Increased level of homocysteine (hHcy) in plasma is an accompanying phenomenon of many diseases, including a brain stroke. This study determines whether hyperhomocysteinemia (which is a risk factor of brain ischemia) itself or in combination with ischemic preconditioning affects the ischemia-induced neurodegenerative changes, generation of reactive oxygen species (ROS), lipoperoxidation, protein oxidation, and activity of antioxidant enzymes in the rat brain cortex. The hHcy was induced by subcutaneous administration of homocysteine (0.45 μmol/g body weight) twice a day in 8 h intervals for 14 days. Rats were preconditioned by 5 min ischemia. Two days later, 15 min of global forebrain ischemia was induced by four vessel's occlusion. The study demonstrates that in the cerebral cortex, hHcy alone induces progressive neuronal cell death and morphological changes. Neuronal damage was associated with the pro-oxidative effect of hHcy, which leads to increased ROS formation, peroxidation of lipids and oxidative alterations of cortical proteins. Ischemic reperfusion injury activates degeneration processes and de-regulates redox balance which is aggravated under hHcy conditions and leads to the augmented lipoperoxidation and protein oxidation. If combined with hHcy, ischemic preconditioning could preserve the neuronal tissue from lethal ischemic effect and initiates suppression of lipoperoxidation, protein oxidation, and alterations of redox enzymes with the most significant effect observed after prolonged reperfusion. Increased prevalence of hyperhomocysteinemia in the Western population and crucial role of elevated Hcy level in the pathogenesis of neuronal disorders makes this amino acid as an interesting target for future research. Understanding the multiple etiological mechanisms and recognition of the co-morbid risk factors that lead to the ischemic/reperfusion injury and ischemic tolerance is therefore important for developing therapeutic strategies in human brain stroke associated with the elevated level of Hcy.

Biomedical Center Martin Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia Department of Medical Biochemistry Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Biomedical Center Martin Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia Department of Medical Biochemistry Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia Department of Medical Biochemistry and BioMed Jessenius Faculty of Medicine Comenius University in Bratislava Mala Hora 11161 4D 036 01 Martin Slovakia

Department of Histology and Embryology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Medical Biochemistry Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Institute of Clinical and Translational Research Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia Department of Physiology Faculty of Medicine Masaryk University Brno Czech Republic

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