heme group of Drosophila phenoxazinone synthase significantly reduce the energy cost of 2AP H-atom abstraction by O₂. We have also shown experimentally that total antioxidant capacity decreases in Drosophila mutant cardinal with L-3HOK excess relative to the wild type Canton-S, and lipid peroxidation decreases in aged cardinal. Taken together, our data supports the conception of hydroxykynurenines' dual role in neurotoxicity: serving as antioxidants themselves, blocking lipid peroxidation by H-atom donation, they also can easily generate ROS upon dimerization, leading to the oxidative stress development. Kynurenines, the products of tryptophan catabolism, are compounds with the multiple neuroactive properties. Hydroxykynurenines are redox modulators with a dual role in the oxidative stress development: being able to block lipid peroxidation, they also produce toxic free radicals during the oxidative self-dimerization. The later can occur both enzymatically and non-enzymatically. Computational study of the dimerization process may reveal the stages and intermediates being the source of the reactive oxygen species. This would help to provide therapeutic strategies aimed at the decrease of kynurenines' dimerization toxic effects. We have modeled oxidative conjugation of kynurenines using quantum-chemical approaches, performing calculations for the energies of the dimerization stages, as well as the redox properties of the intermediates. Phenoxazinone synthase provides a structural basis for the full oxygen reduction to water, prohibiting generation of toxic free radicals. The final non-enzymatic dimerization stages are the most probable source of hydroperoxyl and superoxide anion radical. The accumulation of L-3HOK in Drosophila mutant cardinal with impaired phenoxazinone synthase correlates with decrease in both total antioxidant capacity and lipid peroxidation in an age-dependent manner. Our results support the concept of protective role of proteins converting hydroxykynurenines to their dimeric forms, preventing free radicals overproduction and oxidative stress development.

This review analyzes recent data on mechanisms of cerebral hypoxia and the protective methods of hypoxic and ischemic postconditioning, as well as their interrelationship with the key mechanisms responsible for neuroprotection and neuroplasticity. Upregulation of expression of antiapoptotic factors and neurotrophins and modulation of activity of several protein kinases and transcription factors such as hypoxia-inducible factor-1 (HIF-1) are considered as the most important aspects in the neuroprotective potential of postconditioning. The presented information indicates substantial transformative promise of the noninvasive techniques of hypoxic postconditioning as well as significant similarity between the adaptive pathways activated by various postconditioning methods, which are far from being fully understood.